相关申请的交叉引用CROSS-REFERENCE TO RELATED APPLICATIONS
本申请要求2021年9月15日提交的美国临时申请号63/244,644的优先权和权益，并且本申请还要求2022年3月11日提交的美国临时申请号63/318,901的优先权和权益，所有这些申请均全文以引用方式并入本文。This application claims priority to and the benefit of U.S. Provisional Application No. 63/244,644, filed on September 15, 2021, and this application also claims priority to and the benefit of U.S. Provisional Application No. 63/318,901, filed on March 11, 2022, all of which are incorporated herein by reference in their entirety.
技术领域Technical Field
本公开总体上涉及与可植入设备一起使用的生物活性物质释放或洗脱层或膜，该可植入设备为诸如用于检测生物样品中的分析物浓度的设备。更具体地，本公开涉及新型生物活性物质释放膜、包括这些膜的设备和可植入设备、在可植入设备上或周围形成生物活性物质释放膜的方法、改善和/或延长传感器寿命的方法以及使用可植入分析物检测设备监测生物流体样品中的一种或多种分析物水平的方法。The present disclosure generally relates to bioactive substance release or elution layers or membranes for use with implantable devices, such as devices for detecting analyte concentrations in biological samples. More specifically, the present disclosure relates to novel bioactive substance release membranes, devices and implantable devices including these membranes, methods of forming bioactive substance release membranes on or around implantable devices, methods of improving and/or extending sensor life, and methods of monitoring one or more analyte levels in biological fluid samples using implantable analyte detection devices.
背景技术Background technique
最深入研究的分析物感测设备之一是用于检测患有糖尿病的受者(host)中的葡萄糖水平的可植入葡萄糖设备。尽管有越来越多数量的被诊断患有糖尿病的个体以及可植入葡萄糖监测设备领域的最新进展，但是由于局部组织反应，当前使用的设备不能在特定时间段内安全且可靠地提供数据。举例来说，有两种常用类型的可皮下植入的葡萄糖感测设备。这些类型包括那些经皮植入的类型和那些完全植入的类型。One of the most intensively studied analyte sensing devices is an implantable glucose device for detecting glucose levels in a diabetic host. Despite the increasing number of individuals diagnosed with diabetes and recent advances in the field of implantable glucose monitoring devices, currently used devices cannot safely and reliably provide data over a specific period of time due to local tissue reactions. For example, there are two common types of subcutaneously implantable glucose sensing devices. These types include those that are implanted percutaneously and those that are fully implanted.
发明内容Summary of the invention
在一个方面，提供了一种用于测量分析物的浓度的设备，该设备包括：传感器衬底，该传感器衬底包括与近侧端部分离的远侧端部和定位在远侧端部与近侧端部之间的至少一个传感器部分，该传感器部分被配置为生成与分析物的浓度相关联的信号；和生物活性物质释放膜，该生物活性物质释放膜邻近传感器衬底，该生物活性物质释放膜包括能够改变受试者的组织反应的至少一种可释放生物活性剂。In one aspect, a device for measuring the concentration of an analyte is provided, the device comprising: a sensor substrate comprising a distal end separated from a proximal end and at least one sensor portion positioned between the distal end and the proximal end, the sensor portion being configured to generate a signal associated with the concentration of the analyte; and a bioactive substance releasing membrane adjacent to the sensor substrate, the bioactive substance releasing membrane comprising at least one releasable bioactive agent capable of changing a tissue response of a subject.
在一个方面，远侧端部具有外表面，并且生物活性物质释放膜定位在该外表面上。In one aspect, the distal end has an outer surface, and the bioactive substance releasing membrane is positioned on the outer surface.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜仅定位在远侧端部处。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is positioned only at the distal end.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜直接邻近抵抗膜。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is directly adjacent to the resistant membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜直接邻近干扰膜。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is directly adjacent to the interfering membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜直接邻近电极膜。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is directly adjacent to the electrode membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，该设备还包括邻近生物活性物质释放膜的可溶解涂层。In one aspect, alone or in combination with any of the preceding aspects, the device further comprises a dissolvable coating adjacent to the bioactive substance releasing membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，可溶解涂层还包括可释放生物活性剂。In one aspect, alone or in combination with any of the preceding aspects, the dissolvable coating further comprises a releasable bioactive agent.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种可释放生物活性剂是第一可释放生物活性剂，并且可溶解涂层还包括第二可释放生物活性剂，第一可释放生物活性剂与第二可释放生物活性剂相同或不同。In one aspect, alone or in combination with any of the preceding aspects, the at least one releasable bioactive agent is a first releasable bioactive agent and the dissolvable coating further comprises a second releasable bioactive agent, the first releasable bioactive agent being the same or different from the second releasable bioactive agent.
在一个方面，单独地或与前述方面中的任一方面组合地，可溶解涂层包括与包括一种或多种抗炎剂的纳米颗粒组合的第二可释放生物活性剂。In one aspect, alone or in combination with any of the preceding aspects, the dissolvable coating comprises a second releasable bioactive agent in combination with nanoparticles comprising one or more anti-inflammatory agents.
在一个方面，单独地或与前述方面中的任一方面组合地，可溶解涂层提供第二可释放生物活性剂和纳米颗粒两者的推注释放。In one aspect, the dissolvable coating provides bolus release of both the second releasable bioactive agent and the nanoparticles, alone or in combination with any of the preceding aspects.
在一个方面，单独地或与前述方面中的任一方面组合地，可溶解涂层是亲水性的。In one aspect, alone or in combination with any of the preceding aspects, the dissolvable coating is hydrophilic.
在一个方面，单独地或与前述方面中的任一方面组合地，可溶解涂层是能够扩散分析物的。In one aspect, alone or in combination with any of the preceding aspects, the dissolvable coating is capable of diffusing an analyte.
在一个方面，单独地或与前述方面中的任一方面组合地，该设备还包括邻近生物活性物质释放膜的扩散调节膜，其中该扩散调节膜不同于生物活性物质释放膜。In one aspect, alone or in combination with any of the preceding aspects, the device further comprises a diffusion regulating membrane adjacent to the bioactive substance releasing membrane, wherein the diffusion regulating membrane is different from the bioactive substance releasing membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，扩散调节膜直接邻近生物活性物质释放膜。In one aspect, alone or in combination with any of the preceding aspects, the diffusion regulating membrane is directly adjacent to the bioactive substance releasing membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，扩散调节膜是嵌段共聚物。In one aspect, alone or in combination with any of the preceding aspects, the diffusion regulating membrane is a block copolymer.
在一个方面，单独地或与前述方面中的任一方面组合地，扩散调节膜是链段化嵌段共聚物。In one aspect, alone or in combination with any of the preceding aspects, the diffusion regulating membrane is a segmented block copolymer.
在一个方面，单独地或与前述方面中的任一方面组合地，扩散调节膜是多嵌段共聚物。In one aspect, alone or in combination with any of the preceding aspects, the diffusion regulating membrane is a multi-block copolymer.
在一个方面，单独地或与前述方面中的任一方面组合地，扩散调节膜被退火。In one aspect, alone or in combination with any of the preceding aspects, the diffusion regulating film is annealed.
在一个方面，单独地或与前述方面中的任一方面组合地，经退火的扩散调节膜包括稳定的分离相。In one aspect, alone or in combination with any of the preceding aspects, the annealed diffusion regulating film comprises a stable separate phase.
在一个方面，单独地或与前述方面中的任一方面组合地，稳定的分离相为至少一种可释放生物活性剂提供扩散通道。In one aspect, alone or in combination with any of the preceding aspects, the stable separate phase provides a diffusion pathway for at least one releasable biologically active agent.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括软链段和硬链段，该硬链段包括氨基甲酸酯基团、脲基团或氨基甲酸酯基团与脲基团的组合。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises a soft segment and a hard segment, the hard segment comprising a carbamate group, a urea group or a combination of a carbamate group and a urea group.
在一个方面，单独地或与前述方面中的任一方面组合地，软链段是两种或更多种不同的聚合物链段。In one aspect, alone or in combination with any of the preceding aspects, the soft segments are two or more different polymer segments.
在一个方面，单独地或与前述方面中的任一方面组合地，软链段包括疏水性嵌段和亲水性嵌段。In one aspect, alone or in combination with any of the preceding aspects, the soft segment comprises a hydrophobic block and a hydrophilic block.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括多组分软链段，该多组分软链段包括两种或更多种不同的聚合物链段。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises a multi-component soft segment comprising two or more different polymer segments.
在一个方面，单独地或与前述方面中的任一方面组合地，多组分软链段包括聚硅氧烷、聚碳酸烷基酯和聚碳酸酯中的至少一者与聚烷基醚、聚烷基酯的组合的疏水性嵌段和亲水性嵌段。In one aspect, the multi-component soft segment comprises a hydrophobic block and a hydrophilic block of a combination of at least one of polysiloxane, polyalkyl carbonate and polycarbonate with polyalkyl ether, polyalkyl ester, alone or in combination with any of the preceding aspects.
在一个方面，单独地或与前述方面中的任一方面组合地，软链段包括聚硅氧烷、聚烷基醚、聚烷基酯、聚碳酸烷基酯、聚碳酸酯和聚硅氧烷-聚烷基醚链段化嵌段中的一者或多者的组合，并且其中硬链段包括降冰片烷二异氰酸酯(NBDI)、异佛尔酮二异氰酸酯(IPDI)、甲苯二异氰酸酯(TDI)、1,3-亚苯基二异氰酸酯(MPDI)、反式-1,3-双(异氰酸甲基)环己烷(1,3-H6XDI)、双环己基甲烷-4,4'-二异氰酸酯(HMDI)、4,4'-二苯基甲烷二异氰酸酯(MDI)、反式-1,4-双(异氰酸甲基)环己烷(1,4-H6XDI)、1,4-环己基二异氰酸酯(CHDI)、1,4-亚苯基二异氰酸酯(PPDI)、3,3'-二甲基-4,4'-联苯二异氰酸酯(TODI)和1,6-六亚甲基二异氰酸酯(HDI)中的至少一者。In one aspect, the soft segment comprises a combination of one or more of polysiloxane, polyalkyl ether, polyalkyl ester, polyalkyl carbonate, polycarbonate, and polysiloxane-polyalkyl ether segmented blocks, alone or in combination with any of the preceding aspects, and wherein the hard segment comprises norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1 ,3-H6XDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI) and at least one of 1,6-hexamethylene diisocyanate (HDI).
在一个方面，单独地或与前述方面中的任一方面组合地，软链段包括聚硅氧烷、聚烷基醚、聚烷基酯、聚碳酸烷基酯、聚碳酸酯或聚硅氧烷-聚烷基醚链段化嵌段。In one aspect, alone or in combination with any of the preceding aspects, the soft segments include polysiloxane, polyalkyl ether, polyalkyl ester, polyalkyl carbonate, polycarbonate, or polysiloxane-polyalkyl ether segmented blocks.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜还包括扩链剂。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane further comprises a chain extender.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜是聚氨酯脲。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is a polyurethaneurea.
在一个方面，单独地或与前述方面中的任一方面组合地，按生物活性物质释放膜的总重量计，生物活性物质释放膜包括约10重量％至30重量％的聚硅氧烷和约10重量％至30重量％的聚烷基醚、40重量％至60重量％的硬链段，并且任何剩余重量％是扩链剂，硬链段包括氨基甲酸酯基团、脲基团或氨基甲酸酯基团与脲基团的组合。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance-releasing membrane comprises, based on the total weight of the bioactive substance-releasing membrane, about 10 wt % to 30 wt % of polysiloxane and about 10 wt % to 30 wt % of polyalkyl ether, 40 wt % to 60 wt % of hard segments, and any remaining wt % is a chain extender, the hard segments comprising carbamate groups, urea groups, or a combination of carbamate groups and urea groups.
在一个方面，单独地或与前述方面中的任一方面组合地，按生物活性物质释放膜的总重量计，生物活性物质释放膜包括约20重量％至30重量％的聚硅氧烷、约20重量％至30重量％的聚烷基醚和约40重量％至60重量％的硬链段，并且任何剩余重量％是扩链剂。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance release membrane comprises about 20 wt % to 30 wt % polysiloxane, about 20 wt % to 30 wt % polyalkyl ether, and about 40 wt % to 60 wt % hard segment, based on the total weight of the bioactive substance release membrane, and any remaining wt % is a chain extender.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括软链段，按生物活性物质释放膜的总重量计，软链段包括约10重量％至30重量％的聚硅氧烷、约10重量％至30重量％的聚烷基醚和约0重量％至10重量％的扩链剂。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance-releasing membrane comprises a soft segment, which comprises about 10 wt % to 30 wt % of polysiloxane, about 10 wt % to 30 wt % of polyalkyl ether, and about 0 wt % to 10 wt % of a chain extender, based on the total weight of the bioactive substance-releasing membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，聚烷基醚由式(I)的重复单元表示：-(R5-O)-；其中R5是2至6个碳的直链或支链烷基。In one aspect, alone or in combination with any of the preceding aspects, the polyalkyl ether is represented by a repeating unit of formula (I): -(R5-O)-; wherein R5 is a linear or branched alkyl group of 2 to 6 carbons.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜具有1重量％至4重量％的平衡吸水率。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane has an equilibrium water absorption of 1 wt% to 4 wt%.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜具有小于3重量％的平衡吸水率。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane has an equilibrium water absorption of less than 3 wt%.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜是至少一种可释放生物活性剂的赋形剂。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane is at least one excipient that can release a bioactive agent.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括疏水性软链段、至少一种亲水性软链段和硬链段，该硬链段包括氨基甲酸酯基团、脲基团或氨基甲酸酯基团与脲基团的组合。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance release membrane comprises a hydrophobic soft segment, at least one hydrophilic soft segment and a hard segment comprising a carbamate group, a urea group or a combination of a carbamate group and a urea group.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括硬链段和软链段，硬链段具有比软链段更接近至少一种可释放生物活性剂的希尔德布兰德溶解度参数。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises a hard segment and a soft segment, the hard segment having a Hildebrand solubility parameter closer to that of the at least one releasable bioactive agent than the soft segment.
在一个方面，单独地或与前述方面中的任一方面组合地，衬底的远侧端部包括导线切单部、平面切单部或基本上平面的切单部。In one aspect, alone or in combination with any of the preceding aspects, the distal end of the substrate comprises a wire singulation portion, a planar singulation portion, or a substantially planar singulation portion.
在一个方面，单独地或与前述方面中的任一方面组合地，该设备还包括邻近远侧端部的电绝缘端帽。In one aspect, alone or in combination with any of the preceding aspects, the device further comprises an electrically insulating end cap adjacent the distal end.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽是疏水性涂层。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is a hydrophobic coating.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽对于电化学活性物质是不能够渗透的。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is impermeable to the electrochemically active material.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽对于分析物是不能够渗透的。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating endcap is impermeable to the analyte.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽从远侧端部纵向延伸。In one aspect, alone or in combination with any of the preceding aspects, an electrically insulating end cap extends longitudinally from the distal end.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽从远侧端部延伸直到传感器部分。In one aspect, alone or in combination with any of the preceding aspects, an electrically insulating end cap extends from the distal end up to the sensor portion.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽是热塑性有机硅聚碳酸酯聚氨酯、聚丙烯酸酯、聚氨酯丙烯酸酯、聚丁二烯改性的聚氨酯、聚乙烯乙酸乙烯酯、有机硅或它们的组合。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is a thermoplastic silicone polycarbonate polyurethane, polyacrylate, polyurethane acrylate, polybutadiene modified polyurethane, polyethylene vinyl acetate, silicone, or a combination thereof.
在另一示例中，提供了一种降低或延迟受试者的组织中的免疫应答的方法，该方法包括：(i)提供连续分析物感测设备，该设备包括：可插入部分，该可插入部分能够操作地联接到不可插入部分，该可插入部分包括被配置为插入到组织中的感测部分，该可插入部分具有可插入表面积和可插入体积；至少一个生物活性物质释放膜，该至少一个生物活性物质释放膜设置在可插入表面积的一部分上，该生物活性物质释放膜与感测部分空间分离，该至少一个生物活性物质释放膜包括至少一种生物活性剂；(ii)通过插入可插入部分在组织中形成组织插入体积，该组织插入体积大于或等于可插入体积；(iii)以约0.1μg/天至约5μg/天的平均释放速率将至少一种生物活性剂从至少一个生物活性物质释放膜释放到组织插入体积中；以及(iv)降低或延迟组织中的免疫应答。In another example, a method for reducing or delaying an immune response in a tissue of a subject is provided, the method comprising: (i) providing a continuous analyte sensing device, the device comprising: an insertable portion, the insertable portion being capable of being operably coupled to a non-insertable portion, the insertable portion comprising a sensing portion configured to be inserted into tissue, the insertable portion having an insertable surface area and an insertable volume; at least one bioactive substance releasing membrane, the at least one bioactive substance releasing membrane being disposed on a portion of the insertable surface area, the bioactive substance releasing membrane being spatially separated from the sensing portion, the at least one bioactive substance releasing membrane comprising at least one bioactive agent; (ii) forming a tissue insertion volume in the tissue by inserting the insertable portion, the tissue insertion volume being greater than or equal to the insertable volume; (iii) releasing at least one bioactive agent from the at least one bioactive substance releasing membrane into the tissue insertion volume at an average release rate of about 0.1 μg/day to about 5 μg/day; and (iv) reducing or delaying an immune response in the tissue.
在一个方面，生物活性物质释放膜与感测部分空间分离。In one aspect, the bioactive substance releasing membrane is spatially separated from the sensing portion.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜活性物还包括不可释放生物活性剂。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane active further comprises a non-releasable bioactive agent.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括聚合物，并且至少一种生物活性剂与聚合物的重量/重量比率为约0.1至约2，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance release membrane comprises a polymer and the weight/weight ratio of at least one bioactive agent to the polymer is from about 0.1 to about 2, including all ranges and subranges therebetween.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂包括抗炎化合物或组织反应调节剂。In one aspect, alone or in combination with any of the preceding aspects, the at least one biologically active agent comprises an anti-inflammatory compound or a tissue response modifier.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂包括地塞米松、地塞米松盐、地塞米松衍生物、醋酸地塞米松或地塞米松盐、地塞米松衍生物或醋酸地塞米松与地塞米松的组合。In one aspect, alone or in combination with any of the preceding aspects, the at least one biologically active agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.
在另一示例中，提供了一种减少连续分析物传感器设备中由异物反应引起的信号噪声的方法，该方法包括：提供连续分析物感测设备，该连续分析物感测设备包括：衬底，该衬底包括可插入部分，该可插入部分能够操作地联接到不可插入部分，该可插入部分具有远侧端部；至少一个感测部分，该至少一个感测部分定位在远侧端部的近侧；至少一个生物活性物质释放膜，该至少一个生物活性物质释放膜设置在远侧端部的至少一部分上，该生物活性物质释放膜包括能够减弱异物反应的至少一种生物活性剂；以及减少连续分析物感测设备的使用期间的信号噪声。In another example, a method for reducing signal noise caused by a foreign body reaction in a continuous analyte sensor device is provided, the method comprising: providing a continuous analyte sensing device, the continuous analyte sensing device comprising: a substrate, the substrate comprising an insertable portion, the insertable portion being capable of being operably connected to a non-insertable portion, the insertable portion having a distal end; at least one sensing portion, the at least one sensing portion being positioned proximal to the distal end; at least one bioactive substance releasing membrane, the at least one bioactive substance releasing membrane being disposed on at least a portion of the distal end, the bioactive substance releasing membrane comprising at least one bioactive agent capable of attenuating a foreign body reaction; and reducing signal noise during use of the continuous analyte sensing device.
在一个方面，该方法还包括向组织释放或暴露至少一种生物活性剂。In one aspect, the method further comprises releasing or exposing at least one bioactive agent to the tissue.
在一个方面，单独地或与前述方面中的任一方面组合地，该方法还包括减弱远侧端部附近的异物反应。In one aspect, alone or in combination with any of the preceding aspects, the method further comprises attenuating a foreign body reaction proximate the distal end.
在一个方面，单独地或与前述方面中的任一方面组合地，分析物是葡萄糖，并且信号噪声维持在小于4mg/dL至少10天。In one aspect, alone or in combination with any of the preceding aspects, the analyte is glucose and the signal noise is maintained at less than 4 mg/dL for at least 10 days.
在一个方面，单独地或与前述方面中的任一方面组合地，分析物是葡萄糖，并且信号噪声维持在小于4mg/dL至少15天。In one aspect, alone or in combination with any of the preceding aspects, the analyte is glucose and the signal noise is maintained at less than 4 mg/dL for at least 15 days.
在一个方面，单独地或与前述方面中的任一方面组合地，分析物是葡萄糖，并且信号噪声维持在小于4mg/dL至少21天。In one aspect, alone or in combination with any of the preceding aspects, the analyte is glucose and the signal noise is maintained at less than 4 mg/dL for at least 21 days.
在一个方面，单独地或与前述方面中的任一方面组合地，可插入部分包括可插入表面积和可插入体积。In one aspect, alone or in combination with any of the preceding aspects, the insertable portion comprises an insertable surface area and an insertable volume.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一个生物活性物质释放膜设置在可插入表面积的一部分上，该至少一个生物活性物质释放膜具有小于或等于可插入表面积的生物活性物质释放膜表面积中的至少一者。In one aspect, alone or in combination with any of the preceding aspects, at least one bioactive substance releasing membrane is disposed on a portion of the insertable surface area, the at least one bioactive substance releasing membrane having at least one of a bioactive substance releasing membrane surface area less than or equal to the insertable surface area.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一个生物活性物质释放膜包括聚合物，并且聚合物与至少一种生物活性剂的总量的重量比率为约0.1至约2。In one aspect, alone or in combination with any of the preceding aspects, at least one bioactive substance releasing membrane comprises a polymer, and the weight ratio of the polymer to the total amount of the at least one bioactive agent is from about 0.1 to about 2.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂包括抗炎化合物或组织反应调节剂。In one aspect, alone or in combination with any of the preceding aspects, the at least one biologically active agent comprises an anti-inflammatory compound or a tissue response modifier.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂包括地塞米松、地塞米松盐、地塞米松衍生物、醋酸地塞米松或地塞米松盐、地塞米松衍生物或醋酸地塞米松与地塞米松的组合。In one aspect, alone or in combination with any of the preceding aspects, the at least one biologically active agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.
在一个方面，单独地或与前述方面中的任一方面组合地，可插入部分和不可插入部分设置在衬底上，该衬底是导线、平面衬底或基本上平面的衬底，并且远侧端部还包括切单部。In one aspect, alone or in combination with any of the preceding aspects, the insertable portion and the non-insertable portion are disposed on a substrate that is a wire, a planar substrate, or a substantially planar substrate, and the distal end further comprises a singulation portion.
在一个方面，单独地或与前述方面中的任一方面组合地，该方法还包括邻近远侧端部的电绝缘端帽。In one aspect, alone or in combination with any of the preceding aspects, the method further includes an electrically insulating end cap adjacent the distal end.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽是疏水性涂层。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is a hydrophobic coating.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽从远侧端部纵向延伸。In one aspect, alone or in combination with any of the preceding aspects, an electrically insulating end cap extends longitudinally from the distal end.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽对于电化学活性物质是不能够渗透的。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is impermeable to the electrochemically active material.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽对于分析物是不能够渗透的。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating endcap is impermeable to the analyte.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽从远侧端部延伸直到传感器部分。In one aspect, alone or in combination with any of the preceding aspects, an electrically insulating end cap extends from the distal end up to the sensor portion.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽是热塑性有机硅聚碳酸酯聚氨酯、聚丙烯酸酯、聚氨酯丙烯酸酯、聚丁二烯改性的聚氨酯、聚乙烯乙酸乙烯酯、有机硅或它们的组合。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is a thermoplastic silicone polycarbonate polyurethane, polyacrylate, polyurethane acrylate, polybutadiene modified polyurethane, polyethylene vinyl acetate, silicone, or a combination thereof.
在又一示例中，提供了一种减少连续分析物传感器设备在使用期间由组织中的异物反应引起的灵敏度损失的发生的方法，该方法包括：提供连续分析物感测设备，该连续分析物感测设备包括：衬底，该衬底包括可插入部分，该可插入部分具有能够操作地联接到不可插入部分的远侧端部；至少一个感测部分，该至少一个感测部分定位在远侧端部的近侧和不可插入部分的远侧；至少一个生物活性物质释放膜，该至少一个生物活性物质释放膜设置在远侧端部的一部分上，该至少一个生物活性物质释放膜包括能够减弱异物反应的至少一种生物活性剂；以及减少连续分析物感测设备在使用期间灵敏度损失的发生。In yet another example, a method for reducing the occurrence of sensitivity loss of a continuous analyte sensor device caused by a foreign body reaction in tissue during use is provided, the method comprising: providing a continuous analyte sensing device, the continuous analyte sensing device comprising: a substrate, the substrate comprising an insertable portion, the insertable portion having a distal end capable of being operably connected to a non-insertable portion; at least one sensing portion, the at least one sensing portion being positioned proximal to the distal end and distal to the non-insertable portion; at least one bioactive substance releasing membrane, the at least one bioactive substance releasing membrane being disposed on a portion of the distal end, the at least one bioactive substance releasing membrane comprising at least one bioactive agent capable of attenuating a foreign body reaction; and reducing the occurrence of sensitivity loss of the continuous analyte sensing device during use.
在一个方面，方法还包括向组织释放或暴露至少一种生物活性剂。In one aspect, the method further comprises releasing or exposing at least one bioactive agent to the tissue.
在一个方面，单独地或与前述方面中的任一方面组合地，减少灵敏度损失的发生持续至少14天。In one aspect, alone or in combination with any of the preceding aspects, the occurrence of sensitivity loss is reduced for at least 14 days.
在一个方面，单独地或与前述方面中的任一方面组合地，减少灵敏度损失的发生持续至少20天。In one aspect, alone or in combination with any of the preceding aspects, the occurrence of sensitivity loss is reduced for at least 20 days.
在一个方面，单独地或与前述方面中的任一方面组合地，减少灵敏度损失的发生持续至少30天。In one aspect, alone or in combination with any of the preceding aspects, the occurrence of sensitivity loss is reduced for at least 30 days.
在一个方面，单独地或与前述方面中的任一方面组合地，衬底是导线、平面衬底或基本上平面的衬底，并且远侧端部还包括切单部。In one aspect, alone or in combination with any of the preceding aspects, the substrate is a wire, a planar substrate, or a substantially planar substrate, and the distal end further comprises a singulation portion.
在一个方面，单独地或与前述方面中的任一方面组合地，该方法还包括邻近远侧端部的电绝缘端帽。In one aspect, alone or in combination with any of the preceding aspects, the method further includes an electrically insulating end cap adjacent the distal end.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽不同于生物活性物质释放膜。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is distinct from the biologically active substance releasing membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽是疏水性涂层。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is a hydrophobic coating.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽从远侧端部纵向延伸。In one aspect, alone or in combination with any of the preceding aspects, an electrically insulating end cap extends longitudinally from the distal end.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽对于电化学活性物质是不能够渗透的。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is impermeable to the electrochemically active material.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽对于分析物是不能够渗透的。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating endcap is impermeable to the analyte.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽从远侧端部纵向延伸直到传感器部分。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap extends longitudinally from the distal end to the sensor portion.
在一个方面，单独地或与前述方面中的任一方面组合地，电绝缘端帽是热塑性有机硅聚碳酸酯聚氨酯、聚丙烯酸酯、聚氨酯丙烯酸酯、聚丁二烯改性的聚氨酯、聚乙烯乙酸乙烯酯、有机硅或它们的组合。In one aspect, alone or in combination with any of the preceding aspects, the electrically insulating end cap is a thermoplastic silicone polycarbonate polyurethane, polyacrylate, polyurethane acrylate, polybutadiene modified polyurethane, polyethylene vinyl acetate, silicone, or a combination thereof.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂包括抗炎化合物或组织反应调节剂。In one aspect, alone or in combination with any of the preceding aspects, the at least one biologically active agent comprises an anti-inflammatory compound or a tissue response modifier.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂包括地塞米松、地塞米松盐、地塞米松衍生物、醋酸地塞米松或地塞米松盐、地塞米松衍生物或醋酸地塞米松与地塞米松的组合。In one aspect, alone or in combination with any of the preceding aspects, the at least one biologically active agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.
在又一示例中，提供了一种用于测量分析物的浓度的设备，该设备包括：传感器部分，该传感器部分被配置为生成与分析物的浓度相关联的信号；和生物活性物质释放膜，该生物活性物质释放膜靠近传感器部分，该生物活性物质释放膜被配置为形成与至少一种生物活性剂的复合物，该至少一种生物活性剂被配置为从生物活性物质释放膜释放以改变受试者的组织反应。In yet another example, a device for measuring the concentration of an analyte is provided, the device comprising: a sensor portion configured to generate a signal associated with the concentration of the analyte; and a bioactive substance releasing membrane proximal to the sensor portion, the bioactive substance releasing membrane configured to form a complex with at least one bioactive agent, the at least one bioactive agent configured to be released from the bioactive substance releasing membrane to change a tissue response of a subject.
在一个方面，与至少一种生物活性剂的复合物是共价的或非共价的。In one aspect, the complex with at least one biologically active agent is covalent or non-covalent.
在一个方面，单独地或与前述方面中的任一方面组合地，与至少一种生物活性剂的复合物是离子型的。In one aspect, alone or in combination with any of the preceding aspects, the complex with at least one biologically active agent is ionic.
在一个方面，单独地或与前述方面中的任一方面组合地，与至少一种生物活性剂的复合物提供生物活性剂缀合物。In one aspect, the complex with at least one biologically active agent provides a biologically active agent conjugate, alone or in combination with any of the preceding aspects.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂包括抗炎化合物或组织反应调节剂。In one aspect, alone or in combination with any of the preceding aspects, the at least one biologically active agent comprises an anti-inflammatory compound or a tissue response modifier.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂包括地塞米松、地塞米松盐、地塞米松衍生物、醋酸地塞米松或地塞米松盐、地塞米松衍生物或醋酸地塞米松与地塞米松的组合。In one aspect, alone or in combination with any of the preceding aspects, the at least one biologically active agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂是一氧化氮释放分子、聚合物或寡聚物。In one aspect, alone or in combination with any of the preceding aspects, at least one biologically active agent is a nitric oxide releasing molecule, polymer or oligomer.
在一个方面，单独地或与前述方面中的任一方面组合地，一氧化氮释放分子选自N-二醇二氮烯鎓和S-亚硝基硫醇。In one aspect, alone or in combination with any of the preceding aspects, the nitric oxide releasing molecule is selected from the group consisting of diazenium N-diolates and S-nitrosothiol.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂是共价偶联的因子H。In one aspect, alone or in combination with any of the preceding aspects, at least one biologically active agent is covalently coupled Factor H.
在一个方面，单独地或与前述方面中的任一方面组合地，复合物是包括硼酸酯或硼酸盐的生物活性剂缀合物。In one aspect, alone or in combination with any of the preceding aspects, the complex is a bioactive agent conjugate comprising a boronate ester or a boronate salt.
在一个方面，单独地或与前述方面中的任一方面组合地，复合物是包括能够通过皮下刺激裂解的至少一个可裂解连接子的生物活性剂缀合物。In one aspect, alone or in combination with any of the preceding aspects, the complex is a bioactive agent conjugate comprising at least one cleavable linker capable of being cleaved by subcutaneous stimulation.
在一个方面，单独地或与前述方面中的任一方面组合地，皮下刺激是基质金属肽酶或蛋白酶攻击。In one aspect, alone or in combination with any of the preceding aspects, the subcutaneous stimulation is a matrix metallopeptidase or protease attack.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括亲水性水凝胶，该亲水性水凝胶至少部分地交联并且能够溶解于生物流体中。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises a hydrophilic hydrogel that is at least partially cross-linked and capable of dissolving in a biological fluid.
在一个方面，单独地或与前述方面中的任一方面组合地，亲水性水凝胶包括通过二乙烯基砜或聚乙二醇二乙烯基砜交联的透明质酸。In one aspect, alone or in combination with any of the preceding aspects, the hydrophilic hydrogel comprises hyaluronic acid cross-linked by divinyl sulfone or polyethylene glycol divinyl sulfone.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括银纳米颗粒。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises silver nanoparticles.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括可生物降解聚合物纳米颗粒，该可生物降解聚合物纳米颗粒选自含有至少一种生物活性剂的PLA、PLGA、PCL、PVL、PLLA、PDLA、PEO-b-PLA嵌段共聚物、聚磷酸酯或PEO-b-多肽。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance release membrane comprises biodegradable polymer nanoparticles selected from PLA, PLGA, PCL, PVL, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphates or PEO-b-polypeptides containing at least one bioactive agent.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括有机凝胶载体和/或无机凝胶载体。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises an organic gel carrier and/or an inorganic gel carrier.
在一个方面，单独地或与前述方面中的任一方面组合地，被配置为形成与至少一种生物活性剂的复合物的生物活性物质释放膜包括包封在生物活性物质释放膜中的至少一种生物活性剂和与生物活性物质释放膜共价偶联的至少一种生物活性剂的组合。In one aspect, alone or in combination with any of the preceding aspects, a bioactive substance releasing membrane configured to form a complex with at least one bioactive agent comprises a combination of at least one bioactive agent encapsulated in the bioactive substance releasing membrane and at least one bioactive agent covalently coupled to the bioactive substance releasing membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，被配置为形成与至少一种生物活性剂的复合物的生物活性物质释放膜包括至少一种生物活性剂的空间远侧药物贮库。In one aspect, alone or in combination with any of the preceding aspects, a bioactive substance release membrane configured to form a complex with at least one bioactive agent comprises a spatially distal drug reservoir of the at least one bioactive agent.
在一个方面，单独地或与前述方面中的任一方面组合地，被配置为形成与至少一种生物活性剂的复合物的生物活性物质释放膜包括可水解降解生物聚合物，该可水解降解生物聚合物包括至少一种生物活性剂。In one aspect, alone or in combination with any of the preceding aspects, a bioactive substance releasing membrane configured to form a complex with at least one bioactive agent comprises a hydrolytically degradable biopolymer comprising at least one bioactive agent.
在一个方面，单独地或与前述方面中的任一方面组合地，可水解降解生物聚合物包括水杨酸聚酸酐酯。In one aspect, alone or in combination with any of the preceding aspects, the hydrolytically degradable biopolymer comprises salicylic acid polyanhydride ester.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括聚氨酯链段和/或聚脲链段，按生物活性物质释放膜的总重量计，聚氨酯链段和/或聚脲链段为约15重量％至约75重量％，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance-releasing membrane comprises polyurethane segments and/or polyurea segments, and the polyurethane segments and/or polyurea segments are from about 15 wt % to about 75 wt %, based on the total weight of the bioactive substance-releasing membrane, including all ranges and subranges therebetween.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括至少一种聚合物链段，该至少一种聚合物链段选自由环氧化物、聚烯烃、聚硅氧烷、聚酰胺、聚苯乙烯、聚丙烯酸酯、聚醚、聚吡啶、聚酯、聚烷基酯、聚碳酸烷基酯、聚碳酸酯、聚乙烯乙酸乙烯酯、聚乙烯醇以及它们的共聚物组成的组。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises at least one polymer segment selected from the group consisting of epoxides, polyolefins, polysiloxanes, polyamides, polystyrenes, polyacrylates, polyethers, polypyridines, polyesters, polyalkyl esters, polyalkyl carbonates, polycarbonates, polyethylene vinyl acetate, polyvinyl alcohol, and copolymers thereof.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括聚环氧乙烷链段。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises polyethylene oxide segments.
在一个方面，单独地或与前述方面中的任一方面组合地，按生物活性物质释放膜的总重量计，聚环氧乙烷链段为约5重量％至约60重量％。In one aspect, alone or in combination with any of the preceding aspects, the polyethylene oxide segment is about 5 wt % to about 60 wt % based on the total weight of the bioactive substance release membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜的基础聚合物具有约10kDa至约500kDa的平均分子量，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the base polymer of the bioactive substance release membrane has an average molecular weight of about 10 kDa to about 500 kDa, including all ranges and subranges therebetween.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜具有1至约10的多分散指数，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the bioactive material releasing film has a polydispersity index of 1 to about 10, including all ranges and subranges therebetween.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜具有约90°至约160°的接触角，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film has a contact angle of about 90° to about 160°, including all ranges and subranges therebetween.
在又一示例中，提供了一种用于测量分析物的浓度的设备，该设备包括：传感器部分，该传感器部分被配置为生成与分析物的浓度相关联的信号；和生物活性物质释放膜，该生物活性物质释放膜靠近传感器部分，该生物活性物质释放膜包括与至少一种生物活性剂复合的一个或多个两性离子重复单元，该至少一种生物活性剂被配置为从一个或多个两性离子重复单元释放以改变受试者的组织反应。In yet another example, a device for measuring the concentration of an analyte is provided, the device comprising: a sensor portion configured to generate a signal associated with the concentration of the analyte; and a bioactive substance releasing membrane proximal to the sensor portion, the bioactive substance releasing membrane comprising one or more zwitterionic repeating units complexed with at least one bioactive agent, the at least one bioactive agent being configured to be released from the one or more zwitterionic repeating units to alter a tissue response of a subject.
在一个方面，一个或多个两性离子重复单元包括甜菜碱化合物或其衍生物。In one aspect, the one or more zwitterionic repeating units comprise a betaine compound or a derivative thereof.
在一个方面，单独地或与前述方面中的任一方面组合地，一个或多个两性离子重复单元包括甜菜碱化合物或其前体。In one aspect, alone or in combination with any of the preceding aspects, one or more zwitterionic repeating units comprises a betaine compound or a precursor thereof.
在一个方面，单独地或与前述方面中的任一方面组合地，一个或多个两性离子重复单元包括选自由羧基甜菜碱、磺基甜菜碱、磷甜菜碱以及它们的衍生物组成的组的至少一个部分。In one aspect, alone or in combination with any of the preceding aspects, one or more zwitterionic repeating units comprises at least one moiety selected from the group consisting of carboxybetaine, sulfobetaine, phosphobetaine, and derivatives thereof.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂包括抗炎化合物或组织反应调节剂。In one aspect, alone or in combination with any of the preceding aspects, the at least one biologically active agent comprises an anti-inflammatory compound or a tissue response modifier.
在一个方面，单独地或与前述方面中的任一方面组合地，至少一种生物活性剂包括地塞米松、地塞米松盐、地塞米松衍生物、醋酸地塞米松或地塞米松盐、地塞米松衍生物或醋酸地塞米松与地塞米松的组合。In one aspect, alone or in combination with any of the preceding aspects, the at least one biologically active agent comprises dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or a dexamethasone salt, a dexamethasone derivative, or a combination of dexamethasone acetate and dexamethasone.
在一个方面，单独地或与前述方面中的任一方面组合地，一个或多个两性离子重复单元衍生自选自由以下各项组成的组的单体：In one aspect, alone or in combination with any of the preceding aspects, the one or more zwitterionic repeat units are derived from a monomer selected from the group consisting of:
其中Z是支链或直链烷基、杂烷基、环烷基、环杂烷基、芳基或杂芳基；R1是H、烷基、杂烷基、环烷基、杂环烷基、芳基或杂芳基；并且R2、R3和R4独立地选自烷基、杂烷基、环烷基、杂环烷基、芳基或杂芳基；并且其中R1、R2、R3、R4和Z中的一者或多者被聚合基团取代。wherein Z is a branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; R1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R2, R3 and R4 are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and wherein one or more of R1, R2, R3, R4 and Z are substituted with a polymerizing group.
在一个方面，单独地或与前述方面中的任一方面组合地，聚合基团选自烯烃、炔烃、环氧化物、内酯、胺、羟基、异氰酸酯、羧酸、酸酐、硅烷、卤化物、醛、碳二亚胺或它们的组合。In one aspect, alone or in combination with any of the preceding aspects, the polymeric group is selected from olefins, alkynes, epoxides, lactones, amines, hydroxyls, isocyanates, carboxylic acids, anhydrides, silanes, halides, aldehydes, carbodiimides, or combinations thereof.
在一个方面，单独地或与前述方面中的任一方面组合地，按生物活性物质释放膜的总重量计，一个或多个两性离子重复单元为至少约1重量％。In one aspect, alone or in combination with any of the preceding aspects, the one or more zwitterionic repeating units are at least about 1 wt % based on the total weight of the bioactive agent releasing membrane.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜还包括选自由以下各项组成的组的一种或多种两性离子：椰油酰胺丙基甜菜碱、油酰胺丙基甜菜碱、辛基磺基甜菜碱、癸基磺基甜菜碱、月桂基磺基甜菜碱、肉豆蔻基磺基甜菜碱、棕榈基磺基甜菜碱、硬脂酰基磺基甜菜碱、甜菜碱(三甲基甘氨酸)、辛基甜菜碱、磷脂酰胆碱、甘氨酸甜菜碱、聚(羧基甜菜碱)、聚(磺基甜菜碱)以及它们的衍生物。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance release film further comprises one or more zwitterions selected from the group consisting of cocamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, decyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearoyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly (carboxy betaine), poly (sulfobetaine) and derivatives thereof.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括聚合物链，该聚合物链在聚合物链的末端并沿着聚合物链具有两性离子基团。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises polymer chains having zwitterionic groups at the ends of the polymer chains and along the polymer chains.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括聚合物链，该聚合物链具有亲水性区域和疏水性区域两者，并且其中一种或多种两性离子化合物存在于聚合物链的末端处；生物活性物质释放膜包括基础聚合物，该基础聚合物选自聚烯烃、聚苯乙烯、聚甲醛、聚硅氧烷、聚醚、聚丙烯酸、聚甲基丙烯酸、聚酯、聚烷基酯、聚碳酸烷基酯、聚碳酸酯、聚酰胺、聚吡啶、聚(醚酮)、聚(醚酰亚胺)、聚氨酯、聚氨酯脲、聚乙烯乙酸乙烯酯、聚乙烯醇或它们的共聚物或共混物。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance release membrane comprises a polymer chain having both a hydrophilic region and a hydrophobic region, and wherein one or more zwitterionic compounds are present at the end of the polymer chain; the bioactive substance release membrane comprises a base polymer selected from polyolefins, polystyrenes, polyoxymethylenes, polysiloxanes, polyethers, polyacrylic acids, polymethacrylic acids, polyesters, polyalkyl esters, polyalkyl carbonates, polycarbonates, polyamides, polypyridines, poly(ether ketones), poly(ether imides), polyurethanes, polyurethane ureas, polyethylene vinyl acetate, polyvinyl alcohol, or copolymers or blends thereof.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜的基础聚合物具有约10kDa至约500kDa的平均分子量，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the base polymer of the bioactive substance release membrane has an average molecular weight of about 10 kDa to about 500 kDa, including all ranges and subranges therebetween.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜的基础聚合物具有约1至约10的多分散指数，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the base polymer of the bioactive agent release membrane has a polydispersity index of about 1 to about 10, including all ranges and subranges therebetween.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜的基础聚合物具有约90°至约160°的动态接触角，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the base polymer of the bioactive substance release membrane has a dynamic contact angle of about 90° to about 160°, including all ranges and subranges therebetween.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1A是连续分析物感测设备的示例性示例的剖视图。1A is a cross-sectional view of an illustrative example of a continuous analyte sensing device.
图1B是连续分析物感测设备的示例性示例的剖视图。1B is a cross-sectional view of an illustrative example of a continuous analyte sensing device.
图2A是如本文所公开和所述的示例性连续分析物感测设备的透视图。2A is a perspective view of an exemplary continuous analyte sensing device as disclosed and described herein.
图2B是沿着图2A的剖面线B-B穿过图2A的连续分析物感测设备的横截面图。2B is a cross-sectional view through the continuous analyte sensing device of FIG. 2A along section line B-B of FIG. 2A.
图2C是沿着图2A的剖面线B-B穿过图2A的连续分析物感测设备的横截面图，示出了示例性生物活性物质释放层。2C is a cross-sectional view through the continuous analyte sensing device of FIG. 2A along section line B-B of FIG. 2A, illustrating an exemplary bioactive substance releasing layer.
图2D是沿着图2A的线D-D穿过图2A的连续分析物感测设备的横截面图，示出了如本文所公开和所述的示例性生物活性物质释放膜。2D is a cross-sectional view through the continuous analyte sensing device of FIG. 2A along line D-D of FIG. 2A, illustrating an exemplary bioactive substance releasing membrane as disclosed and described herein.
图2E是沿着图2A的线D-D穿过图2A的连续分析物感测设备的横截面图，示出了如本文所公开和所述的另一示例性生物活性物质释放膜。2E is a cross-sectional view through the continuous analyte sensing device of FIG. 2A along line D-D of FIG. 2A , illustrating another exemplary bioactive substance releasing membrane as disclosed and described herein.
图2F是展示如本文所公开和所述的示例性连续分析物感测设备的体内部分的透视示意图。2F is a perspective schematic diagram showing an in vivo portion of an exemplary continuous analyte sensing device as disclosed and described herein.
图2G是展示如本文所公开和所述的图2F的示例性传感器的体内部分的侧视示意图。2G is a schematic side view showing an in vivo portion of the exemplary sensor of FIG. 2F as disclosed and described herein.
图2H是如本文所公开和所述的一个示例中的连续分析物感测设备的横截面平面图。2H is a cross-sectional plan view of a continuous analyte sensing device in one example as disclosed and described herein.
图2I是如本文所公开和所述的一个示例中的连续分析物感测设备的剖视图。21 is a cross-sectional view of a continuous analyte sensing device in one example as disclosed and described herein.
图2J是如本文所公开和所述的一个示例中的连续分析物感测设备的横截面图。2J is a cross-sectional view of a continuous analyte sensing device in one example as disclosed and described herein.
图3A是如本文所公开和所述的一个示例中的经皮连续分析物感测设备的侧视示意图。3A is a schematic side view of a transcutaneous continuous analyte sensing device in one example as disclosed and described herein.
图3B是如本文所公开和所述的另选示例中的经皮连续分析物感测设备的侧视示意图。3B is a schematic side view of a transcutaneous continuous analyte sensing device in an alternative example as disclosed and described herein.
图3C是一个示例中的可植入连续分析物感测设备的可植入部分的侧视示意图。3C is a schematic side view of an implantable portion of an implantable continuous analyte sensing device in one example.
图3D是另选示例中的可植入分析物传感器的可植入部分的侧视示意图。3D is a schematic side view of an implantable portion of an implantable analyte sensor in an alternative example.
图3E是另一另选示例中的连续分析物感测设备的可植入部分的侧视示意图。3E is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative example.
图3F是连续分析物感测设备的一个示例的侧视图，该连续分析物感测设备电感联接到受者皮肤上的功能上有用的距离内的电子单元。3F is a side view of one example of a continuous analyte sensing device inductively coupled to an electronics unit within a functionally useful distance on the skin of a recipient.
图3G是连续分析物感测设备的可植入部分的一个示例的侧视图，该连续分析物感测设备电感联接到以功能上有用的距离植入受者组织中的电子单元。3G is a side view of one example of an implantable portion of a continuous analyte sensing device inductively coupled to an electronics unit implanted in recipient tissue at a functionally useful distance.
图3H是另一另选示例中的连续分析物感测设备的可植入部分的侧视示意图。3H is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative example.
图3I是另一另选示例中的连续分析物感测设备的可植入部分的剖视图。31 is a cross-sectional view of an implantable portion of a continuous analyte sensing device in another alternative example.
图3J是另一另选示例中的连续分析物感测设备的可植入部分的剖视图。3J is a cross-sectional view of an implantable portion of a continuous analyte sensing device in another alternative example.
图3K是连续分析物感测设备的可植入部分的侧视示意图。3K is a schematic side view of an implantable portion of a continuous analyte sensing device.
图3L是另选示例中的连续分析物感测设备的可植入部分的侧视示意图。3L is a schematic side view of an implantable portion of a continuous analyte sensing device in an alternative example.
图3M是另一另选示例中的连续分析物感测设备的可植入部分的侧视示意图。3M is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative example.
图3N是另一另选示例中的连续分析物感测设备的可植入部分的侧视示意图。3N is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative example.
图3O是另一另选示例中的连续分析物感测设备的可植入部分的侧视示意图。30 is a schematic side view of an implantable portion of a continuous analyte sensing device in another alternative example.
图3P是如本文所公开和所述的生物活性剂随时间推移从生物活性物质释放膜的体内释放的图示。3P is a graphical representation of the in vivo release of a bioactive agent from a bioactive material releasing membrane over time as disclosed and described herein.
图3Q是如本文所公开和所述的生物活性剂随时间推移从生物活性物质释放膜的体内释放的图示。3Q is a graphical representation of the in vivo release of a bioactive agent from a bioactive material releasing membrane over time as disclosed and described herein.
图4A是如本文所公开和所描述的硬链段-软链段聚合物的示意图。4A is a schematic diagram of a hard segment-soft segment polymer as disclosed and described herein.
图4B是指示3-D体积4C的穿过示例性膜的横截面图。FIG. 4B is a cross-sectional view through an exemplary membrane indicating a 3-D volume 4C.
图4C是图4B的3-D体积4C的侧面示意图。FIG. 4C is a side schematic view of the 3-D volume 4C of FIG. 4B .
图5A是如本文所公开和所述的生物活性剂随时间推移从生物活性物质释放膜的累积释放速率的图示。5A is a graphical representation of the cumulative release rate of a bioactive agent over time from a bioactive material releasing membrane as disclosed and described herein.
图5B是如本文所公开和所述的生物活性剂随时间推移从生物活性物质释放膜的累积释放速率的图示。5B is a graphical representation of the cumulative release rate of a bioactive agent over time from a bioactive material releasing membrane as disclosed and described herein.
图5C是如本文所公开和所述的生物活性剂随时间推移从不同的生物活性物质释放膜的累积释放速率的图示。5C is a graphical representation of the cumulative release rate of a bioactive agent over time from different bioactive material releasing membranes as disclosed and described herein.
图6A是如本文所公开和所述的生物活性剂从不同的生物活性物质释放膜的释放相对于它们的吸水率的图示。6A is a graphical representation of the release of bioactive agents from different bioactive material releasing membranes as disclosed and described herein relative to their water absorption.
图6B是如本文所公开和所述的具有和不具有生物活性物质释放膜的传感器在18天内的归一化灵敏度的图示。6B is a graphical representation of the normalized sensitivity of sensors with and without a bioactive substance releasing membrane as disclosed and described herein over 18 days.
图6C是如本文所公开和所述的具有和不具有生物活性物质释放膜的传感器在30天内的归一化灵敏度的图示。6C is a graphical representation of the normalized sensitivity of sensors with and without a bioactive substance releasing membrane as disclosed and described herein over 30 days.
图6D是如本文所公开和所述的具有和不具有生物活性物质释放膜的传感器的归一化灵敏度的存活图表示。6D is a survival plot representation of the normalized sensitivity of sensors with and without a bioactive substance releasing membrane as disclosed and described herein.
图6E是如本文所公开和所述的具有不同的生物活性物质释放膜的传感器的归一化灵敏度的存活图表示。6E is a survival plot representation of normalized sensitivity of sensors having different bioactive substance releasing membranes as disclosed and described herein.
图7A是如本文所公开和所述的来自具有生物活性物质释放膜的传感器的平均绝对噪声随时间推移的图示。7A is a graphical representation of the average absolute noise over time from a sensor having a bioactive substance releasing membrane as disclosed and described herein.
图7B是如本文所公开和所述的具有和不具有生物活性物质释放膜的传感器的平均绝对噪声的存活图表示。7B is a survival plot representation of the mean absolute noise of sensors with and without a bioactive substance releasing membrane as disclosed and described herein.
图7C是如本文所公开和所述的具有不同的生物活性物质释放膜的传感器的平均绝对噪声的存活图表示。7C is a survival plot representation of the mean absolute noise of sensors having different bioactive substance releasing membranes as disclosed and described herein.
图8A是来自不具有生物活性物质释放膜的传感器的异物反应的组织成像图像。FIG. 8A is a histological imaging image of a foreign body reaction from a sensor without a bioactive substance releasing membrane.
图8B是如本文所公开和所述的来自具有生物活性物质释放膜的传感器的异物反应的组织成像图像。8B is a histological imaging image of a foreign body reaction from a sensor having a bioactive substance releasing membrane as disclosed and described herein.
具体实施方式Detailed ways
以下的描述和示例详细地说明了本公开的优选示例。本领域技术人员将认识到，本公开的范围涵盖了本公开的许多变型和修改。因此，对示例的描述不应被视为限制本公开的范围。The following description and examples illustrate preferred examples of the present disclosure in detail. Those skilled in the art will recognize that the scope of the present disclosure encompasses many variations and modifications of the present disclosure. Therefore, the description of the examples should not be considered to limit the scope of the present disclosure.
定义definition
为了便于理解所公开的示例，下面定义多个术语。To facilitate understanding of the disclosed examples, a number of terms are defined below.
如本文所用的术语“约”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)允许值或范围的一定程度的可变性，例如，在所述值或所述范围极限的10％以内、5％以内或1％以内，并且包括精确的所述值或范围。如本文所用，术语“基本上”是指大部分或大多数，如至少约50％、60％、70％、80％、90％、95％、96％、97％、98％、99％、99.5％、99.9％、99.99％、或至少约99.999％或更多、或100％。如本文所用，短语“基本上不含”可意指不具有或具有微量的，使得存在的材料的量不影响包括该材料的组合物的材料性质，使得该材料占该组合物的约0重量％至约5重量％或约0重量％至约1重量％或约5重量％或更少或小于或等于约4.5重量％、4重量％、3.5重量％、3重量％、2.5重量％、2重量％、1.5重量％、1重量％、0.9重量％、0.8重量％、0.7重量％、0.6重量％、0.5重量％、0.4重量％、0.3重量％、0.2重量％、0.1重量％、0.01重量％或约0.001重量％或更少或约0重量％。As used herein, the term "about" is a broad term and will be given its ordinary and customary meaning (and not limited to a special or custom meaning) to those of ordinary skill in the art, and refers to (but is not limited to) a certain degree of variability in the value or range, for example, within 10%, within 5%, or within 1% of the value or range limit, and includes the exact value or range. As used herein, the term "substantially" refers to a large part or majority, such as at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. As used herein, the phrase "substantially free" may mean having no or insignificant amounts of a material such that the amount of material present does not affect the material properties of the composition including the material, such that the material comprises about 0% to about 5% by weight or about 0% to about 1% by weight or about 5% by weight or less or less than or equal to about 4.5%, 4%, 3.5%, 3%, 2.5%, 2%, 1.5%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.01%, or about 0.001% by weight or less or about 0% by weight of the composition.
如本文所用，术语“粘附”和“附着”是广义术语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)例如通过粘合、键合、抓握、相互渗透或融合而保持、结合或粘住。As used herein, the terms "adhere" and "attach" are broad terms and will be given their ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refer to (but are not limited to) holding, combining or sticking, such as by adhesion, bonding, grasping, interpenetration or fusion.
如本文所用，术语“分析物”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)在生物流体(例如，血液、间质液、脑脊髓液、淋巴液、尿液、汗液、唾液等)中可被分析的物质或化学成分。分析物可以包括天然存在的物质、人造物质、代谢物和/或反应产物。在一些示例中，由感测区域、感测设备和感测方法测量的分析物是葡萄糖。然而，也考虑其他分析物，包括但不限于羧基凝血酶原；酰基肉碱；腺嘌呤磷酸核糖转移酶；腺苷脱氨酶；白蛋白；甲胎蛋白；氨基酸谱(精氨酸(克雷布斯循环)、组氨酸/尿刊酸、高半胱氨酸、苯丙氨酸/酪氨酸、色氨酸)；雄烯二酮；安替比林；阿拉伯糖醇对映体；精氨酸酶；苯甲酰芽子碱(可卡因)；胆红素、生物素酶；生物蝶呤；c-反应蛋白；肉毒碱；肌肽酶；CD4；血浆铜蓝蛋白；鹅去氧胆酸；氯喹；胆固醇；胆碱酯酶；缀合的1-β羟基-胆酸；皮质醇；肌酸；肌酸激酶；肌酸激酶MM同功酶；肌酸酐；环孢菌素A；d-青霉胺；去乙基氯喹；硫酸脱氢表雄酮；DNA(乙酰化酶多态性、醇脱氢酶、α1-抗胰蛋白酶、囊性纤维化、杜氏营养不良症/贝克型肌肉萎缩症、葡糖-6-磷酸脱氢酶、血红蛋白A、血红蛋白S、血红蛋白C、血红蛋白D、血红蛋白E、血红蛋白F、D-旁遮普、β-地中海贫血、乙型肝炎病毒、HCMV、HIV-1、HTLV-1、莱伯遗传性视神经病变、MCAD、RNA、PKU、间日疟原虫、21-脱氧皮质醇)；去丁基卤泛群；二氢蝶啶还原酶；白喉/破伤风抗毒素；红细胞精氨酸酶；红细胞原卟啉；酯酶D；脂肪酸/酰基甘氨酸；游离β-人绒毛膜促性腺激素；游离红细胞卟啉；游离甲状腺素(FT4)；游离三碘甲状腺原氨酸(FT3)；富马酰乙酰乙酸酶；半乳糖/gal-1-磷酸；半乳糖-1-磷酸尿苷酰转移酶；庆大霉素；葡萄糖-6-磷酸脱氢酶；谷胱甘肽；谷胱甘肽过氧化物酶；甘油；甘氨胆酸；糖基化血红蛋白；卤泛群；血红蛋白变体；己糖胺酶A；人红细胞碳酸酐酶I；17-α-羟孕酮；次黄嘌呤磷酸核糖转移酶；免疫反应性胰蛋白酶；β-羟基丁酸酯；酮；乳酸盐；铅；脂蛋白((a)、B/A-1、β)；溶菌酶；甲氟喹；奈替米星；氧；苯巴比妥；苯妥英；植烷酸/降植烷酸；钾、钠和/或其他血液电解质；孕酮；催乳素；脯氨酸酶；嘌呤核苷磷酸化酶；奎宁；反向三碘甲状腺原氨酸(rT3)；硒；血清胰脂肪酶；西索米星；生长调节素C；特异性抗体(腺病毒、抗核抗体、抗ζ抗体、虫媒病毒、奥耶斯基病病毒、登革热病毒、麦地那龙线虫、细粒棘球绦虫、痢疾阿米巴、肠道病毒、贾第鞭毛虫属、幽门螺杆菌、乙型肝炎病毒、疱疹病毒、HIV-1、IgE(特应性疾病)、流感病毒、杜氏利什曼原虫、钩端螺旋体、麻疹/痄腮/风疹、麻风分枝杆菌、肺炎支原体、肌红蛋白、盘尾丝虫、副流感病毒、恶性疟原虫、脊髓灰质炎病毒、铜绿假单胞菌、呼吸道合胞病毒、立克次氏体(恙虫病)、曼氏血吸虫、刚地弓形虫、苍白密螺旋体、克氏锥虫/兰氏锥虫、水泡性气孔炎病毒、班氏吴策线虫、黄热病病毒)；特异性抗原(乙型肝炎病毒，HIV-1)；琥珀酰基丙酮；磺胺多辛；茶碱；促甲状腺素(TSH)；甲状腺素(T4)；甲状腺素结合球蛋白；微量元素；转铁蛋白；UDP-半乳糖-4-差向异构酶；脲；尿酸；尿卟啉原I合酶；维生素A；白血细胞；以及锌原卟啉。在某些示例中，血液或间质液中天然存在的盐、糖、蛋白质、脂肪、维生素和激素也可以构成分析物。分析物可以天然存在于生物流体中，或者是内源性的，例如代谢产物、激素、抗原、抗体等。另选地，分析物可以被引入体内或为外源性的，例如用于成像的造影剂、放射性同位素、化学试剂、基于碳氟化合物的合成血液、或药物或药物组合物，包括但不限于胰岛素；乙醇；大麻(大麻、四氢大麻酚、印度大麻)；吸入剂(一氧化二氮、亚硝酸戊酯、亚硝酸丁酯、氯代烃、烃)；可卡因(裂解可卡因)；兴奋剂(安非他明、甲基苯丙胺、)；镇静剂(巴比妥类、甲喹酮、安定剂诸如)；致幻剂(苯环利定、麦角酸、墨斯卡灵、皮约特、裸盖菇素)；麻醉剂(海洛因、可待因、吗啡、鸦片、哌替啶、/>芬太尼、/>TALWIN、/>)；特制药物(芬太尼、哌替啶、苯丙胺、甲基苯丙胺和苯环利定的类似物，例如，摇头丸)；合成代谢类固醇；以及烟碱。药物和药物组合物的代谢产物也是预期的分析物。还可以分析体内产生的分析物诸如神经化学物质和其他化学物质，例如抗坏血酸、尿酸、多巴胺、去甲肾上腺素、3-甲氧基酪胺(3MT)、3,4-二羟基苯乙酸(DOPAC)、高香草酸(HVA)、5-羟基色胺(5HT)和5-羟基吲哚乙酸(FHIAA)以及组胺。As used herein, the term "analyte" is a broad term and will be given its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) a substance or chemical component that can be analyzed in a biological fluid (e.g., blood, interstitial fluid, cerebrospinal fluid, lymph, urine, sweat, saliva, etc.). Analytes can include naturally occurring substances, artificial substances, metabolites, and/or reaction products. In some examples, the analyte measured by the sensing region, sensing device, and sensing method is glucose. However, other analytes are also contemplated, including but not limited to carboxyprothrombin; acylcarnitines; adenine phosphoribosyltransferase; adenosine deaminase; albumin; alpha-fetoprotein; amino acid profile (arginine (Krebs cycle), histidine/urocanic acid, homocysteine, phenylalanine/tyrosine, tryptophan); androstenedione; antipyrine; arabinitol enantiomers; arginase; benzoylecgonine (cocaine); bilirubin, biotinidase; biopterin; c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin; chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase; conjugated 1-beta hydroxy-cholic acid; cortisol; creatine; creatine kinase; creatine kinase MM isozyme; creatinine; cyclosporin A; d-penicillamine; desethylchloroquine; dehydroepiandrosterone sulfate; DNA (acetylase polymorphisms, alcohol dehydrogenase, alpha 1-antitrypsin, cystic fibrosis, Duchenne dystrophy/ Becker muscular dystrophy, glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S, hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax, 21-deoxycortisol); desbutyl halofantrine; dihydropteridine reductase; diphtheria/tetanus antitoxin; erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty acids/acylglycines; free beta-human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine (FT4); free triiodothyronine (FT3); fumaryl acetoacetase; galactose/gal-1-phosphate; galactose-1-phosphate uridyltransferase; gentamicin; glucose-6-phosphate dehydrogenase; glutathione; glutathione Glycine peroxidase; glycerol; glycocholic acid; glycosylated hemoglobin; halofantrine; hemoglobin variants; hexosaminidase A; human erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone; hypoxanthine phosphoribosyltransferase; immunoreactive trypsin; beta-hydroxybutyrate; ketone; lactate; lead; lipoprotein ((a), B/A-1, beta); lysozyme; mefloquine; netilmicin; oxygen; phenobarbital; phenytoin; phytanic acid/pristanic acid; potassium , sodium, and/or other blood electrolytes; progesterone; prolactin; prolinase; purine nucleoside phosphorylase; quinine; reverse triiodothyronine (rT3); selenium; serum pancreatic lipase; sisomicin; somatomedin C; specific antibodies (adenovirus, antinuclear antibody, anti-ζ antibody, arbovirus, Aujeskey's disease virus, dengue virus, Guinea worm, Echinococcus granulosus, Entamoeba histolytica, enterovirus, Giardia lamblia, Helicobacter pylori , hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease), influenza virus, Leishmania donovani, Leptospira, measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae, myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium falciparum, polio virus, Pseudomonas aeruginosa, respiratory syncytial virus, Rickettsia (tsutsugamushi disease), Schistosoma mansoni, Toxoplasma gondii, Treponema pallidum, Trypanosoma cruzi / lamblia trypanosoma, vesicular stoma virus, Wuchereria bancrofti, yellow fever virus); specific antigens (hepatitis B virus, HIV-1); succinylacetone; sulfadoxine; theophylline; thyroid stimulating hormone (TSH); thyroxine (T4); thyroxine binding globulin; trace elements; transferrin; UDP-galactose-4-epimerase; urea; uric acid; uroporphyrinogen I synthase; vitamin A; white blood cells; and zinc protoporphyrin. In some examples, salts, sugars, proteins, fats, vitamins, and hormones naturally present in blood or interstitial fluids may also constitute analytes. Analytes may be naturally present in biological fluids or may be endogenous, such as metabolites, hormones, antigens, antibodies, etc. Alternatively, the analyte may be introduced into the body or exogenous, such as contrast agents for imaging, radioisotopes, chemical agents, fluorocarbon-based synthetic blood, or drugs or drug compositions, including but not limited to insulin; ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants (nitrous oxide, amyl nitrite, butyl nitrite, chlorinated hydrocarbons, hydrocarbons); cocaine (crack cocaine); stimulants (amphetamine, methamphetamine, ); sedatives (barbiturates, methaqualone, tranquilizers such as ); Hallucinogens (phencyclidine, lysergic acid, mescaline, pyotr, psilocybin); Anesthetics (heroin, codeine, morphine, opium, pethidine, /> Fentanyl,/> TALWIN,/> ); designer drugs (fentanyl, pethidine, amphetamine, methamphetamine, and analogs of phencyclidine, e.g., ecstasy); anabolic steroids; and nicotine. Metabolites of drugs and pharmaceutical compositions are also contemplated analytes. Analytes produced in the body such as neurochemicals and other chemicals, e.g., ascorbic acid, uric acid, dopamine, norepinephrine, 3-methoxytyramine (3MT), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5HT), and 5-hydroxyindoleacetic acid (FHIAA), and histamine may also be analyzed.
如本文所用，短语“分析物测量设备”、“分析物监测设备”、“分析物感测设备”、“连续分析物感测设备”、“连续分析物传感器设备”和/或“多分析物传感器设备”是广义的短语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于)负责检测或转导与特定分析物或分析物组合相关联的信号的装置和/或系统。例如，这些短语可指(但不限于)负责检测特定分析物或分析物组合的仪器。在一个示例中，该仪器包括传感器，该传感器耦合到设置在外壳内的电路，并且被配置为将与分析物浓度相关联的信号处理成信息。在一个示例中，此类装置和/或系统能够使用与转导和/或检测元件组合的生物识别元件来提供特定的定量、半定量、定性和/或半定性分析信息。As used herein, the phrases "analyte measuring device," "analyte monitoring device," "analyte sensing device," "continuous analyte sensing device," "continuous analyte sensor device," and/or "multi-analyte sensor device" are broad phrases and will be given their ordinary and customary meanings (and not limited to special or customized meanings) to one of ordinary skill in the art, and refer to (but are not limited to) devices and/or systems responsible for detecting or transducing signals associated with a particular analyte or combination of analytes. For example, these phrases may refer to (but are not limited to) an instrument responsible for detecting a particular analyte or combination of analytes. In one example, the instrument includes a sensor coupled to a circuit disposed within a housing and configured to process signals associated with analyte concentrations into information. In one example, such a device and/or system is capable of using a biorecognition element in combination with a transduction and/or detection element to provide specific quantitative, semi-quantitative, qualitative, and/or semi-qualitative analytical information.
如本文所用，短语“屏障细胞层”是广义短语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)形成基本上阻断分子和其他物质向可植入设备的转运的细胞(例如，巨噬细胞和异物巨细胞)粘着单层的异物反应的一部分。As used herein, the phrase "barrier cell layer" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) the part of the foreign body response that forms an adherent monolayer of cells (e.g., macrophages and foreign body giant cells) that substantially blocks the transport of molecules and other substances to the implantable device.
如本文所用，短语和术语“生物活性剂”和“生物活性物质”是广义的术语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于)对活组织具有影响或引发活组织的应答的任何物质，例如药物、生物制剂、活性氧清除剂(ROS)和金属离子。As used herein, the phrases and terms "bioactive agent" and "bioactive substance" are broad terms and will be given their ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refer to (but not limited to) any substance that has an effect on living tissue or induces a response in living tissue, such as drugs, biologics, reactive oxygen species scavengers (ROS), and metal ions.
如本文可互换使用的，短语“生物界面膜”、“生物界面域”和“生物界面层”是广义的短语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于)在受者组织与可植入设备之间用作生物保护性界面的可渗透膜(其可包括多个域)或层。术语“生物界面”和“生物保护性”在本文可互换使用。As used interchangeably herein, the phrases "biointerface membrane," "biointerface domain," and "biointerface layer" are broad phrases and will be given their ordinary and customary meanings to one of ordinary skill in the art (and are not limited to special or customary meanings), and refer to (but are not limited to) a permeable membrane (which may include multiple domains) or layer that serves as a bioprotective interface between a recipient tissue and an implantable device. The terms "biointerface" and "bioprotective" are used interchangeably herein.
如本文所用，术语“生物传感器”和/或“传感器”是广义的术语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于)分析物测量设备、分析物监测设备、分析物感测设备、连续分析物感测设备、连续分析物传感器设备和/或多分析物传感器设备的一部分，该部分负责检测或转导与特定分析物或分析物组合相关联的信号。在示例中，生物传感器或传感器通常包括主体、工作电极、参比电极和/或反电极，这些电极联接到主体并且形成被配置为在电化学反应期间提供信号的表面。一个或多个膜可固定到主体并覆盖电化学反应表面。在示例中，此类生物传感器和/或传感器能够使用与检测和/或转导元件组合的生物识别元件来提供特定的定量、半定量、定性、半定性分析信号。As used herein, the terms "biosensor" and/or "sensor" are broad terms and will be given their ordinary and customary meanings (and not limited to special or customized meanings) to those of ordinary skill in the art, and refer to (but not limited to) a portion of an analyte measuring device, an analyte monitoring device, an analyte sensing device, a continuous analyte sensing device, a continuous analyte sensor device, and/or a multi-analyte sensor device that is responsible for detecting or transducing a signal associated with a specific analyte or analyte combination. In an example, a biosensor or sensor typically includes a body, a working electrode, a reference electrode, and/or a counter electrode that are coupled to the body and form a surface configured to provide a signal during an electrochemical reaction. One or more membranes may be fixed to the body and cover the electrochemical reaction surface. In an example, such biosensors and/or sensors are capable of providing specific quantitative, semi-quantitative, qualitative, semi-qualitative analytical signals using a biorecognition element combined with a detection and/or transduction element.
如本文所用，术语“生物稳定”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)相对抵抗被体内遇到的过程降解的材料。As used herein, the term "biostable" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) materials that are relatively resistant to degradation by processes encountered in the body.
如本文所用，短语“细胞过程”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)细胞伪足。As used herein, the phrase "cellular process" is a broad term and is to be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customary meaning), and refers to, but is not limited to, cytopodia.
如本文所用，短语“细胞附着”是广义短语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)细胞和/或细胞过程在分子水平上粘附到材料上，和/或细胞和/或细胞过程附着到微孔材料表面或大孔材料表面上。现有技术中使用的促进细胞附着到其多孔表面上的材料的一个示例是由Millipore(Bedford,Mass.)销售的BIOPORETM细胞培养支持物，并且如Brauker等人的美国专利号5,741,330中所述。As used herein, the phrase "cell attachment" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) the adhesion of cells and/or cellular processes to a material at a molecular level, and/or the attachment of cells and/or cellular processes to a microporous material surface or a macroporous material surface. An example of a material used in the prior art that promotes cell attachment to its porous surface is the BIOPORE™ cell culture support sold by Millipore (Bedford, Mass.), and as described in U.S. Pat. No. 5,741,330 to Brauker et al.
如本文所用，术语“包含”与“包括”、“含有”或“以...为特征”同义，并且是包含性的或开放式的，并且不排除附加的、未列举的元素或方法步骤。As used herein, the term "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
如本文所用，术语“缀合物”是广义的术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于)通过连接子共价连接到载体或纳米载体诸如聚合物(例如，生物活性物质释放膜或生物界面层)的生物活性剂，该连接子是生物活性的，因为当暴露于或存在于生物环境诸如皮下或经皮环境时能够允许药物从载体分离。如本文所用，缀合物包括药物释放层-生物活性剂缀合物和纳米颗粒聚合物-生物活性剂缀合物。合适的载体/纳米载体包括PEG和N-(2-羟丙基)甲基丙烯酰胺(HPMA)、聚谷氨酸(PGA)以及它们的共聚物。如本文所用，缀合物包括药物释放层-生物活性剂缀合物和存在于药物释放层中的纳米颗粒聚合物-生物活性剂缀合物。在示例中，生物活性物质释放膜包括具有药物释放-生物活性剂缀合物的域和具有生物活性剂贮库的域，其中所述域可空间垂直或水平布置。As used herein, the term "conjugate" is a broad term and will be given its ordinary and customary meaning (and not limited to a special or customized meaning) to those of ordinary skill in the art, and refers to (but not limited to) a bioactive agent covalently linked to a carrier or nanocarrier such as a polymer (e.g., a bioactive substance release membrane or a biointerface layer) through a linker, which is bioactive because it can allow the drug to separate from the carrier when exposed to or present in a biological environment such as a subcutaneous or transdermal environment. As used herein, conjugates include drug release layer-bioactive agent conjugates and nanoparticle polymer-bioactive agent conjugates. Suitable carriers/nanocarriers include PEG and N-(2-hydroxypropyl) methacrylamide (HPMA), polyglutamic acid (PGA) and copolymers thereof. As used herein, conjugates include drug release layer-bioactive agent conjugates and nanoparticle polymer-bioactive agent conjugates present in the drug release layer. In an example, the bioactive substance release membrane includes a domain with a drug release-bioactive agent conjugate and a domain with a bioactive agent reservoir, wherein the domains can be arranged vertically or horizontally in space.
如本文所用，术语“连续”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)不间断或连续的部分、域、涂层或层。As used herein, the term "continuous" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) an uninterrupted or continuous portion, domain, coating or layer.
如本文所用，短语“连续分析物感测”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)连续地、持续地或间歇地(但定期地)(例如，约每5秒或更短时间至约10分钟或更长时间一次)执行分析物浓度的监测的时间段。在另外的示例中，约每10秒、15秒、20秒、25秒、30秒、35秒、40秒、45秒、50秒、55秒或60秒至约1.25分钟、1.50分钟、1.75分钟、2.00分钟、2.25分钟、2.50分钟、2.75分钟、3.00分钟、3.25分钟、3.50分钟、3.75分钟、4.00分钟、4.25分钟、4.50分钟、4.75分钟、5.00分钟、5.25分钟、5.50分钟、5.75分钟、6.00分钟、6.25分钟、6.50分钟、6.75分钟、7.00分钟、7.25分钟、7.50分钟、7.75分钟、8.00分钟、8.25分钟、8.50分钟、8.75分钟、9.00分钟、9.25分钟、9.50分钟或9.75分钟一次执行分析物浓度的监测。As used herein, the phrase "continuous analyte sensing" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) a period of time during which monitoring of analyte concentration is performed continuously, continuously, or intermittently (but regularly) (e.g., about every 5 seconds or less to about 10 minutes or more). In other examples, about every 10 seconds, 15 seconds, 20 seconds, 25 seconds, 30 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, or 60 seconds to about 1.25 minutes, 1.50 minutes, 1.75 minutes, 2.00 minutes, 2.25 minutes, 2.50 minutes, 2.75 minutes, 3.00 minutes, 3.25 minutes, 3.50 minutes, 3.75 minutes, 4.00 minutes, 4.25 minutes, 4.50 minutes, 4.75 minutes, Monitoring of analyte concentration is performed once every 5 minutes, 5.00 minutes, 5.25 minutes, 5.50 minutes, 5.75 minutes, 6.00 minutes, 6.25 minutes, 6.50 minutes, 6.75 minutes, 7.00 minutes, 7.25 minutes, 7.50 minutes, 7.75 minutes, 8.00 minutes, 8.25 minutes, 8.50 minutes, 8.75 minutes, 9.00 minutes, 9.25 minutes, 9.50 minutes or 9.75 minutes.
如本文所用，术语“耦合”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)两个或更多个系统元件或部件被配置为电子地附接、机械地附接、热附接、可操作地附接、在化学上附接或以其他方式附接中的至少一种。类似地，如本文所用的短语“可操作地连接”、“可操作地链接”和“可操作地耦合”可以指一个或多个部件以促进部件之间的至少一个信号的传输的方式联结到另一部件上。在一些示例中，部件是相同结构的一部分和/或彼此集成(即，“直接耦合”)。在其他示例中，部件经由远程装置连接。例如，一个或多个电极可以用于检测样品中的分析物并且将该信息转换成信号；然后可以将该信号传输到电路。在该示例中，电极“可操作地链接”到电子电路。如本文所用的短语“可移除地耦合”可以指两个或更多个系统元件或部件被配置为或被配置为已经电子地、机械地、热地、可操作地、在化学上或以其他方式附接并且在不损坏任何耦合的元件或部件的情况下被分离。如本文所用的短语“永久地耦合”可以指两个或更多个系统元件或部件被配置为或被配置为已经电子地、机械地、热地、可操作地、在化学上或以其他方式附接，但是在不损坏耦合的元件或部件中的至少一个的情况下不能被解耦合。As used herein, the term "coupling" is a broad term, and will give its common and customary meaning (and not limited to special or customized meaning) to those of ordinary skill in the art, and refers to (but not limited to) two or more system elements or components are configured to be attached electronically, mechanically, thermally, operably, chemically or otherwise attached. At least one. Similarly, the phrases "operably connected", "operably linked" and "operably coupled" as used herein can refer to one or more components being connected to another component in a manner that promotes the transmission of at least one signal between components. In some examples, components are part of the same structure and/or integrated with each other (i.e., "direct coupling"). In other examples, components are connected via remote devices. For example, one or more electrodes can be used to detect analytes in a sample and convert the information into a signal; the signal can then be transmitted to the circuit. In this example, the electrode is "operably linked" to the electronic circuit. As used herein, the phrase "removably coupled" may refer to two or more system elements or components being configured or being configured to have been attached electronically, mechanically, thermally, operatively, chemically, or otherwise and being separated without damaging any of the coupled elements or components. As used herein, the phrase "permanently coupled" may refer to two or more system elements or components being configured or being configured to have been attached electronically, mechanically, thermally, operatively, chemically, or otherwise, but cannot be decoupled without damaging at least one of the coupled elements or components.
如本文所用，术语“确定的边缘”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)在层、域、涂层或部分之间裂状的明显边缘或边界。“确定的边缘”与在层、域、涂层或部分之间的逐渐过渡相反。As used herein, the term "defined edge" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) a distinct edge or boundary that is split between layers, domains, coatings, or portions. A "defined edge" is in contrast to a gradual transition between layers, domains, coatings, or portions.
如本文所用，术语“不连续”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)不连贯的、间断的或分离的部分、层、涂层或域。As used herein, the term "discontinuous" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) a discontinuous, intermittent or separated portion, layer, coating or domain.
如本文所用，术语“远的”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)区域与参比的点(诸如起点或附接点)间隔相对较远。As used herein, the term "distal" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) an area that is relatively far away from a reference point (such as a starting point or attachment point).
如本文所用，术语“域”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)膜系统的区域，其可以是层、均匀或非均匀梯度(例如，膜的各向异性区域)，或能够感测一种、两种或更多种分析物的膜的部分。本文所讨论的域可以形成为单层、两层或更多层、双层对或它们的组合。As used herein, the term "domain" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) a region of a membrane system, which can be a layer, a uniform or non-uniform gradient (e.g., an anisotropic region of a membrane), or a portion of a membrane capable of sensing one, two or more analytes. The domains discussed herein can be formed as a single layer, two or more layers, a bilayer pair, or a combination thereof.
如本文所用，术语“漂移”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)与受者系统分析物浓度(例如，受者餐后葡萄糖浓度)变化无关的随时间推移的信号进行性增加或减少。虽然不希望受理论所束缚，但据信漂移可能是葡萄糖向传感器的转运的局部减少的结果，例如，由于异物囊(FBC)的形成。还据信传感器周围的间质液的量不足可能导致向传感器转运的氧和/或葡萄糖减少。在一个示例中，局部间质液的增加可以减缓或减少漂移并且因此改善传感器性能。漂移还可以是传感器电子器件或用于补偿噪声或其他异常的算法模型的结果，所述噪声或其他异常可以与包括微安培范围、微微安培范围、纳安培范围和毫微微安培范围的范围内的电信号一起发生。As used herein, the term "drift" is a broad term, and will be given its common and customary meaning (and not limited to a special or customized meaning) to those of ordinary skill in the art, and refers to (but not limited to) a progressive increase or decrease in the signal over time that is unrelated to changes in the analyte concentration of the recipient system (e.g., the recipient's postprandial glucose concentration). Although it is not desired to be bound by theory, it is believed that drift may be the result of a local reduction in the transport of glucose to the sensor, for example, due to the formation of a foreign body capsule (FBC). It is also believed that the amount of interstitial fluid around the sensor may result in a reduction in oxygen and/or glucose transported to the sensor. In one example, an increase in local interstitial fluid can slow down or reduce drift and thus improve sensor performance. Drift can also be the result of sensor electronics or an algorithm model for compensating for noise or other anomalies, which can occur with electrical signals in the range of microampere ranges, picoampere ranges, nanoampere ranges, and femtoampere ranges.
短语“生物活性物质释放膜”和“药物释放层”以及“生物活性物质释放域”和“生物活性剂释放膜”在本文中可互换使用，并且各自为广义的短语，并且各自将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于)可渗透一种或多种生物活性剂的可渗透膜或半透性膜。在示例中，“生物活性物质释放膜”和“药物释放层”以及“生物活性物质释放域”和“生物活性剂释放膜”可由两个或更多个域组成，并且通常具有几微米或更大的厚度。在示例中，生物活性物质释放膜和/或生物活性物质释放膜和/或生物活性剂释放膜和/或和生物活性剂释放膜与生物界面层和/或生物界面膜基本上相同。在另一示例中，生物活性物质释放膜和/或生物活性物质释放膜和/或生物活性剂释放膜和/或和生物活性剂释放膜不同于生物界面层和/或生物界面膜。The phrases "bioactive substance release membrane" and "drug release layer" and "bioactive substance release domain" and "bioactive agent release membrane" are used interchangeably herein, and each is a broad phrase, and each will be given its ordinary and customary meaning (and not limited to a special or customized meaning) to a person of ordinary skill in the art, and refers to (but not limited to) a permeable membrane or semipermeable membrane that is permeable to one or more bioactive agents. In an example, the "bioactive substance release membrane" and "drug release layer" and "bioactive substance release domain" and "bioactive agent release membrane" may be composed of two or more domains, and generally have a thickness of several microns or more. In an example, the bioactive substance release membrane and/or the bioactive substance release membrane and/or the bioactive agent release membrane and/or and the bioactive agent release membrane are substantially the same as the biointerface layer and/or the biointerface membrane. In another example, the bioactive substance release membrane and/or the bioactive substance release membrane and/or the bioactive agent release membrane and/or and the bioactive agent release membrane are different from the biointerface layer and/or the biointerface membrane.
如本文所用，术语“电化学反应表面”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)发生电化学反应的电极的表面。在示例中，由被检测分析物的酶催化反应产生的过氧化氢反应可产生可测量的电子流。例如，在葡萄糖的检测中，葡萄糖氧化酶产生过氧化氢(H2O2)作为副产物。H2O2与工作电极的表面反应，产生两个质子(2H+)、两个电子(2e-)和一个氧分子(O2)，从而产生所检测到的电子流。在反电极中，可还原物质(例如O2)在电极表面被还原，以便平衡由工作电极产生的电流。在另一个示例中，在转导元件和分析物的还原-氧化(氧化还原)期间使用介体或“有线酶(wired enzyme)”提供电子转移。As used herein, the term "electrochemical reaction surface" is a broad term and will be given its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) the surface of an electrode where an electrochemical reaction occurs. In an example, a hydrogen peroxide reaction produced by an enzyme-catalyzed reaction of the analyte being detected can produce a measurableelectron flow. For example, in the detection of glucose, glucose oxidase produces hydrogen peroxide (H2O2 ) as a byproduct.H2O2 reacts with the surface of the working electrode to produce two protons (2H+ ), two electrons (2e- ) and one oxygen molecule (O2 ), thereby producing the detected electron flow. In the counter electrode, the reducible species (e.g.,O2 ) is reduced at the electrode surface to balance the current generated by the working electrode. In another example, a mediator or "wired enzyme" is used to provide electron transfer during the reduction-oxidation (redox) of the transduction element and the analyte.
如本文所用，短语“硬链段”是广义的短语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于)共聚物的元素，例如聚氨酯、聚碳酸酯聚氨酯或聚氨酯脲共聚物，其赋予抗性性质，例如抗弯曲性或抗扭曲性。术语“硬链段”还可表征为结晶、半结晶或玻璃状材料，其具有通过动态扫描量热法确定的通常高于环境温度的玻璃化转变温度(“Tg”)，并且通常由具有或不具有扩链剂的二异氰酸酯制成。As used herein, the phrase "hard segment" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customary meaning), and refers to (but is not limited to) an element of a copolymer, such as a polyurethane, polycarbonate polyurethane, or polyurethane urea copolymer, which imparts resistance properties, such as resistance to bending or twisting. The term "hard segment" may also be characterized as a crystalline, semi-crystalline, or glassy material having a glass transition temperature ("Tg") generally above ambient temperature as determined by dynamic scanning calorimetry, and is generally made from a diisocyanate with or without a chain extender.
如本文所用，术语“受者”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)哺乳动物，例如人类。As used herein, the term "recipient" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customary meaning), and refers to (but is not limited to) a mammal, such as a human.
如本文所用，术语“植入的”或“可植入的”是广义术语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)皮下(即，在皮肤与肌肉之间的脂肪层中)或经皮(即，穿透、进入或穿过完整皮肤)插入的物体(例如，传感器)，这可以产生具有体内部分和离体部分的传感器。As used herein, the terms "implanted" or "implantable" are broad terms and will be given their ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refer to (but are not limited to) an object (e.g., a sensor) that is inserted subcutaneously (i.e., in the fat layer between the skin and muscle) or percutaneously (i.e., penetrating, into, or through intact skin), which can result in a sensor having both an in vivo portion and an ex vivo portion.
如本文所用，短语“可插入表面区域”是广义短语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)分析物传感器的可插入部分的表面区域，包括但不限于在如本文所述的分析物传感器中使用的平坦(基本上平面的)和/或导线衬底的表面区域。As used herein, the phrase "insertable surface area" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) the surface area of the insertable portion of an analyte sensor, including but not limited to the surface area of a flat (substantially planar) and/or wire substrate used in an analyte sensor as described herein.
如本文所用，短语“可插入体积”是广义短语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)在如本文所述的分析物传感器的可插入部分的插入路径前方和旁边的体积、以及为了插入分析物传感器的可插入部分而在皮肤中制造的切口。可插入体积还包括径向地或与插入路径前方和旁边的体积垂直的至多5mm。As used herein, the phrase "insertable volume" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or custom meaning), and refers to (but is not limited to) the volume in front of and beside the insertion path of the insertable portion of the analyte sensor as described herein, and the incision made in the skin for inserting the insertable portion of the analyte sensor. The insertable volume also includes up to 5 mm radially or perpendicular to the volume in front of and beside the insertion path.
如本文所用，术语“干扰物”和“干扰性物质”是广义术语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)干扰传感器中感兴趣的分析物的测量以产生不准确地表示分析物测量的信号的效应和/或物质。在电化学传感器的示例中，干扰物质是具有与待测量的分析物或一种或多种介体重叠的氧化电位的化合物。As used herein, the terms "interferor" and "interfering substance" are broad terms and will be given their ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refer to (but not limited to) effects and/or substances that interfere with the measurement of an analyte of interest in a sensor to produce a signal that inaccurately represents the analyte measurement. In the example of an electrochemical sensor, an interfering substance is a compound with an oxidation potential that overlaps with the analyte to be measured or one or more mediators.
如本文所用，术语“体内”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且包括(但不限于此)适于插入受者活体内和/或存在于受者活体内的设备(例如，传感器)的部分。As used herein, the term "in vivo" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and includes (but is not limited to) parts of a device (e.g., a sensor) that are suitable for insertion into and/or presence within a recipient's living body.
如本文所用，术语“离体”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且包括(但不限于此)适于保留和/或存在于受者活体外部的设备(例如，传感器)的部分。As used herein, the term "ex vivo" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and includes (but is not limited to) parts of a device (e.g., a sensor) that are adapted to remain and/or exist outside the living body of a recipient.
如本文所用，术语“膜”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)被配置为执行以下功能的结构，该功能包括但不限于：保护暴露的电极表面免受生物环境影响、分析物的扩散阻力(限制)、充当用于使酶促反应能够进行的催化剂的基质、限制或阻断干扰物质、在传感器界面的电化学反应性表面处提供亲水性、充当受者组织和与可植入设备之间的界面、经由药物(或其他物质)释放调节受者组织反应、以及它们的组合。当在本文中使用时，术语“膜”和“基质”意在可互换使用。As used herein, the term "membrane" is a broad term and will be given its ordinary and customary meaning to those of ordinary skill in the art (and not limited to a special or custom meaning), and refers to (but not limited to) a structure configured to perform the following functions, including but not limited to: protection of exposed electrode surfaces from biological environments, diffusion resistance (restriction) of analytes, acting as a matrix for catalysts that enable enzymatic reactions, limiting or blocking interfering substances, providing hydrophilicity at electrochemically reactive surfaces of sensor interfaces, acting as an interface between recipient tissues and implantable devices, regulating recipient tissue reactions via drug (or other substance) release, and combinations thereof. When used herein, the terms "membrane" and "matrix" are intended to be used interchangeably.
如本文所用，短语“膜系统”是广义短语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)可以由两个或更多个域、两层或更多层或一个域内的两层或更多层组成并且通常由几微米或更大厚度的材料构成的可渗透膜或半透性膜，其可渗透氧并且任选地可渗透例如葡萄糖或另一种分析物。在示例中，膜系统包括固定化葡萄糖氧化酶，其使得能够在葡萄糖与氧之间发生反应，由此可测量葡萄糖浓度。As used herein, the phrase "membrane system" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) a permeable or semipermeable membrane that may be composed of two or more domains, two or more layers, or two or more layers within a domain and is typically composed of a material of a few microns or more thickness, which is permeable to oxygen and optionally permeable to, for example, glucose or another analyte. In an example, the membrane system includes immobilized glucose oxidase, which enables a reaction between glucose and oxygen, whereby glucose concentration can be measured.
如本文所用，术语“微小”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)在不放大的情况下不可见的大约10-6m的小物体或尺度。术语“微小”与术语“大”相反，术语“大”是指在不放大的情况下可见的大物体。类似地，术语“纳米”是指大约10-9m的小物体或尺度。As used herein, the term "micro" is a broad term and will be given its ordinary and customary meaning to those of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) small objects or scales of about10-6 m that are not visible without magnification. The term "micro" is in contrast to the term "large", which refers to large objects that are visible without magnification. Similarly, the term "nano" refers to small objects or scales of about10-9 m.
如本文所用，术语“噪声”是广义术语并且以其普通的含义使用，包括但不限于由传感器或传感器电子器件检测到的与分析物浓度无关并且可能导致传感器性能降低的信号。在传感器插入后的几个小时(例如，约2小时至约24小时)期间已经观察到一种类型的噪声。在前24小时之后，噪声可能消失或减少，但在一些受者中，噪声可能持续约三天至四天。在一些情况下，可以使用预测建模、人工智能和/或算法手段来减少噪声。在其他情况下，可通过诸如使用具有至少一种生物活性剂的生物活性物质释放膜解决与植入的传感器的存在相关联的免疫应答因子来减少噪声。例如，可以确定如本发明所公开的一种或多种示例性生物传感器的噪声，然后定性地或定量地比较。举例来说，通过获得具有固定取样间隔(以皮安培(pA)为单位)的原始信号时间序列，可以(例如)通过应用第3阶切比雪夫II型低通数字滤波器来获得原始信号时间序列的平滑版本。可以使用其他平滑算法。在每个采样间隔，可以计算以pA为单位的绝对差值，以提供平滑的时间序列。可以使用以pA/mg/dL为单位的葡萄糖灵敏度时间序列将该平滑的时间序列转换成以mg/dL为单位(“噪声”的单位)，其中通过使用原始信号与参比血糖测量(例如，从血糖仪获得)之间的数学模型来推导出葡萄糖灵敏度时间序列。任选地，时间序列可以根据需要聚集例如按小时或天来聚集。具有本发明所公开的生物活性物质释放膜和一种或多种生物活性剂的不同示例性生物传感器之间的对应时间序列的比较提供了噪声改善的定性或定量确定。As used herein, the term "noise" is a broad term and is used in its ordinary sense, including but not limited to signals detected by sensors or sensor electronics that are independent of analyte concentration and may cause sensor performance to decrease. One type of noise has been observed during a few hours (e.g., about 2 hours to about 24 hours) after sensor insertion. After the first 24 hours, the noise may disappear or decrease, but in some recipients, the noise may last for about three to four days. In some cases, predictive modeling, artificial intelligence and/or algorithmic means can be used to reduce noise. In other cases, noise can be reduced by solving immune response factors associated with the presence of implanted sensors, such as using a bioactive substance release membrane with at least one bioactive agent. For example, the noise of one or more exemplary biosensors disclosed in the present invention can be determined and then compared qualitatively or quantitatively. For example, by obtaining a raw signal time series with a fixed sampling interval (in picoamperes (pA)), a smoothed version of the raw signal time series can be obtained, for example, by applying a 3rd order Chebyshev II type low-pass digital filter. Other smoothing algorithms can be used. At each sampling interval, the absolute difference in pA can be calculated to provide a smoothed time series. The smoothed time series can be converted to mg/dL (the unit of "noise") using a glucose sensitivity time series in pA/mg/dL, where the glucose sensitivity time series is derived using a mathematical model between the raw signal and a reference blood glucose measurement (e.g., obtained from a blood glucose meter). Optionally, the time series can be aggregated as desired, such as by hour or day. Comparison of corresponding time series between different exemplary biosensors having a bioactive substance release membrane disclosed herein and one or more bioactive agents provides a qualitative or quantitative determination of noise improvement.
如本文所用，术语“任选的”或“任选地”是广义术语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)随后描述的事件或情况可以发生或不发生，并且该描述包括事件或情况发生的情形和事件或情况不发生的情形。As used herein, the terms "optional" or "optionally" are broad terms, and will be given their ordinary and customary meaning to those skilled in the art (and not limited to a special or customized meaning), and mean (but not limited to) that the subsequently described event or circumstance can occur or not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.
如本文所用，术语“聚两性电解质聚合物”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)包含阳离子和阴离子基团的聚合物。此类聚合物可以制备成具有大约相等数目的正电荷和负电荷，并且因此此类种聚合物的表面可以是大约净电荷中性的。另选地，此类种聚合物可以制备成具有过量的正电荷或负电荷，并且因此此类聚合物的表面可以分别是带净正电荷或带净负电荷的。“聚两性电解质聚合物”包括聚两性电解质的聚合物。As used herein, the term "polyampholyte polymer" is a broad term and will be given its common and customary meaning (and not limited to a special or customized meaning) to those of ordinary skill in the art, and refers to (but is not limited to) a polymer containing cationic and anionic groups. Such polymers can be prepared to have approximately equal numbers of positive and negative charges, and thus the surface of such polymers can be approximately net charge neutral. Alternatively, such polymers can be prepared to have excess positive or negative charges, and thus the surface of such polymers can be net positively charged or net negatively charged, respectively. "Polyampholyte polymers" include polymers of polyampholytes.
如本文所用，短语“聚合基团”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)允许单体与其自身聚合形成均聚物或与不同的单体聚合形成共聚物的官能团。根据所采用的聚合方法的类型，聚合基团可以选自烯烃、炔烃、环氧化物、内酯、胺、羟基、异氰酸酯、羧酸、酸酐、硅烷、卤化物、醛和碳二亚胺。As used herein, the phrase "polymeric group" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and is not limited to a special or customary meaning), and refers to (but is not limited to) a functional group that allows a monomer to polymerize with itself to form a homopolymer or with a different monomer to form a copolymer. Depending on the type of polymerization method employed, the polymeric group may be selected from olefins, alkynes, epoxides, lactones, amines, hydroxyls, isocyanates, carboxylic acids, anhydrides, silanes, halides, aldehydes, and carbodiimides.
如本文所用，术语“聚两性离子”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)其中聚合物链的重复单元是两性离子部分的聚合物。聚两性离子也称为聚甜菜碱(polybetaine)。由于聚两性离子同时具有阳离子和阴离子基团，因此它们是一类聚两性电解质的聚合物。然而，它们是独特的，因为阳离子基团和阴离子基团都是相同重复单元的一部分，这意味着聚两性离子具有相同数量的阳离子基团和阴离子基团，然而其他聚两性电解质的聚合物可以具有一种离子基团多于另一种离子基团。同样，聚两性离子具有阳离子基团和阴离子基团作为重复单元的一部分。聚两性电解质的聚合物不需要具有与阴离子基团连接的阳离子基团；它们可以在不同的重复单元上，并且因此可以以随机间隔彼此分开分布，或者一种离子基团的数目可以超过另一种离子基团的数目。As used herein, the term "polyzwitterion" is a broad term and will be given its common and customary meaning (and not limited to a special or custom meaning) to those of ordinary skill in the art, and refers to (but not limited to) a polymer in which the repeating unit of the polymer chain is a zwitterionic portion. Polyzwitterions are also called polybetaines. Since polyzwitterions have both cationic and anionic groups, they are a class of polymers of polyampholytes. However, they are unique because both the cationic group and the anionic group are part of the same repeating unit, which means that the polyzwitterion has the same number of cationic groups and anionic groups, whereas other polymers of polyampholytes may have one ionic group more than another. Similarly, polyzwitterions have cationic groups and anionic groups as part of a repeating unit. Polymers of polyampholytes do not need to have cationic groups connected to anionic groups; they can be on different repeating units, and therefore can be distributed separately from each other at random intervals, or the number of one ionic group can exceed the number of another ionic group.
如本文所用，术语“近的”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)与特定参比点比较在各种元件之间的空间关系。例如，设备的一些示例包括具有生物界面层和酶层的膜系统。如果传感器被认为是参比点并且酶层定位成比生物界面层更靠近传感器，则与生物界面层相比，酶层与传感器更近。As used herein, the term "close" is a broad term and will be given its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) the spatial relationship between various elements compared to a specific reference point. For example, some examples of devices include a membrane system having a biological interface layer and an enzyme layer. If a sensor is considered to be a reference point and the enzyme layer is positioned closer to the sensor than the biological interface layer, then the enzyme layer is closer to the sensor than the biological interface layer.
如本文所用，短语和术语“处理器模块”和“微处理器”各自是广义短语和术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)被设计为使用逻辑电路执行算术或逻辑运算的计算机系统、状态机、处理器等，该逻辑电路响应于并处理驱动计算机的基本指令。As used herein, the phrases and terms "processor module" and "microprocessor" are each broad phrases and terms and will be given their ordinary and customary meanings to those of ordinary skill in the art (and are not limited to special or customized meanings), and refer to (but are not limited to) a computer system, state machine, processor, etc. designed to perform arithmetic or logical operations using logic circuits that respond to and process the basic instructions that drive the computer.
如本文所用，术语“半连续”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)包括一个或多个连续和非连续部分、涂层、域或层的部分、涂层、域或层。例如，在感测区域周围而不是关于感测区域设置的涂层是“半连续的”。As used herein, the term "semi-continuous" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) a portion, coating, domain or layer that includes one or more continuous and non-continuous portions, coatings, domains or layers. For example, a coating that is disposed around a sensing area but not about the sensing area is "semi-continuous."
如本文所用，短语“感测部分”、“感测膜”、“感测区域”、“感测域”和/或“感测机构”是广义的短语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于)生物传感器和/或传感器的一部分，该部分负责检测或转导与特定分析物或分析物组合相关联的信号。在示例中，感测部分、感测膜和/或感测机构通常包括电极，该电极被配置为在与覆盖电化学反应性表面的一个或多个膜的电化学反应期间提供信号。在示例中，此类感测部分、感测膜和/或感测机构能够使用与检测和/或转导元件组合的生物识别元件来提供特定的定量、半定量、定性、半定性分析信号。As used herein, the phrases "sensing portion", "sensing film", "sensing region", "sensing domain" and/or "sensing mechanism" are broad phrases and will be given their ordinary and customary meanings (and not limited to special or customized meanings) to one of ordinary skill in the art, and refer to (but not limited to) a portion of a biosensor and/or sensor that is responsible for detecting or transducing a signal associated with a specific analyte or combination of analytes. In examples, the sensing portion, sensing film and/or sensing mechanism typically includes an electrode that is configured to provide a signal during an electrochemical reaction with one or more membranes covering an electrochemically reactive surface. In examples, such sensing portions, sensing films and/or sensing mechanisms are capable of providing specific quantitative, semi-quantitative, qualitative, semi-qualitative analytical signals using a biorecognition element combined with a detection and/or transduction element.
在分析物测量设备、生物传感器、传感器、感测区域、感测部分或感测机构的一般操作期间，生物样品(例如血液或间质液)或其组分直接地或在穿过一个或多个膜之后接触酶(例如葡萄糖氧化酶)或蛋白质(例如具有一个或多个分析物结合区域的一种或多种周质结合蛋白(PBP)或其突变体或融合蛋白，每个区域能够特异性地且可逆地结合至少一种分析物)。生物样品或其组分与分析物测量设备、生物传感器、传感器、感测区域、感测部分或感测机构的相互作用导致信号转导，所述信号转导允许定性、半定性、定量或半定量确定生物样品中的分析物水平，例如葡萄糖。During the general operation of the analyte measurement device, biosensor, sensor, sensing region, sensing portion or sensing mechanism, a biological sample (e.g., blood or interstitial fluid) or a component thereof is contacted with an enzyme (e.g., glucose oxidase) or a protein (e.g., one or more periplasmic binding proteins (PBPs) or mutants or fusion proteins thereof having one or more analyte binding regions, each region being capable of specifically and reversibly binding at least one analyte) directly or after passing through one or more membranes. The interaction of the biological sample or a component thereof with the analyte measurement device, biosensor, sensor, sensing region, sensing portion or sensing mechanism results in signal transduction, which allows for qualitative, semi-qualitative, quantitative or semi-quantitative determination of the level of an analyte, such as glucose, in the biological sample.
在示例中，感测区域或感测部分可包括导电衬底的至少一部分或导电表面的至少一部分(例如导线或导电迹线或包括基本上平面的迹线的基本上平面的衬底)以及膜。在示例中，感测区域或感测部分可包括非导电主体；在该主体上的一个位置处形成电化学反应性表面并且在该主体上的另一位置处形成电子连接的工作电极、参比电极和反电极(任选的)；以及附着于该主体并且覆盖该电化学反应性表面的感测膜。在一些示例中，感测膜还包含酶域(例如酶层)和电解质相(例如包含下文进一步描述的含电解质流体的自由流动液相)。这些术语足够广泛以包括整个设备或仅其感测部分(或其间的某物)。In an example, the sensing region or sensing portion may include at least a portion of a conductive substrate or at least a portion of a conductive surface (e.g., a wire or conductive trace or a substantially planar substrate comprising a substantially planar trace) and a membrane. In an example, the sensing region or sensing portion may include a non-conductive body; a working electrode, a reference electrode, and a counter electrode (optional) that form an electrochemically reactive surface at one position on the body and form an electronic connection at another position on the body; and a sensing film attached to the body and covering the electrochemically reactive surface. In some examples, the sensing film also includes an enzyme domain (e.g., an enzyme layer) and an electrolyte phase (e.g., a free-flowing liquid phase containing an electrolyte fluid described further below). These terms are broad enough to include the entire device or only its sensing portion (or something in between).
在另一个示例中，感测区域可以包含具有一个或多个分析物结合区域的一种或多种周质结合蛋白(PBP)或其突变体或融合蛋白，每个区域能够特异性地且可逆地结合至少一种分析物。PBP的突变可以促成或改变一个或多个结合常数、延长的蛋白质稳定性(包括热稳定性)，以将蛋白质结合至特定的包封基质、膜或聚合物或者附着可检测的报告基团或“标记”以指示结合区域的变化。结合区域变化的具体示例包括但不限于疏水性/亲水性环境变化、三维构象变化、蛋白质结合区域中氨基酸侧链取向的变化和结合区域的氧化还原状态。结合区域的此类变化提供了与生物流体中存在的一种或多种分析物对应的可检测信号的转导。In another example, the sensing region may comprise one or more periplasmic binding proteins (PBPs) or mutants or fusion proteins thereof having one or more analyte binding regions, each region being capable of specifically and reversibly binding at least one analyte. Mutations in PBPs may contribute to or alter one or more binding constants, extended protein stability (including thermal stability), to bind the protein to a specific encapsulating matrix, membrane or polymer, or to attach a detectable reporter group or "label" to indicate changes in the binding region. Specific examples of changes in the binding region include, but are not limited to, changes in the hydrophobic/hydrophilic environment, changes in three-dimensional conformation, changes in the orientation of amino acid side chains in the protein binding region, and the redox state of the binding region. Such changes in the binding region provide transduction of a detectable signal corresponding to one or more analytes present in the biological fluid.
在示例中，感测区域确定一种或多种分析物之间的选择性，使得只有必须测量的分析物产生(转导)可检测信号。选择可以基于感测区域对分析物的任何化学或物理识别，其中分析物的化学组成未改变，或其中感测区域引起或催化分析物的反应，该反应改变分析物的化学组成。In an example, the sensing region determines the selectivity between one or more analytes so that only the analytes that must be measured produce (transduce) a detectable signal. The selection can be based on any chemical or physical recognition of the analyte by the sensing region, wherein the chemical composition of the analyte is not changed, or wherein the sensing region causes or catalyzes a reaction of the analyte that changes the chemical composition of the analyte.
感测区域将分析物的识别转导成半定量或定量信号。因此，如本文所用的“转导”(“transducing”或“transduction”)以及它们的语法等效物涵盖光学、电化学、声学/机械或比色技术和方法。电化学特性包括电流和/或电压、电容和电位。光学特性包括吸收、荧光/磷光、波长偏移、相位调制、生物/化学发光、反射率、光散射和折射率。The sensing region transduces the recognition of the analyte into a semi-quantitative or quantitative signal. Thus, as used herein, "transduction" ("transducing" or "transduction") and their grammatical equivalents encompass optical, electrochemical, acoustic/mechanical or colorimetric techniques and methods. Electrochemical properties include current and/or voltage, capacitance and potential. Optical properties include absorption, fluorescence/phosphorescence, wavelength shift, phase modulation, bio/chemiluminescence, reflectivity, light scattering and refractive index.
如本文所用，术语“灵敏度”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)由预定量(单位)的测量分析物产生的信号(例如，呈电流和/或电压的形式)的量。例如，对于每1mg/dL的葡萄糖分析物，传感器具有约1皮安培至约100皮安培电流的灵敏度(或斜率)。As used herein, the term "sensitivity" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) the amount of signal (e.g., in the form of current and/or voltage) generated by a predetermined amount (unit) of measured analyte. For example, for each 1 mg/dL of glucose analyte, the sensor has a sensitivity (or slope) of about 1 picoampere to about 100 picoamperes of current.
如本文所用的短语和术语“小直径传感器”、“小结构传感器”和“微传感器”是广义短语和术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)在至少一个维度上小于约2mm的感测机构。在另外的示例中，感测机构在至少一个维度上小于约1mm。在一些示例中，感测机构(传感器)小于约0.95mm、0.9mm、0.85mm、0.8mm、0.75mm、0.7mm、0.65mm、0.6mm、0.5mm、0.4mm、0.3mm、0.2mm或0.1mm。在一些示例中，感测机构的独立测量的长度、宽度、直径、厚度或周长的最大尺寸不超过约2mm。在一些示例中，感测机构是针型传感器，其中直径小于约1mm，参见例如授予Ward等人的美国专利号6,613,379和授予Brister等人的美国专利号7,497,827，这两篇专利全文以引用方式并入本文。在一些另选示例中，感测机构包括沉积在基本上平面的衬底上的电极，其中可植入部分的厚度小于约1mm，参见例如授予Say等人的美国专利号6,175,752和授予Mastrototaro等人的美国专利号5,779,665，这两篇专利均全文以引用方式并入本文。本文所讨论的形成传感器(传感器电极布局和膜)和传感器系统的方法的示例可见于当前未决的美国专利公开号2019-0307371(Boock等人)，该专利全文以引用方式并入本文。As used herein, the phrases and terms "small diameter sensor", "small structure sensor" and "microsensor" are broad phrases and terms and will be given their ordinary and customary meanings to those of ordinary skill in the art (and are not limited to special or customized meanings), and refer to (but are not limited to) sensing mechanisms that are less than about 2 mm in at least one dimension. In other examples, the sensing mechanism is less than about 1 mm in at least one dimension. In some examples, the sensing mechanism (sensor) is less than about 0.95 mm, 0.9 mm, 0.85 mm, 0.8 mm, 0.75 mm, 0.7 mm, 0.65 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm. In some examples, the largest dimension of the independently measured length, width, diameter, thickness, or circumference of the sensing mechanism does not exceed about 2 mm. In some examples, the sensing mechanism is a needle-type sensor, wherein the diameter is less than about 1 mm, see, for example, U.S. Patent No. 6,613,379 to Ward et al. and U.S. Patent No. 7,497,827 to Brister et al., both of which are incorporated herein by reference in their entirety. In some alternative examples, the sensing mechanism includes an electrode deposited on a substantially planar substrate, wherein the thickness of the implantable portion is less than about 1 mm, see, for example, U.S. Patent No. 6,175,752 to Say et al. and U.S. Patent No. 5,779,665 to Mastrototaro et al., both of which are incorporated herein by reference in their entirety. Examples of methods of forming sensors (sensor electrode layouts and membranes) and sensor systems discussed herein can be found in currently pending U.S. Patent Publication No. 2019-0307371 (Boock et al.), which is incorporated herein by reference in its entirety.
如本文所用，短语“软链段”是广义的短语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于)共聚物的元素，例如聚氨酯、聚碳酸酯聚氨酯或聚氨酯脲共聚物，其向链赋予柔性。短语“软链段”还可表征为具有低Tg(例如通常不高于环境温度或正常哺乳动物体温的Tg)的无定形材料。As used herein, the phrase "soft segment" is a broad phrase and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refers to (but is not limited to) an element of a copolymer, such as a polyurethane, polycarbonate polyurethane, or polyurethane urea copolymer, which imparts flexibility to the chain. The phrase "soft segment" can also be characterized as an amorphous material with a low Tg (e.g., a Tg that is generally no higher than ambient temperature or normal mammalian body temperature).
如本文所用，短语“固体部分”是广义术语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)膜材料的部分，其具有界定空腔、空隙或其他非固体部分的机械结构。As used herein, the phrase "solid portion" is a broad term and will be given its ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customized meaning), and refers to (but is not limited to) a portion of a membrane material that has a mechanical structure that defines a cavity, void, or other non-solid portion.
如本文所用，术语和短语“两性离子”和“两性离子化合物”各自是广义术语和短语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)其中化合物的中性分子在分子内的不同位置处具有单位正电荷和单位负电荷的化合物。此类化合物是一类偶极化合物，并且有时也称为“内盐”。As used herein, the terms and phrases "zwitterion" and "zwitterionic compound" are each broad terms and phrases and will be given their ordinary and customary meanings to those of ordinary skill in the art (and are not limited to special or customary meanings), and refer to (but are not limited to) compounds in which the neutral molecule of the compound has a unit positive charge and a unit negative charge at different positions within the molecule. Such compounds are a class of dipolar compounds and are sometimes also referred to as "inner salts".
如本文所用，短语“两性离子前体”或“两性离子化合物前体”是广义短语，并且将向本领域普通技术人员给出其普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)本身不是两性离子，但可以通过化学反应在最终或过渡状态下变成两性离子的任何化合物。在本文所述的一些示例中，设备包含两性离子前体，其可以在体内植入设备之前转化为两性离子。另选地，在本文所述的一些示例中，设备包含两性离子前体，其可以通过在设备体内植入之后发生的一些化学反应转化为两性离子。此类反应是本领域普通技术人员已知的并且包括开环反应、加成反应诸如迈克尔加成(Michael addition)。当含甜菜碱单体的聚合由于技术挑战诸如甜菜碱单体的溶解度而难以实现所需物理性质诸如分子量和机械强度时，该方法特别有用。甜菜碱前体的聚合后改性或转化可以是实现所需聚合物结构和组成的实用方式。此类前体的示例包括叔胺、季胺、吡啶和本文详述的其他物质。As used herein, the phrase "zwitterion precursor" or "zwitterionic compound precursor" is a broad phrase and will be given its ordinary and customary meaning to those of ordinary skill in the art (and is not limited to a special or customized meaning), and refers to (but is not limited to) any compound that is not a zwitterion itself, but can become a zwitterion in a final or transitional state through a chemical reaction. In some examples described herein, the device contains a zwitterion precursor, which can be converted to a zwitterion before the device is implanted in vivo. Alternatively, in some examples described herein, the device contains a zwitterion precursor, which can be converted to a zwitterion through some chemical reaction that occurs after the device is implanted in vivo. Such reactions are known to those of ordinary skill in the art and include ring-opening reactions, addition reactions such as Michael addition. This method is particularly useful when the polymerization of betaine-containing monomers is difficult to achieve the desired physical properties such as molecular weight and mechanical strength due to technical challenges such as the solubility of betaine monomers. Post-polymerization modification or conversion of betaine precursors can be a practical way to achieve the desired polymer structure and composition. Examples of such precursors include tertiary amines, quaternary amines, pyridines, and other substances detailed herein.
如本文所用，短语“两性离子衍生物”或“两性离子化合物衍生物”是广义短语，并且将向本领域普通技术人员给出它们的普通和惯用的含义(并且不限于特殊的或定制的含义)，并且是指(但不限于此)本身不是两性离子而是其中两性离子转化为非两性离子的化学反应的产物的任何化合物。此类反应可以是可逆的，使得在某些条件下两性离子衍生物可以充当两性离子前体。例如，由两性离子甜菜碱形成的可水解甜菜碱酯是阳离子两性离子衍生物，其在适当的条件下能够经历水解以恢复成两性离子甜菜碱。As used herein, the phrases "zwitterionic derivatives" or "zwitterionic compound derivatives" are broad phrases and will be given their ordinary and customary meaning to one of ordinary skill in the art (and not limited to a special or customary meaning), and refer to (but are not limited to) any compound that is not itself a zwitterion but is the product of a chemical reaction in which a zwitterion is converted to a non-zwitterion. Such reactions may be reversible, such that under certain conditions a zwitterionic derivative can act as a zwitterionic precursor. For example, a hydrolyzable betaine ester formed from a zwitterionic betaine is a cationic zwitterionic derivative that is capable of undergoing hydrolysis under appropriate conditions to revert to the zwitterionic betaine.
经皮插入或植入皮下组织的设备和探针通常引发异物反应(FBR)，其包括最终形成异物囊(FBC)的炎症细胞的侵入，作为身体对引入外来物质的反应的一部分。本文所讨论的连续监测系统包括连续分析物监测系统，其被配置为同时、顺序地和/或随机地监测一种、两种或更多种分析物(其包括可以独立地以皮秒、纳秒、毫秒、秒或分钟发生的事件)，以预测健康相关事件和健康系统性能(例如，人体系统(诸如循环系统、呼吸系统、消化系统或其他系统或器官或系统的组合)的当前和未来性能)。在示例中，设备(例如，葡萄糖感测设备)的插入或植入可能导致急性炎症反应，其消退为慢性炎症，同时建立纤维化组织，诸如上文详细描述的。最终，经过一段时间，在设备周围形成成熟的FBC，包括主要收缩的纤维组织。参见Shanker和Greisler,Inflammation and Biomaterials于：Greco RS，编辑，“Implantation Biology:The Host Response and Biomedical Devices”第68-80页，CRCPress(1994)。围绕常规植入设备的FBC已经显示阻碍或阻断穿过设备-组织界面的分析物转运。因此，通常认为体内连续延长寿命的分析物转运(例如，超过前几天)是不可靠或不可能的。Devices and probes inserted or implanted percutaneously into subcutaneous tissue typically trigger a foreign body reaction (FBR), which includes the invasion of inflammatory cells that eventually form a foreign body capsule (FBC) as part of the body's response to the introduction of foreign matter. The continuous monitoring system discussed herein includes a continuous analyte monitoring system that is configured to simultaneously, sequentially and/or randomly monitor one, two or more analytes (including events that can occur independently in picoseconds, nanoseconds, milliseconds, seconds or minutes) to predict health-related events and health system performance (e.g., current and future performance of human systems (such as circulatory systems, respiratory systems, digestive systems or other systems or organs or systems). In an example, the insertion or implantation of a device (e.g., a glucose sensing device) may result in an acute inflammatory response that subsides into chronic inflammation while establishing fibrotic tissue, such as described in detail above. Ultimately, over a period of time, a mature FBC is formed around the device, including primarily contracted fibrous tissue. See Shanker and Greisler, Inflammation and Biomaterials In: Greco RS, ed., "Implantation Biology: The Host Response and Biomedical Devices" pp. 68-80, CRC Press (1994). The FBC surrounding conventional implanted devices has been shown to impede or block analyte transport across the device-tissue interface. Therefore, it is generally believed that continuous extended life analyte transport in vivo (e.g., beyond the first few days) is unreliable or impossible.
在一些示例中，FBR的某些方面在前几天可能在噪声中起作用。已经观察到，一些传感器在插入后的前几个小时期间的功能比它们后来的功能的更差。这通过插入后的前几个小时(例如，约2小时至约24小时)期间信号的噪声和/或抑制来举例说明。这些异常通常自发地消退，之后传感器变得具有更少噪声，具有改善的灵敏度，并且比初期期间更准确。已经观察到，一些经皮传感器和完全可植入的传感器在应用于受者后(即经皮插入或完全植入皮肤下)一段时间经受噪声。In some examples, certain aspects of FBR may play a role in noise in the first few days. It has been observed that some sensors function worse during the first few hours after insertion than they function later. This is illustrated by noise and/or suppression of the signal during the first few hours (e.g., about 2 hours to about 24 hours) after insertion. These abnormalities usually resolve spontaneously, after which the sensor becomes less noisy, has improved sensitivity, and is more accurate than during the initial period. It has been observed that some percutaneous sensors and fully implantable sensors experience noise for a period of time after being applied to a recipient (i.e., inserted percutaneously or fully implanted under the skin).
当首次将传感器插入或植入皮下组织中时，其与多种可能的组织构象接触。在不同受者中的皮下组织在非常健壮的人的情况下可以是相对无脂肪的，或者在大多数人中可能主要由脂肪组成。脂肪以从非常白的蓬松脂肪到非常致密的纤维状脂肪的一系列纹理质地出现。一些脂肪具有非常黄的和致密的外观；一些具有非常清澈的、蓬松的和白色的外观，而在其他情况下，其具有更红或棕色的外观。脂肪可以是几英寸厚或仅1cm厚。其可以具有非常多血管或相对无血管。由于数年的胰岛素泵使用或胰岛素注射，许多糖尿病受者具有一些皮下疤痕组织。有时，在插入期间，传感器可能停留在这种瘢痕区域中。在给定受者的腹部中，皮下组织甚至可以从一个位置到另一个位置变化很大。此外，偶然地，传感器可能停留在给定受者的更密集的血管化区域附近或在较少血管化区域中。虽然不希望受理论所束缚，但据信在传感器表面与周围细胞之间产生空间(包括在传感器周围形成流体袋)可以增强传感器性能。因此，本文所讨论的连续分析物监测系统提供延长的寿命而不损害准确性，这也可以改善受者的体验。When the sensor is first inserted or implanted into the subcutaneous tissue, it contacts a variety of possible tissue conformations. The subcutaneous tissue in different recipients can be relatively fat-free in the case of very fit people, or may be mainly composed of fat in most people. Fat appears in a range of textures from very white fluffy fat to very dense fibrous fat. Some fat has a very yellow and dense appearance; some have a very clear, fluffy and white appearance, while in other cases, it has a more red or brown appearance. Fat can be several inches thick or only 1cm thick. It can have very many blood vessels or relatively no blood vessels. Due to years of insulin pump use or insulin injections, many diabetic recipients have some subcutaneous scar tissue. Sometimes, during insertion, the sensor may stay in this scar area. In the abdomen of a given recipient, the subcutaneous tissue can even vary greatly from one location to another. In addition, occasionally, the sensor may stay near or in a less vascularized area of a given recipient's denser vascularization area. While not wishing to be bound by theory, it is believed that creating space between the sensor surface and surrounding cells (including forming fluid pockets around the sensor) can enhance sensor performance. Thus, the continuous analyte monitoring systems discussed herein provide extended life without compromising accuracy, which can also improve the recipient's experience.
图1A是脂肪细胞与插入的经皮传感器或植入的传感器34接触的侧面示意图。在这种情况下，传感器34被牢固地插入小空间中，脂肪细胞紧贴在表面上。脂肪细胞与传感器的紧密结合也可以发生，例如其中传感器的表面是疏水性的。例如，脂肪细胞200和/或炎症细胞和/或其他组织类型(诸如真皮、肌层和/或结缔组织)可以产生活性代谢界面，该活性代谢界面可以物理地阻断传感器的表面和/或接近工作电极38。FIG. 1A is a side schematic diagram of a fat cell in contact with an inserted transcutaneous sensor or an implanted sensor 34. In this case, the sensor 34 is firmly inserted into a small space and the fat cell is close to the surface. Tight binding of the fat cell to the sensor can also occur, for example, where the surface of the sensor is hydrophobic. For example, the fat cell 200 and/or inflammatory cells and/or other tissue types (such as dermis, muscle layer and/or connective tissue) can create an active metabolic interface that can physically block the surface of the sensor and/or approach the working electrode 38.
通常，脂肪细胞的直径可以为约120微米，并且通常由微小的毛细血管205供给营养。当传感器被压靠在脂肪组织上时，非常少的毛细血管可能实际上靠近传感器的表面。这可以类似于用不可渗透材料(诸如玻璃纸)覆盖传感器的表面。即使在玻璃纸中有几个小孔，传感器的功能也可能受到损害。另外，周围组织具有低代谢率，并且因此不需要大量的葡萄糖和氧。虽然不希望受理论所束缚，但据信在该初期期间，传感器的信号可能有噪声，并且由于传感器表面与脂肪细胞的紧密结合以及由于物理-机械原因和生理原因导致的氧和葡萄糖的可利用度降低，该信号可能被抑制。Typically, the diameter of a fat cell can be about 120 microns, and it is usually supplied with nutrients by tiny capillaries 205. When the sensor is pressed against the fat tissue, very few capillaries may actually be close to the surface of the sensor. This can be similar to covering the surface of the sensor with an impermeable material (such as cellophane). Even if there are a few small holes in the cellophane, the function of the sensor may be impaired. In addition, the surrounding tissue has a low metabolic rate and therefore does not require a large amount of glucose and oxygen. Although it is not desired to be bound by theory, it is believed that during this initial period, the signal of the sensor may be noisy and the signal may be suppressed due to the close combination of the sensor surface with the fat cells and the reduced availability of oxygen and glucose due to physical-mechanical and physiological reasons.
现在参考传感器的延长功能，在植入几天或几周之后，这些设备通常丧失其功能。在一些应用中，细胞攻击或细胞向传感器迁移可能引起设备的灵敏度和/或功能降低，特别是在植入的第一天之后。还参见例如美国专利号5,791,344和Gross等人以及“PerformanceEvaluation of the MiniMed Continuous Monitoring System During Host home Use,”Diabetes Technology and Therapeutics,(2000)2(1):49-56，其报道了由食品和药物管理局(Food and Drug Administration)批准用于人类的基于葡萄糖氧化酶的设备，该设备在植入后几天很好地发挥功能，但在几天后(例如，几天直至约14天)迅速丧失功能。Referring now to the extended function of the sensor, these devices typically lose their function after a few days or weeks of implantation. In some applications, cell attack or cell migration to the sensor may cause the sensitivity and/or function of the device to decrease, particularly after the first day of implantation. See also, for example, U.S. Pat. No. 5,791,344 and Gross et al., and "Performance Evaluation of the MiniMed Continuous Monitoring System During Host home Use," Diabetes Technology and Therapeutics, (2000) 2(1):49-56, which reports a glucose oxidase-based device approved by the Food and Drug Administration for use in humans that functions well for a few days after implantation, but rapidly loses function a few days later (e.g., a few days up to about 14 days).
不受任何理论的束缚，据信设备功能的这种性能降低最可能是由于细胞，诸如在植入后的前几天期间迁移到传感器部位的多形核细胞和单核细胞。这些细胞消耗局部葡萄糖和氧等。如果存在过量的此类细胞，它们可以在葡萄糖和/或氧能够到达设备酶层之前耗尽葡萄糖和/或氧，从而降低设备的灵敏度或使其失去功能。设备功能的进一步抑制可能归因于炎症细胞(例如巨噬细胞)，其例如在界面处与可植入设备和邻近组织缔合并且例如通过形成屏障细胞层而物理地阻断和/或减弱葡萄糖向设备中的转运/流动。另外，这些炎症细胞可以生物降解许多人造生物材料(其中一些直到最近才被认为是不可生物降解的)。当被异物活化时，组织巨噬细胞脱粒，释放次氯酸盐(漂白剂)和已知分解多种聚合物的其他氧化性物质、酶、超过氧化物阴离子、氢氧根离子/自由基生成部分。Without being bound by any theory, it is believed that this reduction in performance of device function is most likely due to cells, such as polymorphonuclear cells and monocytes that migrate to the sensor site during the first few days after implantation. These cells consume local glucose and oxygen, etc. If there are excessive amounts of such cells, they can deplete glucose and/or oxygen before glucose and/or oxygen can reach the device enzyme layer, thereby reducing the sensitivity of the device or rendering it inoperable. Further inhibition of device function may be attributed to inflammatory cells (e.g., macrophages), which, for example, associate with the implantable device and adjacent tissues at the interface and, for example, physically block and/or weaken the transport/flow of glucose into the device by forming a barrier cell layer. In addition, these inflammatory cells can biodegrade many artificial biomaterials (some of which were considered non-biodegradable until recently). When activated by foreign matter, tissue macrophages degranulate, releasing hypochlorite (bleach) and other oxidizing substances, enzymes, superoxide anions, hydroxide ions/free radical generating parts known to decompose various polymers.
图1B是在一个示例性示例中插入的经皮传感器或植入的传感器的生物界面膜的侧面示意图。在该图示中，生物界面膜68围绕传感器34，覆盖工作电极38。在一个示例中，生物界面膜68与生物活性物质释放膜70组合使用，其中生物活性物质释放膜邻近或至少部分地覆盖生物界面膜68的一部分。在另一示例中，生物活性物质释放膜70至少部分地被生物界面膜68覆盖。在另一示例中，在没有生物界面膜68的情况下使用生物活性物质释放膜70。FIG1B is a side schematic diagram of a biointerface membrane of a transcutaneous sensor or implanted sensor in an illustrative example. In this illustration, the biointerface membrane 68 surrounds the sensor 34, covering the working electrode 38. In one example, the biointerface membrane 68 is used in combination with a bioactive substance release membrane 70, wherein the bioactive substance release membrane is adjacent to or at least partially covers a portion of the biointerface membrane 68. In another example, the bioactive substance release membrane 70 is at least partially covered by the biointerface membrane 68. In another example, the bioactive substance release membrane 70 is used without the biointerface membrane 68.
因此，包括生物界面(包括但不限于例如多孔生物界面材料、网笼等，所有这些在本文别处更详细地描述)的传感器可以用于改善传感器功能(例如，前几小时至几天)。Thus, sensors comprising a biointerface (including but not limited to, for example, porous biointerface materials, cages, etc., all of which are described in more detail elsewhere herein) can be used to improve sensor function (e.g., over the first few hours to days).
在一些情况下，例如在延长的传感器中，据信异物反应是围绕植入设备的延长植入的主要事件，并且可以被管理或操纵以支持而非阻碍或阻断分析物转运。在另一个方面，为了延长传感器的寿命，一个示例例如在多孔生物界面膜内采用促进血管化组织向内生长的材料。例如，组织向内生长到围绕延长的传感器的多孔生物界面材料中可在延长的时间段(例如，数周、数月或数年)内促进传感器功能。已经观察到组织床的向内生长和形成可能花费多达3周。组织向内生长和组织床形成被认为是异物反应的一部分。如本文将讨论的，可以通过使用围绕传感器并促进组织和微脉管系统随时间推移向内生长的多孔生物界面材料来操纵异物反应。In some cases, such as in extended sensors, it is believed that the foreign body reaction is the primary event surrounding the extended implantation of the implanted device and can be managed or manipulated to support rather than hinder or block analyte transport. On the other hand, in order to extend the life of the sensor, an example is, for example, the use of a material that promotes vascularized tissue ingrowth in a porous biointerface membrane. For example, tissue ingrowth into the porous biointerface material surrounding the extended sensor can promote sensor function over an extended period of time (e.g., weeks, months, or years). It has been observed that the ingrowth and formation of the tissue bed may take up to 3 weeks. Tissue ingrowth and tissue bed formation are considered to be part of the foreign body reaction. As will be discussed herein, the foreign body reaction can be manipulated by using a porous biointerface material that surrounds the sensor and promotes the ingrowth of tissue and microvasculature over time.
感测机构Sensing mechanism
一般来讲，本公开的分析物传感器包括感测机构36，该感测机构在其至少一部分中具有小结构(例如，有小结构的微直径或小直径传感器)，例如针型传感器。如本文所用，“小结构”优选地是指至少一个维度小于约1mm的构造。有小结构的感测机构可以是基于导线的衬底、基于衬底的，或任何其他构造。在一些另选示例中，术语“小结构”也可以指稍大的结构，诸如其最小维度大于约1mm的那些，然而，该构造(例如，质量或尺寸)被设计成使得由于尺寸和/或质量引起的异物反应最小化。在一个示例中，生物界面膜形成到感测机构36上，如下文更详细地描述的。在另一示例中，生物活性物质释放膜70形成在感测机构36上，邻近工作电极38。在另一示例中，生物活性物质释放膜70与生物界面层68组合使用。在另一示例中，在没有生物界面层68的情况下使用生物活性物质释放膜70。Generally speaking, the analyte sensor of the present disclosure includes a sensing mechanism 36 having a small structure (e.g., a micro-diameter or small-diameter sensor with a small structure), such as a needle-type sensor, in at least a portion thereof. As used herein, "small structure" preferably refers to a structure having at least one dimension less than about 1 mm. The sensing mechanism having a small structure can be a substrate based on a wire, a substrate based, or any other structure. In some alternative examples, the term "small structure" can also refer to a slightly larger structure, such as those having a minimum dimension greater than about 1 mm, however, the structure (e.g., mass or size) is designed to minimize foreign body reactions due to size and/or mass. In one example, a biointerface membrane is formed onto the sensing mechanism 36, as described in more detail below. In another example, a bioactive substance release membrane 70 is formed on the sensing mechanism 36, adjacent to the working electrode 38. In another example, the bioactive substance release membrane 70 is used in combination with the biointerface layer 68. In another example, the bioactive substance release membrane 70 is used without the biointerface layer 68.
图2A是连续式分析物传感器34(也称为经皮分析物传感器或针型传感器)的一个示例性示例的展开图，其具体展示了感测机构36。优选地，感测机构包括如本文所定义的小结构，并且适于插入受者的皮肤下，传感器的剩余主体(例如，电子器件等)可以驻留在体外。在所展示的示例中，连续式分析物传感器34包括两个电极，即工作电极38和至少一个附加电极，该附加电极可以用作反电极和/或参比电极30，在下文中称为参比电极30。FIG2A is an expanded view of an exemplary example of a continuous analyte sensor 34 (also referred to as a transcutaneous analyte sensor or a needle sensor), which specifically illustrates a sensing mechanism 36. Preferably, the sensing mechanism comprises a small structure as defined herein and is adapted to be inserted under the skin of a recipient, and the remaining body of the sensor (e.g., electronics, etc.) may reside outside the body. In the illustrated example, the continuous analyte sensor 34 comprises two electrodes, namely a working electrode 38 and at least one additional electrode, which may be used as a counter electrode and/or a reference electrode 30, hereinafter referred to as a reference electrode 30.
在一些示例性示例中，每个电极由例如直径为约0.001英寸或更小至约0.010英寸或更大的细导线形成，并且由例如电镀绝缘体、电镀导线或块体导电材料形成。尽管所展示的电极配置和相关的文本描述了形成经皮传感器的一种优选方法，但是多种已知的经皮传感器配置可以与本公开的经皮分析物传感器系统一起使用，诸如在授予Ward等人的美国专利号6,695,860、授予Say等人的美国专利号6,565,509、授予Causey III等人的美国专利号6,248,067和授予Heller等人的美国专利号6,514,718中描述的。In some illustrative examples, each electrode is formed of a thin wire, for example, having a diameter of about 0.001 inches or less to about 0.010 inches or more, and is formed of, for example, a plated insulator, a plated wire, or a bulk conductive material. Although the electrode configurations presented and the associated text describe one preferred method of forming a transcutaneous sensor, a variety of known transcutaneous sensor configurations may be used with the transcutaneous analyte sensor system of the present disclosure, such as those described in U.S. Pat. No. 6,695,860 to Ward et al., U.S. Pat. No. 6,565,509 to Say et al., U.S. Pat. No. 6,248,067 to Causey III et al., and U.S. Pat. No. 6,514,718 to Heller et al.
在示例中，工作电极包括由导电材料(诸如铂、铂-铱、钯、石墨、金、碳、导电聚合物、合金等)形成的导线。尽管可以通过多种制造技术(块体金属加工、将金属沉积到衬底上等)来形成电极，但是由电镀金属丝(例如，在钢丝上电镀有铂)或块体金属(例如，铂丝)形成电极可能是有利的。据信，由块体金属导线形成的电极提供优异的性能(例如，与沉积的电极相比)，包括测定稳定性提高、可制造性简化、耐污染(例如，污染可能在沉积过程中引入)，以及表面反应(例如，由于材料的纯度而引起)改善而无剥离或分层。In an example, the working electrode includes a wire formed of a conductive material such as platinum, platinum-iridium, palladium, graphite, gold, carbon, conductive polymers, alloys, etc. Although the electrode can be formed by a variety of manufacturing techniques (bulk metal processing, depositing the metal onto a substrate, etc.), it may be advantageous to form the electrode from a plated metal wire (e.g., platinum plated on a steel wire) or a bulk metal (e.g., a platinum wire). It is believed that electrodes formed from bulk metal wires provide superior performance (e.g., compared to deposited electrodes), including improved assay stability, simplified manufacturability, resistance to contamination (e.g., contamination that may be introduced during the deposition process), and improved surface reactions (e.g., due to the purity of the material) without peeling or delamination.
工作电极38被配置为测量一种或多种分析物的浓度。例如，在用于检测葡萄糖的酶促电化学传感器中，例如，工作电极测量由正被检测的分析物的酶催化反应产生的过氧化氢并且形成可测量的电子电流。例如，在其中葡萄糖氧化酶产生过氧化氢作为副产物的葡萄糖检测中，过氧化氢与工作电极的表面反应，产生两个质子(2H+)、两个电子(2e-)和一个氧分子(O2)，从而产生正被检测到的电子流。The working electrode 38 is configured to measure the concentration of one or more analytes. For example, in an enzymatic electrochemical sensor for detecting glucose, for example, the working electrode measures hydrogen peroxide produced by the enzyme-catalyzed reaction of the analyte being detected and forms a measurable electron current. For example, in a glucose detection in which glucose oxidase produces hydrogen peroxide as a byproduct, the hydrogen peroxide reacts with the surface of the working electrode to produce two protons (2H+), two electrons (2e-) and one oxygen molecule (O2), thereby producing an electron current that is being detected.
工作电极38覆盖有绝缘材料，例如非导电聚合物。浸涂、喷涂、气相沉积或者其他涂覆或沉积技术可以用于将绝缘材料沉积在工作电极上。在一个示例中，绝缘材料包括聚对二甲苯，聚对二甲苯由于其强度、润滑性和电绝缘特性，可以是有利的聚合物涂层。一般来讲，聚对二甲苯通过气相沉积和对二甲苯(或其经取代的衍生物)聚合来生产。然而，也可以使用任何合适的绝缘材料，例如氟化聚合物、聚对苯二甲酸乙二醇酯、聚氨酯、聚酰亚胺、其他非导电聚合物等。也可以采用玻璃或陶瓷材料。适合使用的其他材料包括表面能改性的涂料体系，诸如由Advanced Materials Components Express(Bellafonte,Pa)以商品名AMC18、AMC148、AMC141和AMC321销售的那些。然而，在一些另选示例中，工作电极可以不需要绝缘体涂层。The working electrode 38 is covered with an insulating material, such as a non-conductive polymer. Dip coating, spray coating, vapor deposition or other coating or deposition techniques can be used to deposit the insulating material on the working electrode. In one example, the insulating material includes poly(p-xylene), which can be a favorable polymer coating due to its strength, lubricity and electrical insulation properties. Generally speaking, poly(p-xylene) is produced by vapor deposition and polymerization of p-xylene (or its substituted derivatives). However, any suitable insulating material can also be used, such as fluorinated polymers, polyethylene terephthalate, polyurethane, polyimide, other non-conductive polymers, etc. Glass or ceramic materials can also be used. Other materials suitable for use include surface energy modified coating systems, such as those sold by Advanced Materials Components Express (Bellafonte, Pa) under the trade names AMC18, AMC148, AMC141 and AMC321. However, in some alternative examples, the working electrode may not require an insulator coating.
优选地，参比电极30由银、银/氯化银等形成，其可以单独用作参比电极，或者用作双参比和反电极。优选地，这些电极并列设置并且/或者彼此缠绕或绞绕；然而，其他配置也是可能的。在一个示例中，参比电极30螺旋缠绕在工作电极38周围，如图1B所展示的。然后，可以任选地用绝缘材料将导线组件涂覆在一起，类似于上文描述的，以便提供绝缘附接(例如，将工作电极和参比电极固定在一起)。Preferably, the reference electrode 30 is formed of silver, silver/silver chloride, etc., which can be used alone as a reference electrode, or as a dual reference and counter electrode. Preferably, these electrodes are arranged in parallel and/or are wound or twisted around each other; however, other configurations are also possible. In one example, the reference electrode 30 is spirally wound around the working electrode 38, as shown in Figure 1B. The wire assembly can then be optionally coated together with an insulating material, similar to that described above, to provide an insulated attachment (e.g., to secure the working electrode and the reference electrode together).
在其中设置外部绝缘体35的示例中，可例如通过手、准分子激光、化学蚀刻、激光烧蚀、喷砂(例如，用碳酸氢钠、固体二氧化碳或其他合适的砂粒)等剥离或以其他方式去除经涂覆组件结构的一部分，以暴露电化学活性表面。另选地，可在沉积绝缘体之前将电极的一部分掩蔽，以便维持暴露的电化学活性表面积。在一个示例性示例中，实施喷砂处理以暴露电化学活性表面，优选地利用足够硬以磨蚀聚合物材料同时又足够软以便最大限度减少或避免下层金属电极(例如，铂电极)损坏的砂粒材料。尽管可以使用多种“砂粒”材料(例如，沙子、滑石、胡桃壳、研磨塑料、海盐、固体二氧化碳等)，但是在一些一个示例中，碳酸氢钠是有利的砂粒材料，因为它足够硬以磨蚀例如聚对二甲苯涂层，而又不损坏例如下层的铂导体。碳酸氢钠喷砂的一个附加优点包括当其剥离聚合物层时对金属的抛光作用，从而消除了原本可能必需的清洁步骤。In examples where an external insulator 35 is provided, a portion of the coated component structure may be stripped or otherwise removed, for example by hand, excimer laser, chemical etching, laser ablation, sandblasting (e.g., with sodium bicarbonate, solid carbon dioxide, or other suitable grit), etc., to expose the electrochemically active surface. Alternatively, a portion of the electrode may be masked prior to deposition of the insulator in order to maintain the exposed electrochemically active surface area. In one exemplary example, sandblasting is performed to expose the electrochemically active surface, preferably using a grit material that is hard enough to abrade the polymer material while being soft enough to minimize or avoid damage to the underlying metal electrode (e.g., platinum electrode). Although a variety of "grit" materials may be used (e.g., sand, talc, walnut shells, ground plastic, sea salt, solid carbon dioxide, etc.), in some examples, sodium bicarbonate is an advantageous grit material because it is hard enough to abrade, for example, a polyparaxylene coating without damaging, for example, an underlying platinum conductor. An additional advantage of sodium bicarbonate sandblasting includes its polishing effect on the metal as it strips the polymer layer, thereby eliminating a cleaning step that may otherwise be necessary.
在一些示例中，穿过绝缘材料形成径向窗口以暴露工作电极的圆周电化学活性表面。附加地，暴露参比电极的电化学活性表面的多个区段。例如，电化学活性表面的多个区段可在外绝缘层沉积期间被掩蔽，或者在外绝缘层沉积之后被蚀刻。In some examples, radial windows are formed through the insulating material to expose the circumferential electrochemically active surface of the working electrode. Additionally, multiple segments of the electrochemically active surface of the reference electrode are exposed. For example, multiple segments of the electrochemically active surface can be masked during deposition of the outer insulating layer, or etched after deposition of the outer insulating layer.
在一些应用中，细胞攻击或细胞向传感器迁移可能引起设备的灵敏度和/或功能降低，特别是在植入的第一天之后。然而，当暴露的电活性表面围绕传感器周向分布时(例如，如在径向窗口中)，用于反应的可用表面区域可以充分地分布，以便最小化传感器的局部细胞侵袭对传感器信号的影响。另选地，切向暴露的电化学活性窗口可例如通过仅剥离经涂覆组件结构的一侧而形成。在其他另选示例中，窗口可设置在经涂覆组件结构的顶端处，使得电化学活性表面在传感器的顶端处暴露。还可采用其他方法和配置来暴露电化学活性表面。In some applications, cell attack or cell migration to the sensor may cause the sensitivity and/or function of the device to decrease, especially after the first day of implantation. However, when the exposed electroactive surface is distributed circumferentially around the sensor (e.g., as in a radial window), the available surface area for reaction can be fully distributed so as to minimize the effect of local cell invasion of the sensor on the sensor signal. Alternatively, the electrochemically active window exposed tangentially can be formed, for example, by peeling off only one side of the coated component structure. In other alternative examples, the window can be set at the top of the coated component structure so that the electrochemically active surface is exposed at the top of the sensor. Other methods and configurations can also be used to expose the electrochemically active surface.
优选地，上述例示的传感器的总直径不超过约0.020英寸(约0.51mm)，更优选地不超过约0.018英寸(约0.46mm)，最优选地不超过约0.016英寸(0.41mm)。在一些示例中，工作电极的直径为约0.001英寸或更小至约0.010英寸或更大，优选地为约0.002英寸至约0.008英寸，并且更优选地为约0.004英寸至约0.005英寸，包括其间的所有范围和子范围。窗口的长度可为约0.1mm(约0.004英寸)或更小至约2mm(约0.078英寸)或更大，并且优选地为约0.5mm(约0.02英寸)至约0.75mm(0.03英寸)，包括其间的所有范围和子范围。在此类示例中，工作电极的暴露表面积优选地为约0.000013平方英寸(0.0000839cm2)或更小至约0.0025平方英寸(0.016129cm2)或更大(假设直径为约0.001英寸至约0.010英寸，并且长度为约0.004英寸至约0.078英寸)，包括其间的所有范围和子范围。选择工作电极的暴露表面积以产生具有飞安培范围、皮安培范围、纳安培范围、或微安培范围内的电流的分析物信号，如本文别处更详细地描述的。然而，皮安培或更小范围内的电流可以取决于多种因素，例如电子电路设计(例如，采样率、电流消耗、A/D转换器位分辨率等)、膜系统(例如，分析物穿过膜系统的渗透性)、以及工作电极的暴露表面积。因此，考虑到膜系统和/或电子电路中的变化，可选择工作电极的暴露的电化学活性表面积，以具有大于或小于上述范围的值。在葡萄糖传感器的示例中，可能有利的是使工作电极的表面积最小化，同时使葡萄糖的扩散率最大化，以便优化信噪比，同时在高和低这两种葡萄糖浓度范围内维持传感器性能。Preferably, the overall diameter of the sensor exemplified above is no more than about 0.020 inches (about 0.51 mm), more preferably no more than about 0.018 inches (about 0.46 mm), and most preferably no more than about 0.016 inches (0.41 mm). In some examples, the diameter of the working electrode is about 0.001 inches or less to about 0.010 inches or more, preferably about 0.002 inches to about 0.008 inches, and more preferably about 0.004 inches to about 0.005 inches, including all ranges and sub-ranges therebetween. The length of the window may be about 0.1 mm (about 0.004 inches) or less to about 2 mm (about 0.078 inches) or more, and preferably about 0.5 mm (about 0.02 inches) to about 0.75 mm (0.03 inches), including all ranges and sub-ranges therebetween. In such examples, the exposed surface area of the working electrode is preferably about 0.000013 square inches (0.0000839 cm2) or less to about 0.0025 square inches (0.016129 cm2) or more (assuming a diameter of about 0.001 inches to about 0.010 inches and a length of about 0.004 inches to about 0.078 inches), including all ranges and sub-ranges therebetween. The exposed surface area of the working electrode is selected to produce an analyte signal having a current in the femtoampere range, the picoampere range, the nanoampere range, or the microampere range, as described in more detail elsewhere herein. However, currents in the picoampere or smaller range can depend on a variety of factors, such as electronic circuit design (e.g., sampling rate, current consumption, A/D converter bit resolution, etc.), membrane systems (e.g., the permeability of analytes through the membrane system), and the exposed surface area of the working electrode. Therefore, taking into account variations in the membrane system and/or electronic circuits, the exposed electrochemically active surface area of the working electrode can be selected to have a value greater than or less than the above range. In the example of a glucose sensor, it may be desirable to minimize the surface area of the working electrode while maximizing the diffusion rate of glucose in order to optimize the signal-to-noise ratio while maintaining sensor performance in both high and low glucose concentration ranges.
在一些另选示例中，可以通过改变电极本身的横截面来增加工作(和/或其他)电极的暴露表面积。例如，在一些示例中，可以通过十字形、星形、三叶草形、棱纹形、凹窝形、脊形、不规则形或其他非圆形配置来定义工作电极的横截面；因此，对于任何预定长度的电极，可以实现比表面积增加(与通过圆形横截面实现的面积相比)。例如，增加工作电极的表面积可以有利地响应于分析物浓度提供增大的信号，这进而可以有助于改善信噪比。In some alternative examples, the exposed surface area of the working (and/or other) electrode can be increased by changing the cross-section of the electrode itself. For example, in some examples, the cross-section of the working electrode can be defined by a cross, star, clover, ribbed, dimple, ridge, irregular, or other non-circular configuration; thus, for any predetermined length of electrode, an increase in specific surface area (compared to the area achieved by a circular cross-section) can be achieved. For example, increasing the surface area of the working electrode can advantageously provide an increased signal in response to analyte concentration, which in turn can help improve the signal-to-noise ratio.
在一些另选示例中，组件内可以包括附加电极，例如三电极系统(工作电极、参比电极和反电极)和/或附加工作电极(例如，可以用于生成氧的电极，其被配置为基线扣除电极，或被配置用于测量附加分析物)。2004年12月7日提交的名称为“SYSTEMS AND METHODSFOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS”的美国专利号7,081,195和2004年12月3日提交的名称为“CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR”的美国专利号7,715,893描述了用于实施和使用附加工作电极、反电极和/或参比电极的一些系统和方法。在其中传感器包括两个工作电极的一种实施方式中，这两个工作电极并列设置(例如，彼此平行地延伸)，并且参比电极围绕其设置(例如，螺旋缠绕)。在其中提供两个或更多个工作电极的一些示例中，工作电极可以沿着传感器的长度以双螺旋、三螺旋、四螺旋等配置形成(例如，围绕参比电极、绝缘棒或其他支撑结构)。所得的电极系统可以配置有适当的膜系统，其中第一工作电极被配置为测量包含葡萄糖和基线的第一信号，并且附加工作电极被配置为测量仅由基线组成的基线信号(例如，被配置为基本上类似于其上没有设置酶的第一工作电极)。以这种方式，可以从第一信号中减去基线信号，以产生基本上不受基线波动和/或信号上的干扰物质影响的仅含葡萄糖的信号。因此，上述尺寸可以根据需要改变。尽管本公开公开了包括一根块体金属导线以及螺旋缠绕在其周围的另一根块体金属导线的一种电极配置，但是也可以设想其他电极配置。在一个另选示例中，工作电极包括内部设置或盘绕有参比电极的管，两者间包括绝缘体。另选地，参比电极包括内部设置或盘绕有工作电极的管，两者间包括绝缘体。在另一个另选示例中，提供聚合物(例如，绝缘)棒，其中电极沉积(例如，电镀)在其上。在又一个另选示例中，提供涂覆有绝缘材料的金属(例如，钢)棒，工作电极和参比电极沉积到该金属棒上。在又一个另选示例中，一个或多个工作电极螺旋缠绕在参比电极周围。In some alternative examples, additional electrodes may be included within the assembly, such as a three-electrode system (working electrode, reference electrode, and counter electrode) and/or additional working electrodes (e.g., an electrode that can be used to generate oxygen, configured as a baseline subtraction electrode, or configured to measure additional analytes). U.S. Patent No. 7,081,195, entitled "SYSTEMS AND METHODSFOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS," filed on December 7, 2004, and U.S. Patent No. 7,715,893, entitled "CALIBRATION TECHNIQUES FOR A CONTINUOUS ANALYTE SENSOR," filed on December 3, 2004, describe some systems and methods for implementing and using additional working electrodes, counter electrodes, and/or reference electrodes. In one embodiment in which the sensor includes two working electrodes, the two working electrodes are arranged in parallel (e.g., extending parallel to each other), and the reference electrode is arranged around them (e.g., spirally wound). In some examples where two or more working electrodes are provided, the working electrodes can be formed in a double helix, triple helix, quadruple helix, etc. configuration along the length of the sensor (e.g., around a reference electrode, an insulating rod, or other support structure). The resulting electrode system can be configured with an appropriate membrane system, wherein the first working electrode is configured to measure a first signal comprising glucose and a baseline, and the additional working electrode is configured to measure a baseline signal consisting only of a baseline (e.g., configured to be substantially similar to the first working electrode on which no enzyme is disposed). In this way, the baseline signal can be subtracted from the first signal to produce a glucose-only signal that is substantially unaffected by baseline fluctuations and/or interfering substances on the signal. Therefore, the above dimensions can be changed as needed. Although the present disclosure discloses an electrode configuration comprising a bulk metal wire and another bulk metal wire spirally wound around it, other electrode configurations can also be envisioned. In an alternative example, the working electrode includes a tube having a reference electrode disposed or coiled therein, with an insulator included between the two. Alternatively, the reference electrode includes a tube having a working electrode disposed or coiled therein, with an insulator included between the two. In another alternative example, a polymer (e.g., insulating) rod is provided, wherein the electrode is deposited (e.g., electroplated) thereon. In yet another alternative example, a metal (e.g., steel) rod coated with an insulating material is provided, and the working electrode and the reference electrode are deposited onto the metal rod. In yet another alternative example, one or more working electrodes are spirally wound around the reference electrode.
虽然本公开的方法特别适用于有小结构的、微直径或小直径传感器，但所述方法也可适用于较大直径的传感器，例如，直径为1mm至约2mm或更大的传感器。While the methods of the present disclosure are particularly applicable to micro-diameter or small-diameter sensors having small structures, the methods may also be applicable to larger diameter sensors, for example, sensors having a diameter of 1 mm to about 2 mm or more.
在一些另选示例中，感测机构包括沉积在平面衬底上的电极，其中可植入部分的厚度小于约1mm，参见例如授予Say等人的美国专利号6,175,752和授予Mastrototaro等人的美国专利号5,779,665，这两篇专利均全文以引用方式并入本文。In some alternative examples, the sensing mechanism includes electrodes deposited on a planar substrate, wherein the thickness of the implantable portion is less than about 1 mm, see, for example, U.S. Pat. No. 6,175,752 to Say et al. and U.S. Pat. No. 5,779,665 to Mastrototaro et al., both of which are incorporated herein by reference in their entirety.
感测膜Sensing membrane
在示例中，感测膜32设置在连续分析物传感器34的电化学活性表面上，并且包括一个或多个域或层。一般来讲，感测膜的功能是控制生物流体穿过其中的流量和/或保护传感器的敏感区域免受例如生物流体的污染。一些常规电化学酶基分析物传感器通常包括感测膜，该感测膜控制被测量分析物的流量，保护电极免受生物流体的污染，和/或提供例如催化分析物与辅因子的反应的酶。参见例如2004年5月3日提交的名称为“IMPLANTABLEANALYTE SENSOR”的美国专利公开号2005/0245799和2005年3月10日提交的名称为“TRANSCUTANEOUS ANALYTE SENSOR”的美国专利号7,497,827，它们中的每一者均全文以引用方式并入本文。In the example, the sensing membrane 32 is disposed on the electrochemically active surface of the continuous analyte sensor 34 and includes one or more domains or layers. Generally speaking, the function of the sensing membrane is to control the flow of the biological fluid through it and/or to protect the sensitive area of the sensor from, for example, contamination by the biological fluid. Some conventional electrochemical enzyme-based analyte sensors generally include a sensing membrane that controls the flow of the measured analyte, protects the electrode from contamination by the biological fluid, and/or provides, for example, an enzyme that catalyzes the reaction of the analyte with a cofactor. See, for example, U.S. Patent Publication No. 2005/0245799, entitled "IMPLANTABLE ANALYTE SENSOR", filed on May 3, 2004, and U.S. Patent No. 7,497,827, entitled "TRANSCUTANEOUS ANALYTE SENSOR", filed on March 10, 2005, each of which is incorporated herein by reference in its entirety.
本公开的感测膜可以包括适用于任何分析物传感器(诸如上文更详细地描述的)的任何膜配置。一般来讲，本公开的感测膜包括一个或多个域，所述域的全部或一些可以粘附或沉积在分析物传感器上，如本领域技术人员所理解的。在示例中，感测膜通常提供以下功能中的一种或多种功能：1)保护暴露的电极表面免受生物环境的影响，2)分析物的扩散阻力(限制)，3)用于实现酶促反应的催化剂，4)限制或阻断干扰物质，和5)传感器界面的电化学反应性表面处的亲水性，诸如上文参考的美国专利申请中所述。The sensing membrane of the present disclosure may include any membrane configuration suitable for any analyte sensor (such as described in more detail above). Generally speaking, the sensing membrane of the present disclosure includes one or more domains, all or some of which can be adhered or deposited on the analyte sensor, as understood by those skilled in the art. In an example, the sensing membrane generally provides one or more of the following functions: 1) protection of the exposed electrode surface from the biological environment, 2) diffusion resistance (limitation) of the analyte, 3) catalyst for achieving enzymatic reactions, 4) limiting or blocking interfering substances, and 5) hydrophilicity at the electrochemically reactive surface of the sensor interface, such as described in the U.S. patent application referenced above.
电极域Electrode domain
在一些示例中，膜系统包括任选的电极膜，该电极膜包括电极域。提供电极域以确保在工作电极的电化学活性表面与参比电极的电化学活性表面之间发生电化学反应，并且因此电极域优选地位于比酶域更靠近这些电化学活性表面的位置。优选地，电极域包括在传感器的电化学反应性表面处维持水层的半透性涂层，例如，粘合剂材料中的湿润剂可以用作电极域；这允许离子在含水环境中完全转运。电极域还可以通过克服电极启动以及由电解质不足引起的漂移问题来帮助稳定传感器的操作。形成电极域的材料还可以保护传感器免于pH介导的损坏，该pH介导的损坏可能是由于电极的电化学活性而形成的大pH梯度引起的。In some examples, the membrane system includes an optional electrode membrane that includes an electrode domain. The electrode domain is provided to ensure that an electrochemical reaction occurs between the electrochemically active surface of the working electrode and the electrochemically active surface of the reference electrode, and therefore the electrode domain is preferably located closer to these electrochemically active surfaces than the enzyme domain. Preferably, the electrode domain includes a semipermeable coating that maintains a water layer at the electrochemically reactive surface of the sensor, for example, a wetting agent in an adhesive material can be used as an electrode domain; this allows ions to be fully transported in an aqueous environment. The electrode domain can also help stabilize the operation of the sensor by overcoming electrode startup and drift problems caused by insufficient electrolytes. The material forming the electrode domain can also protect the sensor from pH-mediated damage, which may be caused by a large pH gradient formed due to the electrochemical activity of the electrode.
在示例中，电极域包括柔性的水可溶胀水凝胶膜，其“干膜”厚度为约0.05微米或更小至约20微米或更大，更优选地为约0.05微米、0.1微米、0.15微米、0.2微米、0.25微米、0.3微米、0.35微米、0.4微米、0.45微米、0.5微米、1微米、1.5微米、2微米、2.5微米、3微米或3.5微米至约4微米、5微米、6微米、7微米、8微米、9微米、10微米、11微米、12微米、13微米、14微米、15微米、16微米、17微米、18微米、19微米或19.5微米，并且更优选地为约2微米、2.5微米或3微米至约3.5微米、4微米、4.5微米或5微米，包括其间的所有范围和子范围。“干膜”厚度是指通过标准涂覆技术由涂层配制物流延而成的固化膜的厚度。In an example, the electrode domain comprises a flexible, water-swellable hydrogel film having a "dry film" thickness of about 0.05 micrometers or less to about 20 micrometers or more, more preferably about 0.05 micrometers, 0.1 micrometers, 0.15 micrometers, 0.2 micrometers, 0.25 micrometers, 0.3 micrometers, 0.35 micrometers, 0.4 micrometers, 0.45 micrometers, 0.5 micrometers, 1 micrometers, 1.5 micrometers, 2 micrometers, 2.5 micrometers, 3 micrometers or 3.5 micrometers to about 4 micrometers, 5 micrometers, 6 micrometers, 7 micrometers, 8 micrometers, 9 micrometers, 10 micrometers, 11 micrometers, 12 micrometers, 13 micrometers, 14 micrometers, 15 micrometers, 16 micrometers, 17 micrometers, 18 micrometers, 19 micrometers or 19.5 micrometers, and more preferably about 2 micrometers, 2.5 micrometers or 3 micrometers to about 3.5 micrometers, 4 micrometers, 4.5 micrometers or 5 micrometers, including all ranges and subranges therebetween. "Dry film" thickness refers to the thickness of a cured film cast from a coating formulation by standard coating techniques.
在某些示例中，电极域由氨基甲酸酯聚合物和亲水性聚合物的可固化混合物形成。特别优选的涂层由具有羧酸酯官能团和非离子亲水性聚醚链段的聚氨酯聚合物形成，其中该聚氨酯聚合物与水溶性碳二亚胺(例如，1-乙基-3-(3-二甲基氨基丙基)碳二亚胺(EDC))在聚乙烯吡咯烷酮的存在下交联，并且在约50℃的适当温度处固化。In some examples, the electrode domain is formed of a curable mixture of a urethane polymer and a hydrophilic polymer. A particularly preferred coating is formed of a polyurethane polymer having carboxylate functional groups and nonionic hydrophilic polyether segments, wherein the polyurethane polymer is cross-linked with a water-soluble carbodiimide (e.g., 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)) in the presence of polyvinyl pyrrolidone and cured at an appropriate temperature of about 50°C.
优选地，通过喷涂或浸涂传感器的电化学活性表面来沉积电极域。更优选地，电极域通过以下方式来形成：在电极溶液中浸涂电化学活性表面并在约40℃至约55℃的温度下固化该域约15分钟至约30分钟的时间(并且可在真空下完成(例如，20mmHg至30mmHg))，包括其间的所有范围和子范围。在其中使用浸涂沉积电极域的示例中，用约1英寸/分钟至约3英寸/分钟的优选插入速率、约0.5分钟至约2分钟的优选停留时间和约0.25英寸/分钟至约2英寸/分钟的优选取出速率来提供功能性涂层，包括其间的所有范围和子范围。然而，如本领域技术人员将理解的，在某些示例中，例如取决于粘度和表面张力，上面列出的那些值之外的值可能是可接受的，甚至可能是理想的。在一个示例中，电极系统的电化学活性表面被浸涂一次(一层)，然后在50℃下在真空下固化20分钟。Preferably, the electrode domain is deposited by spraying or dipping the electrochemically active surface of the sensor. More preferably, the electrode domain is formed by dipping the electrochemically active surface in the electrode solution and curing the domain for a time of about 15 minutes to about 30 minutes at a temperature of about 40°C to about 55°C (and can be completed under vacuum (e.g., 20mmHg to 30mmHg)), including all ranges and sub-ranges therebetween. In the example where the electrode domain is deposited using dip coating, a functional coating is provided with a preferred insertion rate of about 1 inch/minute to about 3 inches/minute, a preferred residence time of about 0.5 minutes to about 2 minutes, and a preferred removal rate of about 0.25 inches/minute to about 2 inches/minute, including all ranges and sub-ranges therebetween. However, as will be appreciated by those skilled in the art, in some examples, values other than those listed above may be acceptable, and may even be desirable, for example, depending on viscosity and surface tension. In one example, the electrochemically active surface of the electrode system is dip coated once (one layer) and then cured under vacuum at 50°C for 20 minutes.
尽管本文描述了独立的电极域，但是在一些示例中，可在干扰域和/或酶域(邻近电化学活性表面的域)中提供足够的亲水性，以便在水性环境中提供离子的完全转运(例如，没有明显的电极域)。Although separate electrode domains are described herein, in some examples, sufficient hydrophilicity may be provided in the interference domain and/or enzyme domain (domain adjacent to the electrochemically active surface) to provide complete transport of ions in an aqueous environment (e.g., without a distinct electrode domain).
干扰域Interference Domain
在一些示例中，提供任选的干扰域，其通常包括限制一种或多种干扰物流动的聚合物域。在一些示例中，干扰域充当分子筛，其允许待由电极测量的分析物和其他物质通过，同时防止其他物质(包括诸如抗坏血酸盐和尿素等干扰物)通过(参见授予Shults的美国专利号6,001,067)。葡萄糖氧化酶基电化学传感器的一些已知干扰物包括对乙酰氨基酚、抗坏血酸、胆红素、胆固醇、肌酸酐、多巴胺、麻黄素、布洛芬、左旋多巴、甲基多巴、水杨酸盐、四环素、妥拉磺脲、甲苯磺丁脲、甘油三酯和尿酸。In some examples, an optional interference domain is provided, which generally includes a polymer domain that limits the flow of one or more interferents. In some examples, the interference domain acts as a molecular sieve, which allows the analyte and other substances to be measured by the electrode to pass through, while preventing other substances (including interferents such as ascorbate and urea) from passing through (see U.S. Patent No. 6,001,067 to Shults). Some known interferents of glucose oxidase-based electrochemical sensors include acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen, levodopa, methyldopa, salicylate, tetracycline, tolazamide, tolbutamide, triglycerides and uric acid.
可以用作干扰域的基础材料的几种聚合物类型包括例如聚氨酯、具有离子侧基的聚合物、以及具有受控孔径的聚合物。在一个示例中，干扰域包括疏水性薄膜，该疏水性薄膜不可溶胀并且限制低分子量物质扩散。干扰域可渗透相对低分子量的物质，诸如过氧化氢，但限制包括葡萄糖和抗坏血酸在内的较高分子量物质通过。可应用于本公开的膜系统的用于减少或消除干扰物质的其他系统和方法描述于2004年7月21日提交的名称为“ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS”的美国专利号7,074,307、2004年11月16日提交的名称为“AFFINITY DOMAIN FOR AN ANALYTE SENSOR”的美国专利公开号2005/0176136、2004年12月7日提交的名称为“SYSTEMS AND METHODS FOR IMPROVINGELECTROCHEMICAL ANALYTE SENSORS”的美国专利号7,081,195和2004年12月3日提交的名称为“CALIBRATION TECHNIQUES FOR ACONTINUOUS ANALYTE SENSOR”的美国专利号7,715,893中。在一些另选示例中，不包括明显的干扰域。Several polymer types that can be used as the base material for the interference domain include, for example, polyurethanes, polymers with ionic side groups, and polymers with controlled pore size. In one example, the interference domain includes a hydrophobic film that is non-swellable and restricts the diffusion of low molecular weight species. The interference domain is permeable to relatively low molecular weight species, such as hydrogen peroxide, but restricts the passage of higher molecular weight species, including glucose and ascorbic acid. Other systems and methods for reducing or eliminating interfering species that may be applied to the membrane systems of the present disclosure are described in U.S. Pat. No. 7,074,307, entitled "ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS," filed on July 21, 2004, U.S. Patent Publication No. 2005/0176136, entitled "AFFINITY DOMAIN FOR AN ANALYTE SENSOR," filed on November 16, 2004, U.S. Pat. No. 7,081,195, entitled "SYSTEMS AND METHODS FOR IMPROVING ELECTROCHEMICAL ANALYTE SENSORS," filed on December 7, 2004, and U.S. Pat. No. 7,715,893, entitled "CALIBRATION TECHNIQUES FOR ACONTINUOUS ANALYTE SENSOR," filed on December 3, 2004. In some alternative examples, an explicit interference domain is not included.
在示例中，将干扰域沉积到电极域上(或当不包括明显的电极域时，直接沉积到电化学活性表面上)以获得约0.05微米或更小至约20微米或更大，更优选地约0.05微米、0.1微米、0.15微米、0.2微米、0.25微米、0.3微米、0.35微米、0.4微米、0.45微米、0.5微米、1微米、1.5微米、2微米、2.5微米、3微米或3.5微米至约4微米、5微米、6微米、7微米、8微米、9微米、10微米、11微米、12微米、13微米、14微米、15微米、16微米、17微米、18微米、19微米或19.5微米，并且更优选地约2微米、2.5微米或3微米至约3.5微米、4微米、4.5微米或5微米的域厚度，包括其间的所有范围和子范围。较厚的膜也可能是有用的，但较薄的膜通常是优选的，因为它们对过氧化氢从酶膜到电极的扩散速率只有较低的影响。不幸的是，常规使用的干扰域的薄厚度可以在膜系统加工中引入可变性。例如，如果将太多或太少的干扰域掺入膜系统中，则膜的性能可能受到不利影响。In examples, the interference domain is deposited onto the electrode domain (or directly onto the electrochemically active surface when a distinct electrode domain is not included) to obtain a domain thickness of about 0.05 microns or less to about 20 microns or greater, more preferably about 0.05 microns, 0.1 microns, 0.15 microns, 0.2 microns, 0.25 microns, 0.3 microns, 0.35 microns, 0.4 microns, 0.45 microns, 0.5 microns, 1 micron, 1.5 microns, 2 microns, 2.5 microns, 3 microns or 3.5 microns to about 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns, 17 microns, 18 microns, 19 microns or 19.5 microns, and more preferably about 2 microns, 2.5 microns or 3 microns to about 3.5 microns, 4 microns, 4.5 microns or 5 microns, including all ranges and sub-ranges therebetween. Thicker membranes may also be useful, but thinner membranes are generally preferred because they have only a lower impact on the diffusion rate of hydrogen peroxide from the enzyme membrane to the electrode. Unfortunately, the thin thickness of the conventionally used interference domains can introduce variability in membrane system processing. For example, if too much or too little interference domain is incorporated into a membrane system, the performance of the membrane may be adversely affected.
酶域Enzyme domain
在一个示例中，膜系统还包括比干扰域(或当不包括明显的干扰域时，为电极域)更远离电化学活性表面设置的酶域。在一些示例中，将酶域直接沉积到电化学活性表面上(当既不包括电极也不包括干扰域时)。在一个示例中，酶域提供催化分析物及其共反应物的反应的酶，如下文更详细地描述的。优选地，酶域包括葡萄糖氧化酶；然而也可使用其他氧化酶，例如半乳糖氧化酶、乳酸氧化酶或尿酸酶氧化酶。In one example, the membrane system also includes an enzyme domain that is further away from the electrochemically active surface than the interference domain (or when no obvious interference domain is included, the electrode domain). In some examples, the enzyme domain is directly deposited on the electrochemically active surface (when neither the electrode nor the interference domain is included). In one example, the enzyme domain provides an enzyme that catalyzes the reaction of the analyte and its co-reactant, as described in more detail below. Preferably, the enzyme domain includes glucose oxidase; however, other oxidases, such as galactose oxidase, lactate oxidase or uricase oxidase, may also be used.
为了使基于酶的电化学葡萄糖传感器表现良好，该传感器的响应优选地既不受酶活性也不受共反应物浓度的限制。因为包括葡萄糖氧化酶在内的酶甚至在环境条件下也会随时间而失活，所以这种行为在形成酶域时得到补偿。优选地，酶域由包含酶的胶态聚氨酯聚合物的含水分散体构成。然而，在另选示例中，酶域由氧增强材料(例如，有机硅或碳氟化合物)构成，以便在短暂缺血期间提供过量氧供应。优选地，酶被固定在酶域内。参见2004年7月21日提交的名称为“Oxygen Enhancing Membrane Systems for Implantable Device”的美国专利号7,379,765。In order to make the electrochemical glucose sensor based on enzyme perform well, the response of the sensor is preferably not limited by enzyme activity nor coreactant concentration. Because enzymes including glucose oxidase also can be inactivated over time even under ambient conditions, this behavior is compensated when forming enzyme domain. Preferably, enzyme domain is composed of an aqueous dispersion of a colloidal polyurethane polymer comprising an enzyme. However, in an alternative example, enzyme domain is composed of an oxygen enhancing material (e.g., organosilicon or fluorocarbon) to provide an excessive oxygen supply during transient ischemia. Preferably, enzyme is fixed in enzyme domain. Referring to U.S. Patent No. 7,379,765, entitled "Oxygen Enhancing Membrane Systems for Implantable Device" submitted on July 21, 2004.
在示例中，将酶域沉积到干扰域上以获得约0.05微米或更小至约20微米或更大，更优选地约0.05微米、0.1微米、0.15微米、0.2微米、0.25微米、0.3微米、0.35微米、0.4微米、0.45微米、0.5微米、1微米、1.5微米、2微米、2.5微米、3微米或3.5微米至约4微米、5微米、6微米、7微米、8微米、9微米、10微米、11微米、12微米、13微米、14微米、15微米、16微米、17微米、18微米、19微米或19.5微米，并且更优选地约2微米、2.5微米或3微米至约3.5微米、4微米、4.5微米或5微米的域厚度，包括其间的所有范围和子范围。然而，在一些示例中，将酶域沉积到电极域上或直接沉积到电化学活性表面上。优选地，酶域通过喷涂或浸涂来沉积。更优选地，酶域通过以下方式来形成：在酶域溶液中浸涂电极域并在约40℃至约55℃的温度下固化该域约15分钟至约30分钟(并且可在真空下完成(例如，20mmHg至30mmHg))，包括其间的所有范围和子范围。在其中使用浸涂在室温下沉积酶域的示例中，用约1英寸/分钟至约3英寸/分钟的优选插入速率、约0.5分钟至约2分钟的优选停留时间和约0.25英寸/分钟至约2英寸/分钟的优选取出速率来提供功能性涂层，包括其间的所有范围和子范围。然而，如本领域技术人员将理解的，在某些示例中，例如取决于粘度和表面张力，上面列出的那些值之外的值可能是可接受的，甚至可能是理想的。在一个示例中，通过在涂层溶液中浸涂两次(即，形成两层)并在50℃下在真空下固化20分钟来形成酶域。然而，在一些示例中，可以通过以预定的涂层溶液浓度、插入速率、停留时间、取出速率和/或所需厚度浸涂和/或喷涂一层或多层来形成酶域。In an example, the enzyme domain is deposited onto the interference domain to obtain a domain thickness of about 0.05 micron or less to about 20 microns or greater, more preferably about 0.05 micron, 0.1 micron, 0.15 micron, 0.2 micron, 0.25 micron, 0.3 micron, 0.35 micron, 0.4 micron, 0.45 micron, 0.5 micron, 1 micron, 1.5 micron, 2 microns, 2.5 microns, 3 microns or 3.5 microns to about 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns, 17 microns, 18 microns, 19 microns or 19.5 microns, and more preferably about 2 microns, 2.5 microns or 3 microns to about 3.5 microns, 4 microns, 4.5 microns or 5 microns, including all ranges and subranges therebetween. However, in some examples, the enzyme domain is deposited onto the electrode domain or directly onto the electrochemically active surface. Preferably, the enzyme domain is deposited by spraying or dipping. More preferably, the enzyme domain is formed in the following manner: dip-coating the electrode domain in the enzyme domain solution and curing the domain for about 15 minutes to about 30 minutes at a temperature of about 40°C to about 55°C (and can be completed under vacuum (for example, 20mmHg to 30mmHg)), including all ranges and sub-ranges therebetween. In the example where dip-coating is used to deposit the enzyme domain at room temperature, a functional coating is provided with a preferred insertion rate of about 1 inch/minute to about 3 inches/minute, a preferred residence time of about 0.5 minutes to about 2 minutes, and a preferred removal rate of about 0.25 inches/minute to about 2 inches/minute, including all ranges and sub-ranges therebetween. However, as will be appreciated by those skilled in the art, in some examples, for example, depending on viscosity and surface tension, values outside those values listed above may be acceptable, and may even be desirable. In one example, the enzyme domain is formed by dipping twice (that is, forming two layers) in a coating solution and curing for 20 minutes under vacuum at 50°C. However, in some examples, the enzyme domain may be formed by dip coating and/or spray coating one or more layers at a predetermined coating solution concentration, insertion rate, residence time, withdrawal rate, and/or desired thickness.
抵抗域Resistance Domain
在一个示例中，膜系统包括比酶域更远离电化学活性表面设置的抵抗域。尽管下面的描述涉及葡萄糖传感器的抵抗域，但是该抵抗域也可以针对其他分析物和共反应物来进行改造。In one example, the membrane system includes a resistance domain disposed further away from the electrochemically active surface than the enzyme domain. Although the following description relates to a resistance domain for a glucose sensor, the resistance domain may also be engineered for other analytes and co-reactants.
相对于血液中的氧量，存在摩尔过量的葡萄糖；也就是说，对于细胞外液中的每个游离氧分子，通常存在超过100个葡萄糖分子(参见Updike等人，Diabetes Care 5:207-21(1982))。然而，采用氧作为共反应物的基于固定化酶的葡萄糖传感器优选地以非速率限制过量的方式来得到氧供应，以便传感器线性地响应葡萄糖浓度的变化，而不响应氧浓度的变化。具体地讲，当葡萄糖监测反应是氧受限的反应时，在葡萄糖的最小浓度之上不能实现线性。在没有位于酶域之上的半透性膜来控制葡萄糖和氧的通量的情况下，仅对于最高达约40mg/dL的葡萄糖浓度，可以获得对葡萄糖水平的线性响应。然而，在临床环境中，期望在高达至少约400mg/dL的情况下，也可获得对葡萄糖水平的线性响应。There is a molar excess of glucose relative to the amount of oxygen in the blood; that is, for each free oxygen molecule in the extracellular fluid, there are typically more than 100 glucose molecules (see Updike et al., Diabetes Care 5: 207-21 (1982)). However, an immobilized enzyme-based glucose sensor using oxygen as a co-reactant preferably obtains oxygen supply in a non-rate-limiting excess manner so that the sensor responds linearly to changes in glucose concentration without responding to changes in oxygen concentration. Specifically, when the glucose monitoring reaction is an oxygen-limited reaction, linearity cannot be achieved above the minimum concentration of glucose. In the absence of a semipermeable membrane located above the enzyme domain to control the flux of glucose and oxygen, a linear response to glucose levels can be obtained only for glucose concentrations up to about 40 mg/dL. However, in a clinical setting, it is expected that a linear response to glucose levels can also be obtained up to at least about 400 mg/dL.
抵抗域包括半透性膜，其控制氧和葡萄糖流向下面的酶域的通量，优选地使氧以非速率限制过量的方式流动。因此，葡萄糖测量结果的线性上限被扩展到比没有抵抗域时所实现的值高得多的值。在示例中，抵抗域表现出约50:1或更小至约400:1或更大、优选地约200:1的氧与葡萄糖渗透性比率，包括其间的所有范围和子范围。结果，一维反应物扩散足以在皮下基质中发现的所有合理的葡萄糖浓度和氧浓度下提供过量的氧(参见Rhodes等人，Anal.Chem.,66:1520-1529(1994))。The resistance domain includes a semipermeable membrane, which controls the flux of oxygen and glucose flowing to the enzyme domain below, preferably allowing oxygen to flow in a non-rate-limited excess manner. Therefore, the linear upper limit of the glucose measurement result is extended to a much higher value than the value achieved when there is no resistance domain. In an example, the resistance domain shows an oxygen and glucose permeability ratio of about 50:1 or less to about 400:1 or greater, preferably about 200:1, including all ranges and sub-ranges therebetween. As a result, one-dimensional reactant diffusion is sufficient to provide excess oxygen under all reasonable glucose concentrations and oxygen concentrations found in subcutaneous matrix (see Rhodes et al., Anal.Chem., 66:1520-1529 (1994)).
在另选示例中，较低的氧与葡萄糖比率可能足以通过使用高氧溶解度域(例如，基于有机硅或碳氟化合物的材料或域)来提供过量的氧，以增强氧向酶域的供应/转运。如果向酶供应更多的氧，则也可以向酶供应更多的葡萄糖，而不产生氧速率限制过量。在另选示例中，抵抗域由有机硅组合物形成，诸如2003年10月28日提交的名称为“SILICONECOMPOSITION FOR BIOCOMPATIBLE MEMBRANE”的美国专利公开号2005/0090607中所述。In an alternative example, a lower oxygen to glucose ratio may be sufficient to provide excess oxygen by using a high oxygen solubility domain (e.g., a silicone or fluorocarbon based material or domain) to enhance the supply/transport of oxygen to the enzyme domain. If more oxygen is supplied to the enzyme, more glucose can also be supplied to the enzyme without creating an oxygen rate limiting excess. In an alternative example, the resistance domain is formed of a silicone composition, such as described in U.S. Patent Publication No. 2005/0090607, filed on October 28, 2003, entitled "SILICONE COMPOSITION FOR BIOCOMPATIBLE MEMBRANE".
在优选的示例中，抵抗域包括具有亲水性区域和疏水性区域两者的聚氨酯膜，用于控制葡萄糖和氧向分析物传感器的扩散，该膜由可商购获得的材料容易地和可再现地制造。合适的疏水性聚合物组分是聚氨酯或聚醚聚氨酯脲。聚氨酯是通过二异氰酸酯和双官能含羟基材料的缩合反应制备的聚合物。聚氨酯脲是通过二异氰酸酯和双官能含胺材料的缩合反应制备的聚合物。在一些示例中，二异氰酸酯包括含有约4个至约8个亚甲基单元的脂族二异氰酸酯。含有脂环族部分的二异氰酸酯也可以用于制备本公开的膜的聚合物和共聚物组分。形成抵抗域的疏水性基质的基础的材料可以是本领域已知的适合用作连续分析物传感器设备中的膜并且具有足够大的渗透性以允许相关化合物穿过其中(例如，以允许氧分子从所检查的样品穿过该膜以便到达活性酶电极或电化学电极)的那些材料中的任一种材料。可用于制备非聚氨酯型膜的材料的示例包括乙烯基聚合物、聚乙烯乙酸乙烯酯共聚物、聚醚、聚碳酸烷基酯、聚碳酸酯、聚烷基酯、聚酯、聚酰胺、无机聚合物(诸如聚硅氧烷和聚碳硅氧烷)、天然聚合物(诸如纤维素基材料和蛋白质基材料)以及它们的混合物或组合。In a preferred example, the resistance domain includes a polyurethane film having both a hydrophilic region and a hydrophobic region, for controlling the diffusion of glucose and oxygen to the analyte sensor, and the film is easily and reproducibly manufactured by commercially available materials. Suitable hydrophobic polymer components are polyurethane or polyether polyurethane urea. Polyurethane is a polymer prepared by the condensation reaction of diisocyanate and a difunctional hydroxyl-containing material. Polyurethane urea is a polymer prepared by the condensation reaction of diisocyanate and a difunctional amine-containing material. In some examples, diisocyanate includes an aliphatic diisocyanate containing about 4 to about 8 methylene units. Diisocyanates containing alicyclic moieties can also be used to prepare polymers and copolymer components of the film of the present disclosure. The material forming the basis of the hydrophobic matrix of the resistance domain can be any material known in the art suitable for use as a film in a continuous analyte sensor device and having a sufficiently large permeability to allow related compounds to pass therethrough (e.g., to allow oxygen molecules to pass through the film from the sample being examined so as to reach an active enzyme electrode or an electrochemical electrode). Examples of materials that can be used to prepare non-polyurethane films include vinyl polymers, polyethylene vinyl acetate copolymers, polyethers, polyalkyl carbonates, polycarbonates, polyalkyl esters, polyesters, polyamides, inorganic polymers (such as polysiloxanes and polycarbosiloxanes), natural polymers (such as cellulose-based materials and protein-based materials), and mixtures or combinations thereof.
在优选的示例中，抵抗域的亲水性聚合物组分是聚环氧乙烷。例如，一种可用的疏水性-亲水性共聚物组分是包括约20％的亲水性聚环氧乙烷的聚氨酯聚合物。该共聚物的聚环氧乙烷部分被热力学驱动以与该共聚物的疏水性部分和疏水性聚合物组分分离。用于形成最终共混物的共聚物的20％基于聚环氧乙烷的软链段部分影响膜对水的吸收以及膜随后对葡萄糖的渗透性。In a preferred example, the hydrophilic polymer component of the resistance domain is polyethylene oxide. For example, a useful hydrophobic-hydrophilic copolymer component is a polyurethane polymer including about 20% hydrophilic polyethylene oxide. The polyethylene oxide portion of the copolymer is thermodynamically driven to separate from the hydrophobic portion and hydrophobic polymer component of the copolymer. The 20% polyethylene oxide-based soft segment portion of the copolymer used to form the final blend affects the absorption of water by the membrane and the subsequent permeability of the membrane to glucose.
在示例中，将抵抗域沉积到酶域上以产生约0.05微米或更小至约20微米或更大，更优选地约0.05微米、0.1微米、0.15微米、0.2微米、0.25微米、0.3微米、0.35微米、0.4微米、0.45微米、0.5微米、1微米、1.5微米、2微米、2.5微米、3微米或3.5微米至约4微米、5微米、6微米、7微米、8微米、9微米、10微米、11微米、12微米、13微米、14微米、15微米、16微米、17微米、18微米、19微米或19.5微米，并且更优选地约2微米、2.5微米或3微米至约3.5微米、4微米、4.5微米或5微米的域厚度，包括其间的所有范围和子范围。优选地，通过喷涂或浸涂将抵抗域沉积到酶域上。在某些示例中，喷涂是优选的沉积技术。喷涂过程使溶液雾化并形成薄雾，因此大部分或所有的溶剂在涂层材料沉降到下面的域上之前蒸发，从而最大限度减少溶剂与酶的接触。如本公开中所描述的喷涂抵抗域的一个附加优点包括形成基本上阻断或抵抗抗坏血酸盐(测量过氧化氢的葡萄糖传感器中的已知电化学干扰物)的膜系统。虽然不希望受理论所束缚，但据信在如本公开中所描述的沉积抵抗域的过程期间，形成结构形态，其特征在于抗坏血酸盐基本上不渗透穿过其中。In an example, the resistance domain is deposited on the enzyme domain to produce about 0.05 micron or less to about 20 microns or more, more preferably about 0.05 micron, 0.1 micron, 0.15 micron, 0.2 micron, 0.25 micron, 0.3 micron, 0.35 micron, 0.4 micron, 0.45 micron, 0.5 micron, 1 micron, 1.5 micron, 2 microns, 2.5 microns, 3 microns or 3.5 microns to about 4 microns, 5 microns, 6 microns, 7 microns, 8 microns, 9 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns, 17 microns, 18 microns, 19 microns or 19.5 microns, and more preferably about 2 microns, 2.5 microns or 3 microns to about 3.5 microns, 4 microns, 4.5 microns or 5 microns of domain thickness, including all ranges and subranges therebetween. Preferably, the resistance domain is deposited on the enzyme domain by spraying or dipping. In some examples, spraying is a preferred deposition technique. The spraying process atomizes the solution and forms a mist so that most or all of the solvent evaporates before the coating material settles on the domain below, thereby minimizing contact of the solvent with the enzyme. An additional advantage of spraying the resist domain as described in the present disclosure includes forming a membrane system that substantially blocks or resists ascorbate, a known electrochemical interferent in glucose sensors that measure hydrogen peroxide. Although not wishing to be bound by theory, it is believed that during the process of depositing the resist domain as described in the present disclosure, a structural morphology is formed that is characterized in that ascorbate is substantially impermeable therethrough.
在示例中，通过喷涂约1重量％至约5重量％的聚合物和约95重量％至约99重量％的溶剂的溶液(包括其间的所有范围和子范围)，将抵抗域沉积到酶域上。在将抵抗域材料的溶液(包括溶剂)喷涂到酶域上时，期望减轻或显著减少喷雾溶液中可以使酶域的基础酶失活的任何溶剂与酶的任何接触。四氢呋喃(THF)是一种在喷雾时对酶域中的酶影响最小或可忽略不计的溶剂。如本领域技术人员所理解的，其他溶剂也可能适用。In an example, a solution of a polymer of about 1 wt % to about 5 wt % and a solvent of about 95 wt % to about 99 wt % (including all ranges and sub-ranges therebetween) is sprayed onto the enzyme domain. When a solution of the resistance domain material (including a solvent) is sprayed onto the enzyme domain, it is desirable to mitigate or significantly reduce any contact of any solvent with the enzyme that can inactivate the base enzyme of the enzyme domain in the spray solution. Tetrahydrofuran (THF) is a solvent that has minimal or negligible effect on the enzyme in the enzyme domain when spraying. As will be appreciated by those skilled in the art, other solvents may also be applicable.
尽管可以使用多种喷涂或沉积技术，但喷涂抵抗域材料并将传感器旋转至少一次180°可以提供抵抗域的足够覆盖。喷涂抵抗域材料并将传感器旋转至少两次120度提供甚至更大的覆盖(360°覆盖的一层)，从而确保对葡萄糖的抵抗力，诸如上文更详细地描述的。Although a variety of spraying or deposition techniques may be used, spraying the resistive domain material and rotating the sensor at least once 180° may provide adequate coverage of the resistive domain. Spraying the resistive domain material and rotating the sensor at least twice 120 degrees provides even greater coverage (one layer for 360° coverage), thereby ensuring resistance to glucose, such as described in more detail above.
在示例中，将抵抗域喷涂并随后在约40℃至约60℃的温度下固化约15分钟至约90分钟的时间(并且可在真空下完成(例如，20mmHg至30mmHg))，包括其间的所有范围和子范围。长达约90分钟或更长的固化时间可能有利地确保抵抗域的完全干燥。虽然不希望受理论所束缚，但据信抵抗域的完全干燥有助于稳定葡萄糖传感器信号的灵敏度。其减少了信号灵敏度随时间推移的漂移，并且认为完全干燥稳定了在低氧环境中葡萄糖传感器信号的性能。In an example, the resist domain is sprayed and then cured at a temperature of about 40°C to about 60°C for a time of about 15 minutes to about 90 minutes (and may be done under vacuum (e.g., 20 mmHg to 30 mmHg)), including all ranges and sub-ranges therebetween. Curing times of up to about 90 minutes or longer may advantageously ensure complete drying of the resist domain. While not wishing to be bound by theory, it is believed that complete drying of the resist domain helps stabilize the sensitivity of the glucose sensor signal. It reduces the drift of the signal sensitivity over time, and it is believed that complete drying stabilizes the performance of the glucose sensor signal in a hypoxic environment.
在示例中，通过喷涂至少六层(即，对于360°覆盖的至少六层，将传感器旋转十七次120°)并在50℃下在真空下固化60分钟来形成抵抗域。然而，取决于溶液的浓度、插入速率、停留时间、取出速率和/或所得膜的所需厚度，可以通过浸涂或喷涂任何一层或多层来形成抵抗域。In an example, the resistive domain is formed by spraying at least six layers (i.e., rotating the sensor seventeen times 120° for at least six layers for 360° coverage) and curing under vacuum at 50° C. for 60 minutes. However, the resistive domain may be formed by dip coating or spray coating of any one or more layers, depending on the concentration of the solution, the insertion rate, the residence time, the withdrawal rate, and/or the desired thickness of the resulting film.
有利地，具有本公开的膜系统的传感器提供对约40mg/dL至约400mg/dL(包括其间的所有范围和子范围)的增加的葡萄糖水平的稳定信号应答，并且甚至在低氧水平(例如，在约0.6mg/L O2)下也提供持续的功能(至少90％信号强度)，该膜系统包括电极域和/或干扰域、酶域和抵抗域。虽然不希望受理论所束缚，但据信抵抗域提供足够的抵抗力，或酶域提供足够的酶，使得与现有技术传感器相比，在低得多的氧浓度下才看到氧限制。Advantageously, sensors having a membrane system of the present disclosure, including an electrode domain and/or an interference domain, an enzyme domain, and a resistance domain, provide a stable signal response to increasing glucose levels of about 40 mg/dL to about 400 mg/dL (including all ranges and subranges therebetween), and provide sustained functionality (at least 90% signal strength) even at low oxygen levels (e.g., at about 0.6 mg/L O2 ). While not wishing to be bound by theory, it is believed that the resistance domain provides sufficient resistance, or the enzyme domain provides sufficient enzyme, such that oxygen limitation is seen at much lower oxygen concentrations than prior art sensors.
在示例中，提供具有在皮安培或更小范围内的电流的传感器信号，其在本文别处更详细地描述。然而，产生具有在皮安培范围内的电流的信号的能力可以取决于多个因素的组合，包括电子电路设计(例如，A/D转换器、位分辨率等)、膜系统(例如，分析物通过抵抗域的渗透性、酶浓度和/或在电极处的电化学反应的电解质可用性)以及工作电极的暴露表面积。例如，取决于电子电路、膜系统和/或工作电极的暴露的电化学活性表面积的设计，抵抗域可被设计成或多或少地限制分析物。In an example, a sensor signal having a current in the picoampere range or less is provided, which is described in more detail elsewhere herein. However, the ability to generate a signal having a current in the picoampere range can depend on a combination of factors, including electronic circuit design (e.g., A/D converter, bit resolution, etc.), membrane system (e.g., permeability of the analyte through the resistance domain, enzyme concentration, and/or electrolyte availability for electrochemical reactions at the electrode), and the exposed surface area of the working electrode. For example, depending on the design of the electronic circuit, membrane system, and/or the exposed electrochemically active surface area of the working electrode, the resistance domain can be designed to more or less restrict the analyte.
因此，在示例中，膜系统被设计成具有约1pA/mg/dL至约100pA/mg/dL，优选地约5pA/mg/dL至25pA/mg/dL，并且更优选地约4pA/mg/dL至约7pA/mg/dL的灵敏度，包括其间的所有范围和子范围。虽然不希望受任何特定理论所束缚，但据信设计成具有在优选范围内的灵敏度的膜系统允许在低分析物和/或低氧情形下测量分析物信号。即，常规的分析物传感器由于分析物对传感器的较低可用性而在低分析物范围内显示出降低的测量准确性，和/或由于与被测量的分析物的量反应所必需的氧不足而在高分析物范围内显示出增加的信号噪声。虽然不希望受理论所束缚，但据信本公开的膜系统与电子电路设计和暴露的电化学反应性表面积设计相结合，支持在皮安培范围或更小范围内的分析物测量，这使得能够在低和高这两种分析物范围内实现改进水平的分辨率和准确性，这在现有技术中是不可见的。Therefore, in the example, the membrane system is designed to have a sensitivity of about 1pA/mg/dL to about 100pA/mg/dL, preferably about 5pA/mg/dL to 25pA/mg/dL, and more preferably about 4pA/mg/dL to about 7pA/mg/dL, including all ranges and sub-ranges therebetween. Although it is not desired to be bound by any particular theory, it is believed that the membrane system designed to have a sensitivity within the preferred range allows the analyte signal to be measured in low analyte and/or hypoxic situations. That is, conventional analyte sensors show reduced measurement accuracy in the low analyte range due to the lower availability of analyte to the sensor, and/or show increased signal noise in the high analyte range due to insufficient oxygen necessary for the amount of the analyte being measured. Although it is not desired to be bound by theory, it is believed that the membrane system of the present disclosure is combined with the electronic circuit design and the exposed electrochemical reactive surface area design to support analyte measurement in the picoampere range or less, which enables the resolution and accuracy of improved levels to be achieved in the low and high analyte ranges, which is not visible in the prior art.
尽管本文所述的一些示例的传感器包括任选的干扰域以阻断或减少一种或多种干扰物，但具有本公开的膜系统(包括电极域、酶域和抵抗域)的传感器已显示在没有附加干扰域的情况下抑制抗坏血酸盐。即，包括电极域、酶域和抵抗域的本公开的膜系统已显示在生理学可接受的范围内对抗坏血酸盐基本上无应答。虽然不希望受理论所束缚，但据信如本文所述，通过喷涂沉积抵抗域的方法导致基本上对抗坏血酸盐具有抵抗力的结构形态。Although some of the example sensors described herein include optional interference domains to block or reduce one or more interferents, sensors with membrane systems of the present disclosure (including electrode domains, enzyme domains, and resistance domains) have been shown to inhibit ascorbate without additional interference domains. That is, the membrane systems of the present disclosure including electrode domains, enzyme domains, and resistance domains have been shown to be substantially unresponsive to ascorbate within a physiologically acceptable range. Although not wishing to be bound by theory, it is believed that as described herein, the method of depositing the resistance domain by spraying results in a structural morphology that is substantially resistant to ascorbate.
无干扰域的膜系统Membrane systems without interference zones
一般来讲，据信可以为形成一个或多个过渡域的膜系统的一个或多个域选择适当的溶剂和/或沉积方法，使得干扰物基本上不渗透穿过其中。因此，可以构建没有明显或沉积的干扰域的传感器，该传感器对干扰物无应答。虽然不希望受理论所束缚，但据信可以提供简化的多层膜系统、更稳健的多层制造方法、以及由沉积的微米薄干扰域的厚度和相关氧和葡萄糖灵敏度引起的降低的可变性。另外，消除了通常抑制过氧化氢扩散的任选的聚合物基干扰域，从而提高了通过膜系统的过氧化氢的量。Generally speaking, it is believed that suitable solvents and/or deposition methods can be selected for one or more domains of the membrane system forming one or more transition domains so that the interferer does not substantially penetrate therethrough. Therefore, a sensor without a significant or deposited interference domain can be constructed that is unresponsive to the interferer. Although it is not desired to be bound by theory, it is believed that a simplified multilayer membrane system, a more robust multilayer manufacturing method, and reduced variability caused by the thickness of the deposited micrometer-thin interference domain and the associated oxygen and glucose sensitivity can be provided. In addition, the optional polymer-based interference domain that usually inhibits the diffusion of hydrogen peroxide is eliminated, thereby increasing the amount of hydrogen peroxide passing through the membrane system.
氧导管Oxygen catheter
如上文所述，某些传感器依赖于膜系统内的酶，受者的体液通过该膜系统，并且在该膜系统中，体液中的分析物(例如，葡萄糖)在共反应物(例如，氧)的存在下反应以产生产物。然后使用电化学方法测量产物，因此电极系统的输出用作分析物的量度。例如，当传感器是基于葡萄糖氧化酶的葡萄糖传感器时，在工作电极处测量的物质是H2O2。酶(葡萄糖氧化酶)根据以下反应催化氧和葡萄糖向过氧化氢和葡糖酸盐的转化：葡萄糖+O2→葡糖酸盐+H2O2As described above, some sensors rely on enzymes within a membrane system through which the recipient's body fluid passes and in which the analyte in the body fluid (e.g., glucose) reacts in the presence of a co-reactant (e.g., oxygen) to produce a product. The product is then measured electrochemically, so the output of the electrode system serves as a measure of the analyte. For example, when the sensor is a glucose sensor based on glucose oxidase, the substance measured at the working electrode isH2O2 . The enzyme (glucose oxidase) catalyzes the conversion of oxygen and glucose to hydrogen peroxide and gluconate according to the following reaction: Glucose + O2 → Gluconate +H2O2
因为对于那里反应的每个葡萄糖分子，在产物H2O2中存在成比例的变化，所以可监测H2O2的变化以确定葡萄糖浓度。工作电极对H2O2的氧化通过例如反电极处的环境氧、酶生成的H2O2和其他可还原物质的还原来平衡。参见Fraser,D.M.,“An Introduction to Invivo Biosensing:Progress and Problems”。于“Biosensors and the Body,”D.M.Fraser编辑，1997，第1-56页John Wiley and Sons,New York))Because there is a proportional change in the productH2O2 for each glucose molecule reacted there, the changeinH2O2 can be monitored to determine the glucose concentration. The oxidation ofH2O2by the working electrode is balanced by reductionof , for example, ambient oxygen, enzyme-generatedH2O2, and other reducible species at the counter electrode. See Fraser, DM, "An Introduction to Invivo Biosensing: Progress and Problems." In "Biosensors and the Body," DM Fraser, ed., 1997, pp. 1-56 (John Wiley and Sons, New York))
在体内，葡萄糖浓度通常为氧浓度的约100倍或更多倍。因此，氧是电化学反应中的限制性反应物，并且当向传感器提供的氧不足时，传感器不能准确地测量葡萄糖浓度。因此，抑制的传感器功能或不准确性被认为是氧对酶和/或电化学活性表面的可用性问题的结果。In vivo, glucose concentrations are typically about 100 or more times greater than oxygen concentrations. Oxygen is therefore the limiting reactant in the electrochemical reaction, and the sensor cannot accurately measure glucose concentration when insufficient oxygen is provided to the sensor. Thus, inhibited sensor function or inaccuracy is believed to be a result of oxygen availability issues to the enzyme and/or electrochemically active surface.
因此，在另选示例中，提供从传感器的离体部分延伸到传感器的体内部分的氧导管(例如，由有机硅或含氟化合物形成的高氧溶解度域)以增加氧对酶的可用性。氧导管可以形成为涂层(绝缘)材料的一部分，或者可以是与形成传感器的导线组件相关联的单独导管。Therefore, in an alternative example, an oxygen conduit (e.g., a high oxygen solubility domain formed of silicone or fluorochemical) extending from the ex vivo portion of the sensor to the in vivo portion of the sensor is provided to increase the availability of oxygen to the enzyme. The oxygen conduit may be formed as part of the coating (insulating) material, or may be a separate conduit associated with the wire assembly forming the sensor.
图2B是沿着线B-B穿过图2A的传感器的横截面图，示出了芯39，该芯具有被感测膜32包围的至少一个工作电极38的暴露的电化学活性表面。芯39被配置用于多轴弯曲，并且可以是不锈钢、钛、钽或聚合物。一般来讲，本公开的感测膜包括多个域或多层，例如干扰域44、酶域46和抵抗域48，并且可包括附加域，诸如电极域、细胞不可渗透域(未示出)、氧域(未示出)、生物活性物质释放膜70和/或生物界面膜68(未示出)，诸如在下面和/或在上文引用的美国专利申请中更详细地描述的。然而，应当理解，例如通过包括更少的域或附加的域而修改用于其他传感器的感测膜在本公开的范围内。FIG. 2B is a cross-sectional view of the sensor of FIG. 2A along line B-B, showing a core 39 having an exposed electrochemically active surface of at least one working electrode 38 surrounded by a sensing membrane 32. The core 39 is configured for multi-axis bending and can be stainless steel, titanium, tantalum, or a polymer. In general, the sensing membrane of the present disclosure includes multiple domains or layers, such as an interference domain 44, an enzyme domain 46, and a resistance domain 48, and may include additional domains, such as an electrode domain, a cell-impermeable domain (not shown), an oxygen domain (not shown), a bioactive substance release membrane 70, and/or a biointerface membrane 68 (not shown), such as described in more detail below and/or in the U.S. patent application cited above. However, it should be understood that it is within the scope of the present disclosure to modify the sensing membrane for other sensors, for example by including fewer domains or additional domains.
膜系统Membrane system
在一些示例中，感测膜的一个或多个域由以下材料形成：诸如有机硅；聚四氟乙烯；聚乙烯-共-四氟乙烯；聚烯烃；聚酯；聚烷基酯；聚碳酸烷基酯；聚碳酸酯；生物稳定的聚四氟乙烯；聚氨酯的均聚物、共聚物、三元共聚物或聚氨酯脲共聚物；聚丙烯(PP)；聚氯乙烯(PVC)；聚偏二氟乙烯(PVDF)；聚对苯二甲酸丁二醇酯(PBT)；聚甲基丙烯酸甲酯(PMMA)；聚乙烯乙酸乙烯酯；聚醚醚酮(PEEK)；聚氨酯；纤维素聚合物；聚(环氧乙烷)、聚(环氧丙烷)以及它们的共聚物和共混物；聚砜及其嵌段共聚物，包括例如二嵌段共聚物、三嵌段共聚物、交替共聚物、无规共聚物和接枝共聚物。美国专利公开号2005/0245799(其全文以引用方式并入本文)描述了可应用于本发明所公开的传感器的生物界面和感测膜配置和材料。In some examples, one or more domains of the sensing film are formed of materials such as silicone; polytetrafluoroethylene; polyethylene-co-tetrafluoroethylene; polyolefins; polyesters; polyalkyl esters; polyalkyl carbonates; polycarbonates; biostable polytetrafluoroethylene; homopolymers, copolymers, terpolymers or polyurethane urea copolymers of polyurethane; polypropylene (PP); polyvinyl chloride (PVC); polyvinylidene fluoride (PVDF); polybutylene terephthalate (PBT); polymethyl methacrylate (PMMA); polyethylene vinyl acetate; polyether ether ketone (PEEK); polyurethane; cellulosic polymers; poly(ethylene oxide), poly(propylene oxide) and copolymers and blends thereof; polysulfones and block copolymers thereof, including, for example, diblock copolymers, triblock copolymers, alternating copolymers, random copolymers and graft copolymers. U.S. Patent Publication No. 2005/0245799 (incorporated herein by reference in its entirety) describes biointerfaces and sensing film configurations and materials that can be applied to the sensors disclosed herein.
可使用已知的薄膜或厚膜技术(例如，喷涂、电沉积、浸渍等)将感测膜沉积在电极材料的电化学活性表面上。需注意，围绕工作电极的感测膜不必具有与围绕参比电极等的感测膜相同的结构。例如，沉积在工作电极之上的酶域不一定需要沉积在参比电极和/或反电极之上。The sensing film can be deposited on the electrochemically active surface of the electrode material using known thin film or thick film techniques (e.g., spraying, electrodeposition, dipping, etc.) It should be noted that the sensing film surrounding the working electrode does not necessarily have the same structure as the sensing film surrounding the reference electrode, etc. For example, the enzyme domain deposited on the working electrode does not necessarily need to be deposited on the reference electrode and/or the counter electrode.
在所展示的示例中，传感器是酶基电化学传感器，其中工作电极38测量电子流，例如利用葡萄糖氧化酶检测葡萄糖产生过氧化氢作为副产物，H2O2与工作电极的表面反应产生两个质子(2H+)、两个电子(2e-)和一个氧分子(O2)，这产生被检测到的电子流，或者经由氧化还原系统(例如“有线酶”系统)的直接电子转移，诸如上文更详细地描述的并且如本领域技术人员所了解的。采用一个或多个恒电位仪来监测在工作电极的电化学活性表面处的电化学反应。恒电位仪向工作电极及其相关联的参比电极施加恒定电位，以决定在工作电极处产生的电流。在工作电极处产生(并且流过电路到达反电极)的电流基本上与扩散到工作电极的H2O2或促进有线酶系统中的电子转移的分析物的量成比例。例如，输出信号通常是用于向受者或医生提供受者中的实测分析物浓度的可用值的原始数据流。In the illustrated example, the sensor is an enzyme-based electrochemical sensor in which the working electrode 38 measures electron flow, such as the detection of glucose using glucose oxidase to produce hydrogen peroxide as a byproduct, the H2 O2 reacting with the surface of the working electrode to produce two protons (2H+), two electrons (2e-) and one oxygen molecule (O2), which produces the detected electron flow, or direct electron transfer via a redox system (e.g., a "wired enzyme" system), such as described in more detail above and as understood by those skilled in the art. One or more potentiostats are used to monitor the electrochemical reaction at the electrochemically active surface of the working electrode. The potentiostat applies a constant potential to the working electrode and its associated reference electrode to determine the current generated at the working electrode. The current generated at the working electrode (and flowing through the circuit to the counter electrode) is substantially proportional to the amount of H2 O2 diffused to the working electrode or the amount of analyte that promotes electron transfer in the wired enzyme system. For example, the output signal is typically a raw data stream used to provide a usable value of the measured analyte concentration in the recipient to the recipient or a physician.
可受益于本公开的系统和方法的一些另选分析物传感器包括例如授予Ward等人的美国专利号5,711,861、授予Vachon等人的美国专利号6,642,015、授予Say等人的美国专利号6,654,625、授予Say等人的美国专利号6,565,509、授予Heller的美国专利号6,514,718、授予Essenpreis等人的美国专利号6,465,066、授予Offenbacher等人的美国专利号6,214,185、授予Cunningham等人的美国专利号5,310,469和授予Shaffer等人的美国专利号5,683,562、授予Bonnecaze等人的美国专利号6,579,690、授予Say等人的美国专利号6,484,046、授予Colvin等人的美国专利号6,512,939、授予Mastrototaro等人的美国专利号6,424,847、授予Mastrototaro等人的美国专利号6,424,847。所有上述专利全文以引用方式并入本文，并且不包括所有可应用的分析物传感器；一般来讲，应当理解，所公开的示例适用于多种分析物传感器配置。示例性传感器配置Some alternative analyte sensors that may benefit from the systems and methods of the present disclosure include, for example, U.S. Pat. No. 5,711,861 to Ward et al., U.S. Pat. No. 6,642,015 to Vachon et al., U.S. Pat. No. 6,654,625 to Say et al., U.S. Pat. No. 6,565,509 to Say et al., U.S. Pat. No. 6,514,718 to Heller, U.S. Pat. No. 6,465,066 to Essenpreis et al., U.S. Pat. No. 6,214,071 to Offenbacher et al. ,185, U.S. Patent No. 5,310,469 to Cunningham et al. and U.S. Patent No. 5,683,562 to Shaffer et al., U.S. Patent No. 6,579,690 to Bonnecaze et al., U.S. Patent No. 6,484,046 to Say et al., U.S. Patent No. 6,512,939 to Colvin et al., U.S. Patent No. 6,424,847 to Mastrototaro et al., U.S. Patent No. 6,424,847 to Mastrototaro et al. All of the above patents are incorporated herein by reference in their entirety and do not include all applicable analyte sensors; in general, it should be understood that the disclosed examples are applicable to a variety of analyte sensor configurations. Exemplary sensor configurations
图2C是沿着线B-B穿过图2A的传感器的横截面图，示出了被感测膜包围的至少一个工作电极38的未暴露的电化学活性表面，该感测膜包括多个域或多层，例如干扰域44、酶域46和抵抗域48，并且包括附加域/膜，诸如电极域、细胞不可渗透域(未示出)、氧域(未示出)、生物活性物质释放膜70和/或生物界面膜68(未示出)，诸如下文更详细地描述的。生物活性物质释放膜70被定位成邻近工作电极38表面，并且不覆盖工作电极38或邻近工作电极表面的感测膜32的多个域或多层，例如干扰域44、酶域46和抵抗域48。在一个示例中，生物活性物质释放膜70定位在传感器34的远侧端部37处。在另一示例中，生物活性物质释放膜70横跨工作电极38的电化学活性部分，并且不覆盖与工作电极38相关联的感测膜32。FIG. 2C is a cross-sectional view through the sensor of FIG. 2A along line B-B, showing an unexposed electrochemically active surface of at least one working electrode 38 surrounded by a sensing membrane, the sensing membrane including multiple domains or layers, such as interference domains 44, enzyme domains 46, and resistance domains 48, and including additional domains/membranes, such as electrode domains, cell impermeable domains (not shown), oxygen domains (not shown), bioactive substance release membranes 70, and/or biointerface membranes 68 (not shown), such as described in more detail below. The bioactive substance release membrane 70 is positioned adjacent to the surface of the working electrode 38 and does not cover the working electrode 38 or multiple domains or layers of the sensing membrane 32 adjacent to the working electrode surface, such as interference domains 44, enzyme domains 46, and resistance domains 48. In one example, the bioactive substance release membrane 70 is positioned at the distal end 37 of the sensor 34. In another example, the bioactive substance release membrane 70 spans the electrochemically active portion of the working electrode 38 and does not cover the sensing membrane 32 associated with the working electrode 38.
图2D是在传感器34的示例性生物活性物质释放膜沉积的线D-D上穿过图2A的传感器的横截面图，其中生物活性物质释放膜70比抵抗域48和/或生物界面域68更远离电极38，并且邻近但不覆盖酶域46或转导元件和/或干扰域44和/或感测区域或感测区域的电化学活性表面。生物活性物质释放膜70可使用丝网印刷、喷涂或浸涂方法中的一者或多者布置在传感器34上，如图2D所示。2D is a cross-sectional view through the sensor of FIG. 2A on line D-D of an exemplary bioactive substance release film deposition of sensor 34, wherein the bioactive substance release film 70 is further away from electrode 38 than resistance domain 48 and/or biointerface domain 68, and is adjacent to but does not cover enzyme domain 46 or transduction element and/or interference domain 44 and/or sensing region or electrochemically active surface of sensing region. The bioactive substance release film 70 can be arranged on sensor 34 using one or more of screen printing, spray coating or dip coating methods, as shown in FIG. 2D.
图2E是在另一示例性生物活性物质释放膜沉积的线B-B上穿过图2A的传感器的横截面图，其中生物活性物质释放膜70比抵抗域48和/或生物界面层68更远离电极38，并且邻近并通常覆盖仅传感器34的顶端或远侧端部37，直到并邻近同时不覆盖酶域46或转导元件和/或干扰域44和/或感测区域或感测区域的电化学活性表面。生物活性物质释放膜70可使用丝网印刷、喷涂或浸涂方法中的一者或多者布置在传感器34上，如图2E所示。FIG2E is a cross-sectional view through the sensor of FIG2A on line B-B of another exemplary bioactive substance release film deposition, wherein the bioactive substance release film 70 is further away from the electrode 38 than the resistance domain 48 and/or the biointerface layer 68, and is adjacent to and generally covers only the top or distal end 37 of the sensor 34, up to and adjacent to while not covering the enzyme domain 46 or the transduction element and/or the interference domain 44 and/or the sensing region or the electrochemically active surface of the sensing region. The bioactive substance release film 70 can be arranged on the sensor 34 using one or more of screen printing, spray coating or dip coating methods, as shown in FIG2E.
图2F可以被认为构建在如图2A中所描绘的一般结构上，其中添加两个或更多个附加层以产生一个或多个附加电极。还可以采用用于选择性地去除两个或更多个窗口以产生两个或更多个电极的方法。例如，通过在参比电极层30下添加另一个导电层38b和绝缘层35b，然后可以形成两个电极(第一工作电极和(任选的)第二工作电极等)，从而产生双电极传感器或多电极传感器。例如，相同的概念可以应用于产生反电极、测量附加分析物(例如，氧)的电极等。图2G展示了具有附加电极38b的传感器，其中窗口被选择性地去除以暴露在参比电极(包括多个链段)30之间的工作电极38a、38b，少量绝缘体35a、35b暴露在其间。FIG. 2F can be considered to be built on a general structure as depicted in FIG. 2A , in which two or more additional layers are added to produce one or more additional electrodes. A method for selectively removing two or more windows to produce two or more electrodes can also be used. For example, by adding another conductive layer 38b and an insulating layer 35b under the reference electrode layer 30, two electrodes (a first working electrode and (optional) a second working electrode, etc.) can then be formed, thereby producing a dual-electrode sensor or a multi-electrode sensor. For example, the same concept can be applied to produce a counter electrode, an electrode for measuring an additional analyte (e.g., oxygen), etc. FIG. 2G shows a sensor with an additional electrode 38b, in which a window is selectively removed to expose working electrodes 38a, 38b between the reference electrode (comprising a plurality of segments) 30, with a small amount of insulator 35a, 35b exposed therebetween.
虽然本文的一些附图展示了可具有同轴芯和圆形或椭圆形横截面的传感器，但在包括生物活性物质释放膜的传感器系统的其他示例中，传感器可以是基本上平面的传感器，如图2H中用于图示目的的横截面所示。例如，如图2H所示，连续分析物感测设备100可包括基本上平面的衬底142以及以基本上平面的方式在具有一个或多个工作电极的基本上平面的衬底142周围布置的干扰域144、酶域146、抵抗域148和生物界面/生物保护性域168和/或生物活性物质释放域170。参考图2G至图2H，在一些示例中，参比电极30包括应用于绝缘材料35的至少一部分上的含银材料。在一些示例中，使用薄膜和/或厚膜技术应用含银材料，诸如但不限于浸渍、喷涂、印刷、电沉积、气相沉积、旋涂和溅射沉积，如本文别处所述。例如，在示例中，将含银或含氯化银的涂料(或类似制剂)应用于绝缘导电芯的卷轴上。在另一示例中，将绝缘细长主体(或芯)的卷轴切割成单个单元片(例如，“单片化”)并且将含银油墨移印到其上。在再其他示例中，含银材料作为银箔应用。例如，可将粘合剂应用于绝缘细长主体，然后将银箔包裹在该细长主体周围。另选地，可在Ag/AgC1颗粒中滚动传感器，使得足够量的银粘到和/或嵌入和/或以其他方式粘附到粘合剂，以使颗粒用作参比电极。在一些示例中，传感器的参比电极包括足够量的氯化银，使得传感器测量和/或检测分析物至少三天。Although some of the figures herein show sensors that may have a coaxial core and a circular or elliptical cross-section, in other examples of sensor systems including a bioactive substance release membrane, the sensor may be a substantially planar sensor, as shown in the cross-section for illustration purposes in FIG. 2H. For example, as shown in FIG. 2H, the continuous analyte sensing device 100 may include a substantially planar substrate 142 and an interference domain 144, an enzyme domain 146, a resistance domain 148, and a biointerface/bioprotective domain 168 and/or a bioactive substance release domain 170 arranged in a substantially planar manner around the substantially planar substrate 142 having one or more working electrodes. Referring to FIG. 2G to FIG. 2H, in some examples, the reference electrode 30 includes a silver-containing material applied to at least a portion of the insulating material 35. In some examples, the silver-containing material is applied using thin film and/or thick film techniques, such as, but not limited to, dipping, spraying, printing, electrodeposition, vapor deposition, spin coating, and sputtering deposition, as described elsewhere herein. For example, in an example, a silver-containing or silver chloride-containing coating (or similar formulation) is applied to a reel of an insulating conductive core. In another example, a reel of an insulating elongated body (or core) is cut into individual unit pieces (e.g., "singulated") and a silver-containing ink is pad printed thereon. In still other examples, the silver-containing material is applied as a silver foil. For example, an adhesive may be applied to the insulating elongated body and then the silver foil is wrapped around the elongated body. Alternatively, the sensor may be rolled in Ag/AgCl particles such that a sufficient amount of silver is adhered to and/or embedded in and/or otherwise attached to the adhesive to allow the particles to serve as a reference electrode. In some examples, the reference electrode of the sensor includes a sufficient amount of silver chloride such that the sensor measures and/or detects the analyte for at least three days.
在一些示例中，传感器由细长主体33(例如，细长导电主体)形成，诸如图2G所示，其中细长主体包括芯39、第一层38a、绝缘体35a和含银材料层30。在一些示例中，诸如图2H所示，通过形成穿过含银材料和绝缘体两者的窗口31来暴露细长主体的电化学活性表面(例如，还有第一层38a的(电活性)表面)。在一个示例性示例中，图2G的细长主体被提供为卷轴上的延伸长度，该卷轴被单片化为具有一定长度(例如，小于0.5英寸、0.5英寸、1英寸、1.5英寸、2英寸、2.5英寸、3英寸、3.5英寸、4英寸、4.5英寸、5英寸、5.5英寸、6英寸、6.5英寸、7英寸、7.5英寸、8英寸、8.5英寸、9英寸、9.5英寸、10英寸、10.5英寸、11英寸、11.5英寸、12英寸、12.5英寸、13英寸、13.5英寸、14英寸、14.5英寸、15英寸、15.5英寸、16英寸、16.5英寸、17英寸、17.5英寸、18英寸、18.5英寸、19英寸、19.5英寸、20英寸、20.5英寸、21英寸、21.5英寸、22英寸、22.5英寸、23英寸、23.5英寸或24英寸或更长的长度)并且适合于所选传感器配置的多个片。例如，被配置用于经皮植入的第一传感器可采用2.5英寸长度，而被配置用于经皮植入的第二传感器可采用3英寸长度。在另一示例中，被配置用于植入成年受者的外周静脉的第一传感器可采用3英寸长度，而被配置用于植入成年受者的中央静脉的第二传感器可采用12英寸长度。在每个传感器上形成窗口，诸如通过刮削和/或蚀刻穿过含银材料和绝缘体的径向窗口，使得铂表面暴露(例如，“工作电极”的电化学活性表面)。在一些示例中，细长主体的卷轴被单片化，然后形成窗口。在其他示例中，窗口沿着细长主体的卷轴的长度形成，并且随后被单片化。在另外的示例中，在单片化之前执行附加制造步骤。将感测膜32应用于由窗口的边缘限定的暴露的电化学活性表面(例如，工作电极)，使得电化学活性表面可用作传感器的工作电极，以生成与分析物相关联的信号(例如，当传感器与受者的样品接触时)。可使用另选的制造技术和/或步骤顺序来生产具有图2H所示配置的传感器，诸如但不限于在应用绝缘体和含银材料之前掩蔽细长主体(或芯)的一部分。In some examples, the sensor is formed of an elongated body 33 (e.g., an elongated conductive body), such as shown in FIG. 2G , wherein the elongated body includes a core 39, a first layer 38a, an insulator 35a, and a layer 30 of a silver-containing material. In some examples, such as shown in FIG. 2H , an electrochemically active surface of the elongated body (e.g., also the (electroactive) surface of the first layer 38a) is exposed by forming a window 31 through both the silver-containing material and the insulator. In an exemplary example, the elongated body of FIG. 2G is provided as an extended length on a reel that is singulated to have a certain length (e.g., less than 0.5 inches, 0.5 inches, 1 inch, 1.5 inches, 2 inches, 2.5 inches, 3 inches, 3.5 inches, 4 inches, 4.5 inches, 5 inches, 5.5 inches, 6 inches, 6.5 inches, 7 inches, 7.5 inches, 8 inches, 8.5 inches, 9 inches, 9.5 inches, 10 inches, 10.5 inches, 11 inches, 11.5 inches, 12 inches, 13 inches, 14 inches, 15 inches, 16 inches, 17 inches, 18 inches, 19 inches, 20 inches, 21 inches, 22 inches, 23 inches, 24 inches, 25 inches, 26 inches, 27 inches, 28 inches, 29 inches, 30 inches, 31 inches, 32 inches, 33 inches, 34 inches, 35 inches, 36 inches, 37 inches, 38 inches, 39 inches, 40 inches, 41 inches, 42 inches, 43 inches, 44 inches, 45 inches, 46 inches, 47 inches, 48 inches In one embodiment, the invention can include a plurality of sheets of a first sensor configured for percutaneous implantation that is 2.5 inches in length and a second sensor configured for percutaneous implantation that is 3 inches in length. In another example, a first sensor configured for implantation in a peripheral vein of an adult recipient can be implemented in a 3 inch length and a second sensor configured for implantation in a central vein of an adult recipient can be implemented in a 12 inch length. A window is formed on each sensor, such as by scraping and/or etching a radial window through the silver-containing material and the insulator, so that the platinum surface is exposed (e.g., the electrochemically active surface of the "working electrode"). In some examples, the scroll of the elongated body is singulated and then the window is formed. In other examples, the window is formed along the length of the scroll of the elongated body and then singulated. In another example, an additional manufacturing step is performed before singulation. The sensing film 32 is applied to the exposed electrochemically active surface (e.g., the working electrode) defined by the edge of the window so that the electrochemically active surface can be used as the working electrode of the sensor to generate a signal associated with the analyte (e.g., when the sensor is in contact with a sample of the recipient). Alternative manufacturing techniques and/or step sequences can be used to produce sensors having the configuration shown in Figure 2H, such as, but not limited to, masking a portion of the elongated body (or core) before applying the insulator and the silver-containing material.
图2G是示出了切除的层的图示，但是在制造过程中，通常获得的材料具有在顶端处终止的所有层。可执行去除层30和30的步骤，以便形成窗口。图2I通过侧视图/横截面展示了该去除/切除过程的结果。去除过程可通过已经描述的方法或本领域已知的其他方法完成。在一个示例中，去除步骤是例如通过激光刮削来进行的，并且可在连续串上以卷轴到卷轴工艺来执行。例如，通过以不同的长度去除不同的层，被去除的区域可以是阶梯状的(图2I)。在此类涉及连续串的制造方法中，传感器可在去除步骤之后被单片化，从而产生切单部29(图7A至图7C)。在一些示例中，如果芯是金属，则可采用端帽，例如通过将绝缘或其他隔离材料浸渍、喷涂、热缩管式、卷曲包装到顶端上等。如果芯是聚合物(例如，疏水性材料)，则端帽可以不是必需的。例如，在图2I所描绘的传感器中，端帽40(例如，由聚合物或绝缘材料制成)或其他结构可设置在芯上(例如，如果芯39不是绝缘的)。FIG. 2G is a diagram showing the layers removed, but in the manufacturing process, the material generally obtained has all layers that terminate at the top. The steps of removing layers 30 and 30 can be performed to form a window. FIG. 2I shows the result of the removal/removal process by a side view/cross section. The removal process can be completed by the method already described or other methods known in the art. In one example, the removal step is performed, for example, by laser scraping, and can be performed on a continuous string with a reel-to-reel process. For example, by removing different layers at different lengths, the removed area can be stepped (FIG. 2I). In such a manufacturing method involving a continuous string, the sensor can be singulated after the removal step, thereby producing a singulated portion 29 (FIG. 7A to FIG. 7C). In some examples, if the core is metal, an end cap can be used, for example, by dipping, spraying, heat shrinking, curling, etc., an insulating or other isolating material onto the top. If the core is a polymer (e.g., a hydrophobic material), an end cap may not be necessary. For example, in the sensor depicted in FIG. 2I , an end cap 40 (eg, made of a polymer or insulating material) or other structure may be disposed on the core (eg, if the core 39 is not insulated).
图2J可被认为构建在如图2G所描绘的一般结构上，其中添加两个或更多个附加层以产生一个或多个附加电极。还可以采用用于选择性地去除两个或更多个窗口以产生两个或更多个电极的方法。例如，通过在参比电极层30下添加另一导电层38b和绝缘层35b，然后可形成两个电极(第一工作电极和第二工作电极)，从而产生双电极传感器。例如，相同的概念可以应用于产生反电极、测量附加分析物(例如，氧)的电极等。FIG. 2J can be considered to be built on the general structure as depicted in FIG. 2G, where two or more additional layers are added to produce one or more additional electrodes. Methods for selectively removing two or more windows to produce two or more electrodes can also be used. For example, by adding another conductive layer 38b and an insulating layer 35b under the reference electrode layer 30, two electrodes (a first working electrode and a second working electrode) can then be formed, thereby producing a two-electrode sensor. For example, the same concept can be applied to produce a counter electrode, an electrode for measuring an additional analyte (e.g., oxygen), etc.
图2K展示了具有附加电极38b(与图2G至图2I相比)的传感器，其中窗口被选择性地去除以暴露在参比电极(包括多种链段)30之间的工作电极38a、38b，少量绝缘体35a、35b暴露在其间。图2L展示了另一示例，其中各层的选择性去除是逐步进行的，以沿着细长主体的长度暴露电极38a、38b和绝缘体35a、35b。FIG2K shows a sensor with an additional electrode 38b (compared to FIG2G to FIG2I ) where a window is selectively removed to expose working electrodes 38a, 38b between reference electrodes (comprising various segments) 30 with a small amount of insulator 35a, 35b exposed therebetween. FIG2L shows another example where the selective removal of layers is performed stepwise to expose electrodes 38a, 38b and insulators 35a, 35b along the length of the elongated body.
图2J是另选传感器配置的横截面图，示出了被感测膜32包围的至少一个工作电极38的未暴露的电化学活性表面，该感测膜包括多个域或多层，例如干扰域44、酶域46和抵抗域48，并且包括附加的域/膜，诸如电极域、细胞不可渗透域(未示出)、氧域(未示出)、生物活性物质释放膜70和/或生物界面膜68(未示出)，诸如下文更详细地描述的。生物活性物质释放膜70被定位成邻近工作电极38表面，并且不覆盖工作电极38或与工作电极相关联的感测膜32的多个域或多层，例如干扰域44、酶域46和抵抗域48。如图2J所示，邻近生物活性物质释放膜70提供生物活性扩散调节膜73。在一个示例中，扩散调节膜73直接邻近生物活性物质释放膜70。在另一示例中，扩散调节膜73在化学上、结构上或功能上不同于生物活性物质释放膜70。在另一示例中，扩散调节膜73是嵌段共聚物，例如具有硬链段和软链段的聚氨酯嵌段聚合物，其中软链段可包括疏水性部分、亲水性部分或疏水性部分/亲水性部分的组合。疏水性部分/亲水性部分中的每一者可独立地具有不同的平均分子量或链长。在另一示例中，扩散调节膜73是软链段和一种或多种独立的硬链段的链段化嵌段共聚物，软链段包括疏水性部分/亲水性部分的组合，诸如多元醇(聚环氧乙烷、聚乙烯环氧丙烷、聚四氢呋喃或聚四亚甲基氧化物、聚醚、聚硅氧烷、聚胺、聚硅氧烷胺、聚酯、聚烷基酯、聚碳酸烷基酯、聚碳酸酯，一种或多种独立的硬链段为例如脂族或芳族二异氰酸酯，诸如降冰片烷二异氰酸酯(NBDI)、异佛尔酮二异氰酸酯(IPDI)、甲苯二异氰酸酯(TDI)、1,3-亚苯基二异氰酸酯(MPDI)、反式-1,3-双(异氰酸甲基)环己烷(1,3-H6XDI)、双环己基甲烷-4,4'-二异氰酸酯(HMDI)、4,4'-二苯基甲烷二异氰酸酯(MDI)、反式-1,4-双(异氰酸甲基)环己烷(1,4-H6XDI)、1,4-环己基二异氰酸酯(CHDI)、1,4-亚苯基二异氰酸酯(PPDI)、3,3'-二甲基-4,4'-联苯二异氰酸酯(TODI)、1,6-六亚甲基二异氰酸酯(HDI)或它们的组合。FIG. 2J is a cross-sectional view of an alternative sensor configuration, showing an unexposed electrochemically active surface of at least one working electrode 38 surrounded by a sensing membrane 32, the sensing membrane including multiple domains or layers, such as interference domains 44, enzyme domains 46, and resistance domains 48, and including additional domains/membranes, such as electrode domains, cell impermeable domains (not shown), oxygen domains (not shown), bioactive substance release membranes 70, and/or biointerface membranes 68 (not shown), such as described in more detail below. The bioactive substance release membrane 70 is positioned adjacent to the surface of the working electrode 38 and does not cover the working electrode 38 or the multiple domains or layers of the sensing membrane 32 associated with the working electrode, such as interference domains 44, enzyme domains 46, and resistance domains 48. As shown in FIG. 2J, a bioactive diffusion regulating membrane 73 is provided adjacent to the bioactive substance release membrane 70. In one example, the diffusion regulating membrane 73 is directly adjacent to the bioactive substance release membrane 70. In another example, the diffusion regulating membrane 73 is chemically, structurally, or functionally different from the bioactive substance release membrane 70. In another example, the diffusion regulating film 73 is a block copolymer, such as a polyurethane block polymer having a hard segment and a soft segment, wherein the soft segment may include a hydrophobic portion, a hydrophilic portion or a combination of a hydrophobic portion/hydrophilic portion. Each of the hydrophobic portion/hydrophilic portion may independently have a different average molecular weight or chain length. In another example, the diffusion regulating film 73 is a segmented block copolymer of a soft segment and one or more independent hard segments, and the soft segment includes a combination of a hydrophobic portion/hydrophilic portion, such as a polyol (polyethylene oxide, polyethylene propylene oxide, polytetrahydrofuran or polytetramethylene oxide, polyether, polysiloxane, polyamine, polysiloxane amine, polyester, polyalkyl ester, polyalkyl carbonate, polycarbonate, one or more independent hard segments are, for example, aliphatic or aromatic diisocyanates, such as norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene diisocyanate (TDI), 1,3-isocyanate phenyl diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or a combination thereof.
在另一示例中，扩散调节膜73是多嵌段共聚物。在另一示例中，扩散调节膜被退火，以提供稳定的分离相和/或为释放生物活性剂提供扩散通道。在示例中，扩散调节膜73连续地、半连续地或分段地(随机地或以一定模式)应用于生物活性物质释放膜70上。In another example, the diffusion regulating film 73 is a multi-block copolymer. In another example, the diffusion regulating film is annealed to provide a stable separation phase and/or provide a diffusion channel for releasing the bioactive agent. In an example, the diffusion regulating film 73 is applied to the bioactive substance release film 70 continuously, semi-continuously or segmentally (randomly or in a certain pattern).
在一些示例中，在基本上连续的过程中将含银材料应用于传感器(例如，绝缘导电芯)，诸如本文别处所述。因此，在一些示例中，在全自动过程中应用含银材料。在其他示例中，在半自动过程中应用含银材料。In some examples, the silver-containing material is applied to the sensor (e.g., the insulated conductive core) in a substantially continuous process, such as described elsewhere herein. Thus, in some examples, the silver-containing material is applied in a fully automated process. In other examples, the silver-containing material is applied in a semi-automated process.
虽然本公开的方法特别适用于有小结构的、微直径或小直径传感器，但所述方法也可适用于较大直径的传感器，例如，直径为1mm至约2mm或更大的传感器。While the methods of the present disclosure are particularly applicable to micro-diameter or small-diameter sensors having small structures, the methods may also be applicable to larger diameter sensors, for example, sensors having a diameter of 1 mm to about 2 mm or more.
图3A是一个示例中的经皮分析物传感器50的侧面示意图。传感器50包括适于安装在受者皮肤上的安装单元52、适于通过受者皮肤经皮插入的小(直径)结构传感器34(如本文所定义)、以及被配置为在传感器与优选地容纳在安装单元52内的电子器件之间提供安全电接触的电连接。一般来讲，安装单元52被设计成保持传感器在受者中的完整性，以便减少或消除安装单元、受者和/或传感器之间的运动转换。参见2005年3月10日提交的名称为“TRANSCUTANEOUS ANALYTE SENSOR”的美国专利公开号2006/0020187，其全文以引用方式并入本文。在一个示例中，在感测机构36上形成生物活性物质释放膜，如下文更详细地描述的。Fig. 3A is a side schematic diagram of a transcutaneous analyte sensor 50 in an example. The sensor 50 includes a mounting unit 52 suitable for mounting on the recipient's skin, a small (diameter) structure sensor 34 (as defined herein) suitable for percutaneous insertion through the recipient's skin, and an electrical connection configured to provide safe electrical contact between the sensor and the electronic device preferably contained in the mounting unit 52. Generally speaking, the mounting unit 52 is designed to maintain the integrity of the sensor in the recipient so as to reduce or eliminate the motion conversion between the mounting unit, the recipient and/or the sensor. See U.S. Patent Publication No. 2006/0020187, entitled "TRANSCUTANEOUS ANALYTE SENSOR" filed on March 10, 2005, which is incorporated herein by reference in its entirety. In one example, a bioactive substance release membrane is formed on the sensing mechanism 36, as described in more detail below.
图3B是在另选示例中的经皮分析物传感器54的侧面示意图。经皮分析物传感器54包括安装单元52，其中感测机构36包括如本文所定义的小结构，并且经由缆线56拴系到安装单元52(另选地，可以利用无线连接)。安装单元适于安装在受者的皮肤上，并且经由系绳等可操作地连接到有小结构的传感器34上，该有小结构的传感器适于通过受者的皮肤经皮插入并且测量其中的分析物；参见例如授予Causey III等人的美国专利号6,558,330，其全文以引用方式并入本文。在一个示例中，在感测机构36的至少一部分上形成生物活性物质释放膜70，如下文更详细地描述的。FIG. 3B is a side schematic diagram of a transcutaneous analyte sensor 54 in an alternative example. The transcutaneous analyte sensor 54 includes a mounting unit 52, wherein the sensing mechanism 36 includes a small structure as defined herein, and is tethered to the mounting unit 52 via a cable 56 (alternatively, a wireless connection can be utilized). The mounting unit is suitable for mounting on the skin of a recipient, and is operably connected to the sensor 34 having a small structure via a tether, etc., which is suitable for percutaneous insertion through the skin of the recipient and measuring the analyte therein; see, for example, U.S. Patent No. 6,558,330 to Causey III et al., which is incorporated herein by reference in its entirety. In one example, a bioactive substance release membrane 70 is formed on at least a portion of the sensing mechanism 36, as described in more detail below.
可以将本公开的传感器插入受者身体上的各种位置，诸如腹部、大腿、上臂和颈部或耳后。尽管本公开可能建议通过腹部区域插入，但是本文所述的系统和方法既不限于腹部插入也不限于皮下插入。本领域技术人员理解，这些系统和方法可以针对其他插入部位实施和/或修改，并且可以取决于分析物传感器的类型、配置和尺寸。The sensors of the present disclosure may be inserted into various locations on the recipient's body, such as the abdomen, thigh, upper arm and neck, or behind the ear. Although the present disclosure may suggest insertion through the abdominal area, the systems and methods described herein are not limited to abdominal insertion nor to subcutaneous insertion. Those skilled in the art will appreciate that these systems and methods may be implemented and/or modified for other insertion sites and may depend on the type, configuration, and size of the analyte sensor.
可以在各种时间长度内在体内使用经皮连续式分析物传感器。例如，该设备包括用于测量受者中的分析物的传感器、覆盖传感器的至少一部分的多孔的生物相容性基质和用于将传感器通过受者皮肤插入的施用器。在一些示例中，传感器具有至少一个维度小于约1mm的构造。这种结构的示例在图3A和图3B中示出，如本文别处所描述。然而，本领域技术人员将认识到，替代的配置是可能的并且可能是期望的，例如取决于诸如预期的插入位置等因素。传感器通过受者的皮肤插入并进入下面的组织，诸如软组织或脂肪组织。Transcutaneous continuous analyte sensors can be used in vivo in various time lengths. For example, the device includes a sensor for measuring an analyte in a recipient, a porous biocompatible matrix covering at least a portion of the sensor, and an applicator for inserting the sensor through the recipient's skin. In some examples, the sensor has a configuration with at least one dimension less than about 1 mm. Examples of such structures are shown in Figures 3A and 3B, as described elsewhere herein. However, those skilled in the art will recognize that alternative configurations are possible and may be desirable, for example depending on factors such as an expected insertion location. The sensor is inserted through the recipient's skin and enters underlying tissue, such as soft tissue or adipose tissue.
在插入后，流体移动进入间隔区，例如生物相容性基质或膜，诸如生物活性物质释放膜70和/或生物界面膜68，在其中产生流体填充袋。该过程可以立即发生或可以在一段时间内发生，诸如插入后几分钟或几小时。然后检测来自传感器的信号，诸如通过位于受者皮肤表面上的安装单元中的传感器电子器件。一般来讲，传感器可以连续使用数天(诸如1天至7天、14天或21天)的时间段。使用后，将传感器简单地从受者的皮肤上移除。在一个示例中，受者可以根据需要重复插入和检测步骤许多次。在一些实施方式中，可以在约3天后移除传感器，然后插入另一个传感器，等等。类似地，在其他实施方式中，在约3天、5天、7天、10天或14天后移除传感器，随后插入新的传感器，等等。After insertion, the fluid moves into the compartment, such as a biocompatible matrix or membrane, such as a bioactive substance release membrane 70 and/or a biointerface membrane 68, creating a fluid-filled pocket therein. This process can occur immediately or can occur over a period of time, such as a few minutes or hours after insertion. The signal from the sensor is then detected, such as by the sensor electronics in a mounting unit located on the surface of the recipient's skin. Generally speaking, the sensor can be used continuously for a period of several days (such as 1 day to 7 days, 14 days or 21 days). After use, the sensor is simply removed from the recipient's skin. In one example, the recipient can repeat the insertion and detection steps many times as needed. In some embodiments, the sensor can be removed after about 3 days, and then another sensor is inserted, and so on. Similarly, in other embodiments, the sensor is removed after about 3 days, 5 days, 7 days, 10 days or 14 days, and then a new sensor is inserted, and so on.
经皮分析物传感器的一些示例在以下文献中有描述：授予Brauker等人的美国专利号8,133,178(其全文以引用方式并入本文)以及美国专利号8,828,201,Simpson等人；9,131,885,Simpson等人；9,237,864,Simpson等人；和9,763,608,Simpson等人，它们各自全文以引用方式并入本文。一般来讲，经皮分析物传感器包括传感器和具有与其相关联的电子器件的安装单元。Some examples of transcutaneous analyte sensors are described in U.S. Pat. No. 8,133,178 to Brauker et al., which is incorporated herein by reference in its entirety, and U.S. Pat. Nos. 8,828,201 to Simpson et al.; 9,131,885 to Simpson et al.; 9,237,864 to Simpson et al.; and 9,763,608 to Simpson et al., each of which is incorporated herein by reference in its entirety. In general, a transcutaneous analyte sensor includes a sensor and a mounting unit having electronics associated therewith.
一般来讲，安装单元包括适于安装在受者皮肤上的基座、适于通过受者皮肤经皮插入的传感器、以及被配置为在传感器与传感器电子器件之间提供安全电接触的一个或多个接触点。安装单元被设计成保持传感器在受者中的完整性，以便减少或消除安装单元、受者和/或传感器之间的运动转换。基座可以由多种硬质或软质材料形成，并且优选地包括薄型轮廓，以最小化设备在使用期间从受者的突出。在一些示例中，基座至少部分地由柔性材料形成，据信该柔性材料提供优于常规经皮传感器的许多优点，不幸的是，当受者使用该设备时，该常规经皮传感器可能会遭受与受者的移动相关联的运动相关伪影。例如，当经皮分析物传感器被插入到受者中时，传感器的各种运动(例如，在体内部分与离体部分之间的相对运动、皮肤的运动和/或受者内(真皮或皮下)的运动)在设备上产生应力并且可能在传感器信号中产生噪声。据信，即使皮肤的小运动也可能转化为不适和/或运动相关的伪影，这可以通过柔性或铰接基座来减少或排除。因此，通过提供设备对受者皮肤的柔性和/或铰接，可以实现传感器系统对受者的常规使用和运动的更好的一致性。柔性或铰接被认为增加了安装单元在皮肤上的粘附(通过使用粘合垫)，从而减少了与运动相关的伪影，否则该伪影可以由受者的运动转化并且降低传感器性能。Generally speaking, the mounting unit includes a base suitable for mounting on the skin of a recipient, a sensor suitable for percutaneous insertion through the skin of the recipient, and one or more contact points configured to provide safe electrical contact between the sensor and the sensor electronics. The mounting unit is designed to maintain the integrity of the sensor in the recipient so as to reduce or eliminate the motion conversion between the mounting unit, the recipient and/or the sensor. The base can be formed of a variety of hard or soft materials, and preferably includes a thin profile to minimize the protrusion of the device from the recipient during use. In some examples, the base is at least partially formed of a flexible material, which is believed to provide many advantages over conventional transcutaneous sensors, which unfortunately may suffer from motion-related artifacts associated with the movement of the recipient when the recipient uses the device. For example, when the transcutaneous analyte sensor is inserted into the recipient, various movements of the sensor (e.g., relative movement between the in vivo part and the ex vivo part, movement of the skin and/or movement within the recipient (dermis or subcutaneous)) generate stress on the device and may generate noise in the sensor signal. It is believed that even small movements of the skin may translate into discomfort and/or motion-related artifacts, which may be reduced or eliminated by a flexible or articulated base. Thus, by providing flexibility and/or articulation of the device to the recipient's skin, better conformance of the sensor system to regular use and movement of the recipient may be achieved. The flexibility or articulation is believed to increase the adhesion of the mounting unit to the skin (through the use of adhesive pads), thereby reducing motion-related artifacts that may otherwise be translated by the recipient's movement and degrade sensor performance.
在某些示例中，安装单元可以设置有粘合垫，该粘合垫优选地设置在安装单元的后表面上并且优选地包括可释放背衬层。因此，移除背衬层并将安装单元的基座部分按压到受者皮肤上使安装单元粘附到受者的皮肤上。另外地或另选地，在传感器插入完成之后，可以将粘合垫放置在传感器系统的一些或全部上以确保粘合，并且任选地确保围绕伤口出口部位(或传感器插入部位)的气密密封或水密密封。可以选择和设计适当的粘合垫以拉伸、拉长、贴合和/或通气该区域(例如，受者的皮肤)。In some examples, the mounting unit can be provided with an adhesive pad, which is preferably provided on the rear surface of the mounting unit and preferably includes a releasable backing layer. Thus, removing the backing layer and pressing the base portion of the mounting unit onto the recipient's skin causes the mounting unit to adhere to the recipient's skin. Additionally or alternatively, after the sensor insertion is completed, an adhesive pad can be placed on some or all of the sensor system to ensure adhesion, and optionally to ensure an airtight or watertight seal around the wound exit site (or sensor insertion site). Appropriate adhesive pads can be selected and designed to stretch, elongate, fit and/or ventilate the area (e.g., the recipient's skin).
在示例中，粘合垫由射流喷网法、开孔或闭孔泡沫和/或非织造纤维形成，并且包括设置在其上的粘合剂，然而，如医疗粘合垫领域的技术人员所理解的，可使用适于粘附到受者皮肤的多种粘合垫。在一些示例中，双面粘合垫用于将安装单元粘附到受者的皮肤上。在其他示例中，粘合垫包括泡沫层，例如其中泡沫设置在粘合垫的侧边缘之间并充当减震器的层。In examples, the adhesive pad is formed of spunlaced, open or closed cell foam and/or nonwoven fibers and includes an adhesive disposed thereon, however, as will be appreciated by those skilled in the art of medical adhesive pads, a variety of adhesive pads suitable for adhesion to the recipient's skin may be used. In some examples, a double-sided adhesive pad is used to adhere the mounting unit to the recipient's skin. In other examples, the adhesive pad includes a foam layer, such as a layer in which the foam is disposed between the side edges of the adhesive pad and acts as a shock absorber.
在一些示例中，粘合垫的表面积大于安装单元后表面的表面积。另选地，粘合垫的尺寸可以设定成具有与基座部分的后表面基本上相同的表面积。优选地，粘合垫在待安装在受者皮肤上的一侧上的表面积大于安装单元基底后表面的表面积约1倍、1.25倍、1.5倍、1.75倍、2倍、2.25倍或2.5倍。这种更大的表面积可以增加安装单元与受者皮肤之间的粘附，使安装单元与受者皮肤之间的运动最小化，和/或保护伤口出口部位(传感器插入部位)免受环境和/或生物污染。然而，在一些另选示例中，假定可以实现足够的粘附，则粘合垫的表面积可以小于后表面。In some examples, the surface area of the adhesive pad is larger than the surface area of the rear surface of the mounting unit. Alternatively, the size of the adhesive pad can be set to have a surface area substantially the same as the rear surface of the base portion. Preferably, the surface area of the adhesive pad on the side to be mounted on the recipient's skin is approximately 1 times, 1.25 times, 1.5 times, 1.75 times, 2 times, 2.25 times or 2.5 times larger than the surface area of the rear surface of the mounting unit substrate. This larger surface area can increase the adhesion between the mounting unit and the recipient's skin, minimize the movement between the mounting unit and the recipient's skin, and/or protect the wound exit site (sensor insertion site) from environmental and/or biological contamination. However, in some alternative examples, assuming that sufficient adhesion can be achieved, the surface area of the adhesive pad can be smaller than the rear surface.
在一些示例中，粘合垫具有与基座的后表面基本上相同的形状，但是也可以有利地采用其他形状，例如蝶形、圆形、正形或矩形。粘合垫背衬可以设计成两步释放，例如初次剥离(其中最初仅暴露粘合垫的一部分以允许设备的可调节定位)以及二次剥离(其中稍后暴露剩余粘合垫以在适当定位后将设备牢固且安全地粘附到受者皮肤上)。粘合垫优选地是防水的。优选地，在基座部分的后表面上设置拉伸剥离粘合垫，以使得在传感器的可使用寿命终止时能够容易地从受者的皮肤剥离。In some examples, the adhesive pad has substantially the same shape as the rear surface of the base, although other shapes, such as butterfly, circular, orthogonal, or rectangular, may also be advantageously employed. The adhesive pad backing may be designed for a two-step release, such as a primary peel (in which only a portion of the adhesive pad is initially exposed to allow adjustable positioning of the device) and a secondary peel (in which the remaining adhesive pad is later exposed to securely and safely adhere the device to the recipient's skin after proper positioning). The adhesive pad is preferably waterproof. Preferably, a stretch release adhesive pad is provided on the rear surface of the base portion to enable easy peeling from the recipient's skin at the end of the useful life of the sensor.
在一些情况下，已经发现，在粘合垫与安装单元之间的常规结合可能是不充分的，例如，由于可能导致粘合垫从安装单元剥离的湿度。因此，在一些示例中，可以使用通过紫外线、声波、射频或湿气固化活化或加速的粘结剂来粘结粘合垫。在一些示例中，第一复合材料和第二复合材料的共晶结合可以形成强粘附。在一些示例中，安装单元的表面可以利用臭氧、等离子体、化学品等进行预处理，以便增强表面的粘结性。In some cases, it has been found that conventional bonding between the adhesive pad and the mounting unit may be insufficient, for example, due to humidity that may cause the adhesive pad to peel from the mounting unit. Therefore, in some examples, an adhesive activated or accelerated by ultraviolet, sonic, radio frequency, or moisture curing may be used to bond the adhesive pad. In some examples, a eutectic bond of the first composite material and the second composite material may form a strong adhesion. In some examples, the surface of the mounting unit may be pre-treated with ozone, plasma, chemicals, etc. to enhance the adhesion of the surface.
优选地在传感器插入之前或期间将生物活性剂局部施用于插入部位。合适的生物活性剂包括已知阻碍或防止细菌生长和感染的那些，例如，抗炎剂、抗微生物剂、抗生素等。据信，生物活性剂的扩散或存在可能有助于防止或消除与出口部位邻近的细菌。另外地或另选地，生物活性剂可以与粘合垫整合或涂覆在粘合垫上，或根本不采用生物活性剂。The bioactive agent is preferably applied topically to the insertion site before or during sensor insertion. Suitable bioactive agents include those known to hinder or prevent bacterial growth and infection, for example, anti-inflammatory agents, antimicrobial agents, antibiotics, etc. It is believed that the diffusion or presence of the bioactive agent may help prevent or eliminate bacteria adjacent to the exit site. Additionally or alternatively, the bioactive agent may be integrated with or coated on the adhesive pad, or no bioactive agent may be used at all.
在一些示例中，提供施用器用于在针的帮助下以适当的插入角度将传感器通过受者皮肤插入，并且用于随后使用连续推拉动作移除针。优选地，施用器包括引导施用器并且包括施用器本体基座的施用器本体，该施用器本体基座被配置为在将传感器插入到受者内期间与安装单元配合。施用器本体基座与安装单元之间的配合可以使用任何已知的配合配置，例如卡扣配合、压入配合、干涉配合等，以在使用期间阻碍分离。一个或多个释放簧键使得能够释放施用器主体基座，例如，当施用器主体基座卡扣配合到安装单元中时。In some examples, an applicator is provided for inserting the sensor through the skin of a recipient at an appropriate insertion angle with the aid of a needle, and for subsequently removing the needle using a continuous push-pull motion. Preferably, the applicator includes an applicator body that guides the applicator and includes an applicator body base that is configured to cooperate with the mounting unit during insertion of the sensor into the recipient. The cooperation between the applicator body base and the mounting unit can use any known cooperation configuration, such as a snap fit, a press fit, an interference fit, etc., to hinder separation during use. One or more release spring keys enable release of the applicator body base, for example, when the applicator body base is snap-fitted into the mounting unit.
传感器电子器件包括能够通过传感器测量分析物水平的硬件、固件和/或软件。例如，传感器电子器件可以包括恒电位仪、用于向传感器提供电力的电源、用于信号处理的其他部件、以及优选地用于将数据从传感器电子器件传输到接收器的RF模块。电子器件可以固定到印刷电路板(PCB)等，并且可以采取各种形式。例如，电子器件可以采取集成电路(IC)的形式，诸如专用集成电路(ASIC)、微控制器或处理器。优选地，传感器电子器件包括用于处理传感器分析物数据的系统和方法。用于处理传感器分析物数据的系统和方法的示例在下文和2003年8月1日提交的名称为“SYSTEM AND METHODS FOR PROCESSING ANALYTESENSOR DATA”的美国专利号7,778,680中更详细地描述。Sensor electronics include hardware, firmware and/or software that can measure analyte levels by sensors. For example, sensor electronics may include a potentiostat, a power supply for providing power to the sensor, other components for signal processing, and preferably an RF module for transmitting data from sensor electronics to a receiver. Electronics may be fixed to a printed circuit board (PCB), etc., and may take various forms. For example, electronics may take the form of an integrated circuit (IC), such as an application specific integrated circuit (ASIC), a microcontroller, or a processor. Preferably, sensor electronics include systems and methods for processing sensor analyte data. Examples of systems and methods for processing sensor analyte data are described in more detail below and in U.S. Patent No. 7,778,680, filed on August 1, 2003, entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA".
在该示例中，在使用施用器插入传感器并且随后从安装单元释放施用器之后，传感器电子器件被配置为与安装单元可释放地配合。在示例中，电子器件被配置有编程，例如每当电子器件初始被插入到安装单元中和/或每当电子器件初始与传感器通信时初始化、校准复位、故障测试等。In this example, after the sensor is inserted using the applicator and the applicator is subsequently released from the mounting unit, the sensor electronics are configured to releasably mate with the mounting unit. In an example, the electronics are configured with programming, such as initialization, calibration reset, fault testing, etc., whenever the electronics are initially inserted into the mounting unit and/or whenever the electronics are initially in communication with the sensor.
传感器电子器件Sensor electronics
与传感器相关联的电子器件的以下描述适用于多种连续分析物传感器，诸如无创、微创和/或有创(例如，经皮和完全可植入)传感器。例如，下面描述的传感器电子器件和数据处理以及接收器电子器件和数据处理可被并入在2004年5月3日提交的名称为“IMPLANTABLE ANALYTE SENSOR”的美国专利公开号2005/0245799和2004年7月6日提交的名称为“SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE-MEASURING DEVICEINCLUDING A MEMBRANE SYSTEM”的美国专利公开号2006/0015020中公开的完全可植入葡萄糖传感器中。The following description of electronics associated with the sensor is applicable to a variety of continuous analyte sensors, such as non-invasive, minimally invasive, and/or invasive (e.g., transcutaneous and fully implantable) sensors. For example, the sensor electronics and data processing and receiver electronics and data processing described below may be incorporated into the fully implantable glucose sensor disclosed in U.S. Patent Publication No. 2005/0245799, entitled “IMPLANTABLE ANALYTE SENSOR,” filed on May 3, 2004, and U.S. Patent Publication No. 2006/0015020, entitled “SYSTEMS AND METHODS FOR MANUFACTURE OF AN ANALYTE-MEASURING DEVICE INCLUDING A MEMBRANE SYSTEM,” filed on July 6, 2004.
在一个示例中，可操作地连接到电极系统(诸如上文所述)的恒电位仪向电极提供电压，该电压使传感器偏置以能够测量指示受者体内的分析物浓度的电流信号(也称为模拟部分)。在一些示例中，恒电位仪包括将电流转换成电压的电阻器。在一些另选示例中，提供了一种电流与频率转换器，其被配置为例如使用电荷计数设备对测量的电流连续求积分。A/D转换器将模拟信号数字化为用于处理的数字信号(也称为“计数”)。因此，计数中所得的原始数据流(也称为原始传感器数据)与由恒电位仪测量的电流直接相关。In one example, a potentiostat operably connected to an electrode system (such as described above) provides a voltage to the electrode that biases the sensor to enable measurement of a current signal (also referred to as an analog portion) indicating the concentration of an analyte in a recipient. In some examples, the potentiostat includes a resistor that converts the current into a voltage. In some alternative examples, a current to frequency converter is provided that is configured to continuously integrate the measured current, for example, using a charge counting device. The A/D converter digitizes the analog signal into a digital signal (also referred to as a "count") for processing. Therefore, the raw data stream (also referred to as raw sensor data) obtained in the count is directly related to the current measured by the potentiostat.
处理器模块包括控制传感器电子器件的处理的中央控制单元。在一些示例中，处理器模块包括微处理器，然而除微处理器之外的计算机系统可以用于处理如本文所述的数据，例如ASIC可以用于一些或全部传感器中央处理。处理器通常提供数据的半永久存储，例如，存储诸如传感器标识符(ID)等数据和用于处理数据流的编程(例如，用于数据平滑和/或替换信号伪影的编程，诸如在2003年8月22日提交的名称为“SYSTEMS AND METHODS FORREPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM”的美国专利号8,010,174中所述)。处理器另外可以用于系统的高速缓冲存储器，例如用于临时储存最近的传感器数据。在一些示例中，处理器模块包括存储器存储部件，例如ROM、RAM、动态RAM、静态RAM、非静态RAM、EEPROM、可重写ROM、闪速存储器等。The processor module includes a central control unit that controls the processing of the sensor electronics. In some examples, the processor module includes a microprocessor, however, a computer system other than a microprocessor can be used to process data as described herein, for example, an ASIC can be used for some or all of the sensor central processing. The processor generally provides semi-permanent storage of data, for example, storing data such as sensor identifiers (IDs) and programming for processing data streams (e.g., programming for data smoothing and/or replacing signal artifacts, such as described in U.S. Patent No. 8,010,174, filed on August 22, 2003, entitled "SYSTEMS AND METHODS FORREPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM"). The processor can also be used for a cache memory of the system, for example, for temporarily storing recent sensor data. In some examples, the processor module includes a memory storage component, such as a ROM, RAM, dynamic RAM, static RAM, non-static RAM, EEPROM, rewritable ROM, flash memory, etc.
在一些示例中，处理器模块包括数字滤波器(例如IIR或FIR滤波器)，其被配置为平滑来自A/D转换器的原始数据流。通常，数字滤波器被编程以对以预定时间间隔取样的数据(也称为取样率)进行滤波。在一些示例中，其中恒电位仪被配置为以离散的时间间隔测量分析物，这些时间间隔确定数字滤波器的取样率。在一些另选示例中，其中恒电位仪被配置为连续地测量分析物，例如使用如上文所述的电流与频率转换器，处理器模块可以被编程以在预定时间间隔(也称为采集时间)从A/D转换器请求数字值。在这些另选示例中，由于电流测量的连续性，由处理器获得的值有利地在采集时间内取平均值。因此，采集时间决定了数字滤波器的取样率。在一个示例中，处理器模块被配置有可编程的采集时间，即，用于从A/D转换器请求数字值的预定时间间隔可由用户在处理器模块的数字电路内编程。约2秒至约512秒的采集时间是优选的；然而，任何采集时间均可以被编程到处理器模块中。可编程的采集时间在优化噪声过滤、时滞和处理/电池功率方面是有利的。In some examples, the processor module includes a digital filter (e.g., an IIR or FIR filter) configured to smooth the raw data stream from the A/D converter. Typically, the digital filter is programmed to filter data sampled at predetermined time intervals (also referred to as a sampling rate). In some examples, where the potentiostat is configured to measure the analyte at discrete time intervals, these time intervals determine the sampling rate of the digital filter. In some alternative examples, where the potentiostat is configured to measure the analyte continuously, such as using a current and frequency converter as described above, the processor module can be programmed to request digital values from the A/D converter at predetermined time intervals (also referred to as acquisition time). In these alternative examples, due to the continuity of the current measurement, the values obtained by the processor are advantageously averaged within the acquisition time. Therefore, the acquisition time determines the sampling rate of the digital filter. In one example, the processor module is configured with a programmable acquisition time, that is, the predetermined time interval for requesting digital values from the A/D converter can be programmed by the user in the digital circuit of the processor module. An acquisition time of about 2 seconds to about 512 seconds is preferred; however, any acquisition time can be programmed into the processor module. Programmable acquisition time is advantageous in optimizing noise filtering, latency, and processing/battery power.
优选地，处理器模块被配置为构建用于传输到外部源的数据包，例如，传输到接收器的RF，如下文更详细地描述的。通常，数据包包括多个比特，这些比特可以包括传感器ID码、原始数据、滤波数据和/或错误检测或校正。处理器模块可以被配置为传输原始数据及/或滤波数据的任何组合。Preferably, the processor module is configured to construct a data packet for transmission to an external source, such as an RF transmission to a receiver, as described in more detail below. Typically, the data packet includes a plurality of bits, which may include a sensor ID code, raw data, filtered data, and/or error detection or correction. The processor module may be configured to transmit any combination of raw data and/or filtered data.
在一些示例中，处理器模块还包括确定传感器数据到接收器的传输间隔的传输器部分等。在一些示例中，确定传输间隔的传输器部分被配置为可编程的。在一个此类示例中，可以选择系数(例如，从约1到约100或更大的数)，其中将该系数乘以采集时间(或取样率)(诸如上文所述)以界定数据包的传输间隔。因此，在一些示例中，传输间隔在约2秒与约850分钟之间、更优选地在约30秒与5分钟之间是可编程的。然而，任何传输间隔均可以是可编程的或被编程到处理器模块中。然而，也可以采用用于提供可编程传输间隔的各种另选系统和方法。通过提供可编程传输间隔，可以定制数据传输以满足多种设计准则(例如，减少的电池消耗、报告传感器值的及时性等)。In some examples, the processor module also includes a transmitter part that determines the transmission interval of the sensor data to the receiver, etc. In some examples, the transmitter part that determines the transmission interval is configured to be programmable. In one such example, a coefficient (e.g., from about 1 to about 100 or more) can be selected, wherein the coefficient is multiplied by the acquisition time (or sampling rate) (such as described above) to define the transmission interval of the data packet. Therefore, in some examples, the transmission interval is programmable between about 2 seconds and about 850 minutes, more preferably between about 30 seconds and 5 minutes. However, any transmission interval can be programmable or programmed into the processor module. However, various alternative systems and methods for providing programmable transmission intervals can also be adopted. By providing a programmable transmission interval, data transmission can be customized to meet a variety of design criteria (e.g., reduced battery consumption, timeliness of reporting sensor values, etc.).
常规的葡萄糖传感器测量纳安培范围内的电流。与常规葡萄糖传感器相比，本发明所公开的传感器被配置为测量在皮安培范围(以及在一些示例中飞安培)内的电流。即，对于所测量的每单位(mg/dL)葡萄糖，测量至少1皮安培的电流。优选地，A/D转换器的模拟部分被配置为连续地测量在工作电极处流动的电流并且将电流测量结果转换为表示电流的数字值。在示例中，通过电荷计数设备(例如，电容器)测量电流。因此，提供了信号，由此高灵敏度使通过最小量的所测量的过氧化氢接收的信号最大化(例如，即使在低葡萄糖范围内也不牺牲准确性的最小葡萄糖要求)，从而降低对体内氧限制的灵敏度(例如，在氧依赖性葡萄糖传感器中)。Conventional glucose sensors measure currents in the nanoampere range. Compared to conventional glucose sensors, the sensor disclosed in the present invention is configured to measure currents in the picoampere range (and in some examples, femtoamperes). That is, for each unit (mg/dL) of glucose measured, a current of at least 1 picoampere is measured. Preferably, the analog portion of the A/D converter is configured to continuously measure the current flowing at the working electrode and convert the current measurement result into a digital value representing the current. In the example, the current is measured by a charge counting device (e.g., a capacitor). Therefore, a signal is provided, whereby high sensitivity maximizes the signal received by the minimum amount of measured hydrogen peroxide (e.g., the minimum glucose requirement that does not sacrifice accuracy even in the low glucose range), thereby reducing the sensitivity to oxygen limitation in the body (e.g., in an oxygen-dependent glucose sensor).
电池可操作地连接到传感器电子器件并且为传感器提供电力。在示例中，电池是锂二氧化锰电池；然而，可以使用任何适当尺寸和电力的电池(例如，七号电池(AAA)、镍镉电池、锌碳电池、碱性电池、锂电池、镍金属氢化物电池、锂离子电池、锌空气电池、锌氧化汞电池、银锌电池和/或全密封电池)。在一些示例中，电池是可再充电的，并且/或者可以使用多个电池为该系统供电。例如，传感器可以经由电感耦合而经皮供电。在一些示例中，石英晶体可操作地连接到处理器并且维持用于作为整体的计算机系统的系统时间，例如用于处理器模块内的可编程采集时间。The battery is operably connected to the sensor electronics and provides power to the sensor. In an example, the battery is a lithium manganese dioxide battery; however, any battery of appropriate size and power may be used (e.g., AAA, nickel-cadmium, zinc-carbon, alkaline, lithium, nickel-metal hydride, lithium-ion, zinc-air, zinc-mercury oxide, silver-zinc, and/or fully sealed). In some examples, the battery is rechargeable and/or multiple batteries may be used to power the system. For example, the sensor may be transcutaneously powered via inductive coupling. In some examples, a quartz crystal is operably connected to the processor and maintains system time for the computer system as a whole, such as for programmable acquisition time within a processor module.
可以提供任选的温度探针，其中温度探针位于电子组件或葡萄糖传感器自身上。温度探针可以用于测量葡萄糖传感器附近的环境温度。该温度测量可以用于向计算的葡萄糖值添加温度补偿。An optional temperature probe may be provided, wherein the temperature probe is located on the electronics assembly or the glucose sensor itself. The temperature probe may be used to measure the ambient temperature near the glucose sensor. This temperature measurement may be used to add temperature compensation to the calculated glucose value.
RF模块可操作地连接到处理器并且经由天线在无线传输内将传感器数据从传感器传输到接收器。在一些示例中，第二石英晶体为用于来自RF收发器的数据传输的RF载波频率提供时基。然而，在一些另选示例中，其他机构诸如光学、红外辐射(IR)、超声波等可以用于传输和/或接收数据。The RF module is operably connected to the processor and transmits the sensor data from the sensor to the receiver via the antenna in a wireless transmission. In some examples, the second quartz crystal provides a time base for the RF carrier frequency used for data transmission from the RF transceiver. However, in some alternative examples, other mechanisms such as optics, infrared radiation (IR), ultrasound, etc. can be used to transmit and/or receive data.
在本公开的RF遥测模块中，硬件和软件被设计成低功率要求以增加设备的寿命(例如，使得能够实现约3个月至约24个月或更长时间的寿命)，其中对于完全可植入传感器具有从体内环境到离体环境的最大RF传输(例如，约1米至10米或更长的距离)。优选地，采用约402MHz至约433MHz的高频载波信号以便维持较低的功率要求。附加地，在完全可植入设备中，载波频率适于生理衰减水平，这通过在模拟体内环境中调谐RF模块以确保植入后的RF功能性来实现；因此，优选的葡萄糖传感器可以将传感器功能维持3个月、6个月、12个月或24个月或更长时间。In the RF telemetry module of the present disclosure, the hardware and software are designed for low power requirements to increase the life of the device (e.g., enabling a life of about 3 months to about 24 months or more), where there is a maximum RF transmission from the in vivo environment to the ex vivo environment for a fully implantable sensor (e.g., a distance of about 1 meter to 10 meters or more). Preferably, a high frequency carrier signal of about 402 MHz to about 433 MHz is used to maintain low power requirements. Additionally, in a fully implantable device, the carrier frequency is adapted to physiological attenuation levels, which is achieved by tuning the RF module in a simulated in vivo environment to ensure RF functionality after implantation; therefore, the preferred glucose sensor can maintain sensor functionality for 3 months, 6 months, 12 months, or 24 months or more.
在一些示例中，输出信号(来自传感器电子器件)被发送到接收器(例如，计算机或其他通信站)。例如，输出信号通常是用于向患者或医生提供测量的分析物浓度的可用值的原始数据流。在一些示例中，原始数据流可被连续地或周期性地算法平滑或以其他方式修改，以减少例如由于信号噪声或其他信号伪影而不准确地表示分析物浓度的偏离点，诸如在2003年8月1日提交的名称为“SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTSIN A GLUCOSE SENSOR DATA STREAM”的美国专利号6,931,327中所述，该专利全文以引用方式并入本文。In some examples, the output signal (from the sensor electronics) is sent to a receiver (e.g., a computer or other communication station). For example, the output signal is typically a raw data stream used to provide a patient or physician with a usable value of the measured analyte concentration. In some examples, the raw data stream may be algorithmically smoothed or otherwise modified continuously or periodically to reduce deviation points that inaccurately represent the analyte concentration, for example due to signal noise or other signal artifacts, such as described in U.S. Pat. No. 6,931,327, entitled "SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM," filed on August 1, 2003, which is incorporated herein by reference in its entirety.
当首先将传感器植入到受者组织中时，初始化传感器和接收器。这可以被称为启动模式，并且包括任选地重置传感器数据和校准传感器。在选定的示例中，将电子单元配合到安装单元触发启动模式。在其他示例中，启动模式由接收器触发。When the sensor is first implanted into the recipient tissue, the sensor and receiver are initialized. This may be referred to as a startup mode and includes optionally resetting the sensor data and calibrating the sensor. In selected examples, mating the electronics unit to the mounting unit triggers the startup mode. In other examples, the startup mode is triggered by the receiver.
接收器receiver
在一些示例中，传感器电子器件经由单向或双向RF传输等无线地连接到接收器。然而，也设想了有线连接。接收器提供传感器数据的许多处理和显示，并且可以在受者方便时选择性地佩戴和/或移除。因此，传感器系统可以被谨慎地佩戴，并且提供传感器数据的许多处理和显示的接收器可以在受者方便时选择性地佩戴和/或移除。特别地，接收器包括用于回顾性地和/或前瞻性地启动校准、转换传感器数据、更新校准、评价接收到的参考和传感器数据以及评价分析物传感器的校准的编程，诸如参考2003年8月1日提交的名称为“SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA”的美国专利号7,778,680更详细地描述的。In some examples, the sensor electronics are wirelessly connected to the receiver via unidirectional or bidirectional RF transmission, etc. However, wired connections are also envisioned. The receiver provides many processing and displays of sensor data and can be selectively worn and/or removed when convenient for the recipient. Therefore, the sensor system can be worn discreetly, and the receiver that provides many processing and displays of sensor data can be selectively worn and/or removed when convenient for the recipient. In particular, the receiver includes programming for retrospectively and/or prospectively initiating calibration, converting sensor data, updating calibration, evaluating received reference and sensor data, and evaluating the calibration of analyte sensors, such as described in more detail in U.S. Patent No. 7,778,680, entitled "SYSTEM AND METHODS FOR PROCESSING ANALYTE SENSOR DATA" filed on August 1, 2003.
图3C是在一个示例中的完全可植入的分析物传感器53的侧面示意图。传感器包括适于皮下植入的传感器主体60，并且包括如本文所定义的有小结构的传感器34。授予Brauker等人的公开的美国专利公开号2004/0199059描述了适合用于传感器主体60的系统和方法，并且其全文以引用方式并入本文。在一个示例中，生物界面膜68形成到感测机构36上，如本文别处更详细地描述的。传感器主体60包括传感器电子器件并且优选地与接收器通信，如上文更详细地描述的。如图3C所示，生物活性物质释放膜70设置在生物界面膜68和/或感测膜32的至少一部分上。Fig. 3C is a side schematic diagram of a fully implantable analyte sensor 53 in one example. The sensor includes a sensor body 60 suitable for subcutaneous implantation, and includes a sensor 34 with a small structure as defined herein. The disclosed U.S. Patent Publication No. 2004/0199059 granted to Brauker et al. describes a system and method suitable for sensor body 60, and is incorporated herein by reference in its entirety. In one example, a biointerface membrane 68 is formed on the sensing mechanism 36, as described in more detail elsewhere herein. The sensor body 60 includes a sensor electronic device and preferably communicates with a receiver, as described in more detail above. As shown in Fig. 3C, a bioactive substance release membrane 70 is disposed on at least a portion of the biointerface membrane 68 and/or the sensing membrane 32.
图3D是在另选示例中的完全可植入的分析物传感器62的侧面示意图。完全可植入的分析物传感器62包括传感器主体60和如本文所定义的有小结构的传感器34。传感器主体60包括传感器电子器件并且优选地与接收器通信，如上文更详细地描述的。3D is a side schematic diagram of a fully implantable analyte sensor 62 in an alternative example. The fully implantable analyte sensor 62 includes a sensor body 60 and a sensor 34 having a small structure as defined herein. The sensor body 60 includes sensor electronics and preferably communicates with a receiver, as described in more detail above.
在一个示例中，生物界面膜68形成到感测机构36上，如本文别处更详细地描述的。在另一示例中，在感测机构36的至少一部分上形成生物活性物质释放膜70。在另一示例中，在感测机构36的离散、分离的部分上形成生物活性物质释放膜70。在又一示例中，在生物活性物质释放膜70的至少一部分上形成生物界面膜68。在又一示例中，在生物界面膜68的至少一部分上形成生物活性物质释放膜70。在一个示例中，基质或框架64围绕感测机构36，用于例如通过使组织压靠或围绕框架64而不是感测机构36来保护传感器免受一些异物过程。In one example, a biointerface membrane 68 is formed onto the sensing mechanism 36, as described in more detail elsewhere herein. In another example, a bioactive substance release membrane 70 is formed on at least a portion of the sensing mechanism 36. In another example, the bioactive substance release membrane 70 is formed on discrete, separate portions of the sensing mechanism 36. In yet another example, the biointerface membrane 68 is formed on at least a portion of the bioactive substance release membrane 70. In yet another example, the bioactive substance release membrane 70 is formed on at least a portion of the biointerface membrane 68. In one example, a matrix or frame 64 surrounds the sensing mechanism 36 for protecting the sensor from some foreign body processes, such as by pressing tissue against or around the frame 64 instead of the sensing mechanism 36.
一般来讲，任选的保护性框架64由二维或三维的柔性、半刚性或刚性基质(例如，网)形成，并且其包括分析物可以通过的空间或孔。在一些示例中，框架作为生物界面膜的一部分被并入，然而以提供单独的框架。虽然不希望受理论所束缚，但据信框架64保护有小结构的感测机构免受体内产生的机械力的影响。Generally, the optional protective frame 64 is formed of a two-dimensional or three-dimensional flexible, semi-rigid or rigid matrix (e.g., a mesh) and includes spaces or holes through which analytes can pass. In some examples, the frame is incorporated as part of the biointerface membrane, but a separate frame is provided. Although not wishing to be bound by theory, it is believed that the frame 64 protects the sensing mechanism with small structures from the mechanical forces generated in the body.
图3E是另一个另选示例中的完全可植入的分析物传感器66的侧面示意图。传感器66包括传感器主体60和有小结构的传感器34，如本文所定义的，具有生物界面膜68和/或生物活性物质释放膜70，诸如本文别处更详细地描述的。优选地，框架64保护感测机构36，诸如上文更详细地描述的。传感器主体60包括传感器电子器件并且优选地与接收器通信，如上文更详细地描述的。FIG. 3E is a side schematic diagram of a fully implantable analyte sensor 66 in another alternative example. The sensor 66 includes a sensor body 60 and a sensor 34 having a small structure, as defined herein, with a biointerface membrane 68 and/or a bioactive substance release membrane 70, such as described in more detail elsewhere herein. Preferably, the frame 64 protects the sensing mechanism 36, such as described in more detail above. The sensor body 60 includes a sensor electronic device and preferably communicates with a receiver, as described in more detail above.
在某些示例中，适于完全植入受者内(诸如皮下面的软组织中)的感测设备被皮下植入，诸如植入例如受者的腹部中。由于传感器的小尺寸，本领域技术人员理解多种合适的植入部位可用。在一些示例中，传感器构造在至少一个维度上小于约0.5mm，例如具有小于约0.5mm的直径的基于导线的传感器。在另一个示例性示例中，例如，传感器可以是0.5mm厚、3mm长和2cm宽，诸如可能是窄的衬底、针、导线、棒、片或袋。在另一个示例性示例中，多个约1mm宽、约5mm长的导线可以在它们的第一端连接，从而产生叉状传感器结构。在又一个示例中，1mm宽的传感器可以被盘绕，以产生平面的螺旋传感器结构。尽管上文引用了几个示例，但是本公开设想了许多其他有用的示例，如本领域的技术人员理解的。In some examples, a sensing device adapted to be fully implanted in a recipient (such as in the soft tissue beneath the skin) is implanted subcutaneously, such as in the abdomen of the recipient, for example. Due to the small size of the sensor, those skilled in the art understand that a variety of suitable implantation sites are available. In some examples, the sensor is constructed to be less than about 0.5 mm in at least one dimension, such as a wire-based sensor with a diameter less than about 0.5 mm. In another exemplary example, for example, the sensor may be 0.5 mm thick, 3 mm long, and 2 cm wide, such as a substrate, needle, wire, rod, sheet, or bag that may be narrow. In another exemplary example, a plurality of wires of about 1 mm wide and about 5 mm long may be connected at their first ends, thereby producing a forked sensor structure. In yet another example, a 1 mm wide sensor may be coiled to produce a planar spiral sensor structure. Although several examples are cited above, the present disclosure contemplates many other useful examples, as understood by those skilled in the art.
植入后，允许组织在生物界面内向内生长一段时间。组织向内生长所需的时间长度随受者的不同而不同，诸如约一周至约3周，但其他时间段也是可能的。一旦血管化组织的成熟床已生长到生物界面中，就可从传感器检测信号，如本文别处和授予Brauker等人的名称为“IMPLANTABLE ANALYTE SENSOR”的美国专利公开号2005/0245799中所述，该专利全文并入本文。长期传感器可以保持植入并产生数月至数年的葡萄糖信号信息，如上述专利申请中所述。After implantation, tissue is allowed to grow inwardly in the biological interface for a period of time. The length of time required for tissue ingrowth varies with the recipient, such as from about one week to about three weeks, but other time periods are also possible. Once the mature bed of vascularized tissue has grown into the biological interface, a signal can be detected from the sensor, as described elsewhere herein and in U.S. Patent Publication No. 2005/0245799 entitled "IMPLANTABLE ANALYTE SENSOR" to authorize Brauker et al., which is incorporated herein in its entirety. Long-term sensors can remain implanted and generate glucose signal information for months to years, as described in the above-mentioned patent application.
在某些示例中，设备被配置使得感测单元通过系绳或缆线或类似结构(类似于图3B中所展示的结构)与电子单元分离。本领域技术人员将认识到，可以使用各种已知且有用的装置将传感器栓系到电子器件上。虽然不希望受理论所束缚，但据信例如由于电子器件单元的较大质量，对单独的电子单元的FBR可能大于对单独的感测单元的FBR。因此，感测单元和电子单元的分离有效地减少了到感测单元的FBR并导致改进的设备功能。如本文别处所述，可实施感测单元的构造和/或组成(例如，包括具有某些生物活性剂的生物活性物质释放膜)以进一步降低对栓系的感测单元的异物反应。In some examples, the device is configured so that the sensing unit is separated from the electronic unit by a tether or cable or similar structure (similar to the structure shown in Figure 3B). Those skilled in the art will recognize that various known and useful devices can be used to tether the sensor to the electronic device. Although it is not desired to be bound by theory, it is believed that, for example, due to the larger mass of the electronic device unit, the FBR to the separate electronic unit may be greater than the FBR to the separate sensing unit. Therefore, the separation of the sensing unit and the electronic unit effectively reduces the FBR to the sensing unit and leads to improved device function. As described elsewhere herein, the construction and/or composition of the sensing unit (e.g., including a bioactive substance release film with certain bioactive agents) can be implemented to further reduce the foreign body reaction to the tethered sensing unit.
在另一个示例中，分析物传感器被设计成具有分离的电子器件和感测单元，其中该感测单元被电感耦合到电子器件单元上。在该示例中，电子单元向感测单元提供电力和/或使得能够在其间进行数据通信。图3F和图3G展示了在电子单元52和感测单元58之间采用电感耦合的示例性系统。In another example, the analyte sensor is designed with separate electronics and sensing units, wherein the sensing unit is inductively coupled to the electronics unit. In this example, the electronics unit provides power to the sensing unit and/or enables data communication therebetween. FIG. 3F and FIG. 3G illustrate an exemplary system using inductive coupling between the electronics unit 52 and the sensing unit 58.
图3F是在受者皮肤上在功能上有用的距离内电感耦合到电子单元上的植入传感器的一个示例的侧视图。图3F展示了感测单元58(包括感测机构36)、在传感器34的远侧端部37处的生物界面膜68和生物活性物质释放膜70以及植入在受者皮肤212下方在受者组织210内的小电子芯片216。在该示例中，与传感器相关联的大部分电子器件被容纳在电子单元52(也被称为安装单元)中，该电子单元位于受者皮肤上的适当紧密接近处。电子单元52电感耦合到感测单元58上的小电子芯片216，并且由此例如将电力传输到传感器和/或收集数据。耦合到感测单元58的小电子芯片216提供向传感器提供偏置电位、测量信号输出的必要电子器件和/或允许感测单元58的机构起作用的其他必要要求(例如，芯片216可以包括ASIC(专用集成电路)、天线和本领域技术人员理解的其他必要部件)。FIG. 3F is a side view of an example of an implanted sensor inductively coupled to an electronics unit within a functionally useful distance on the recipient's skin. FIG. 3F shows a sensing unit 58 (including a sensing mechanism 36), a biointerface membrane 68 and a bioactive substance release membrane 70 at the distal end 37 of the sensor 34, and a small electronic chip 216 implanted beneath the recipient's skin 212 within the recipient's tissue 210. In this example, most of the electronics associated with the sensor are housed in an electronics unit 52 (also referred to as a mounting unit), which is located in a suitable close proximity on the recipient's skin. The electronics unit 52 is inductively coupled to the small electronic chip 216 on the sensing unit 58, and thereby, for example, transmits power to the sensor and/or collects data. The small electronic chip 216 coupled to the sensing unit 58 provides the necessary electronics to provide bias potentials to the sensor, measure signal outputs, and/or other necessary requirements to allow the mechanism of the sensing unit 58 to function (e.g., the chip 216 may include an ASIC (application specific integrated circuit), an antenna, and other necessary components understood by those skilled in the art).
在又一个示例中，植入的传感器另外还包括电容器以提供用于设备功能的必要电力。便携式扫描仪(例如，棒状设备)用于收集储存在电路上的数据和/或对设备再充电。In yet another example, the implanted sensor additionally includes a capacitor to provide the necessary power for device function.A portable scanner (eg, a wand-like device) is used to collect data stored on the circuit and/or to recharge the device.
一般来讲，如本文所述，电感耦合使得电力能够被传输到传感器以进行连续供电、再充电等。另外，电感耦合利用感测单元和电子单元上的适当间隔和定向的天线(例如，线圈)，以便在其间有效地传输/接收电力(例如，电流)和/或数据通信。每个感测和电子单元中的一个或多个线圈可以提供必要的电力感应和/或数据传输。Generally speaking, as described herein, inductive coupling enables power to be transferred to the sensor for continuous powering, recharging, etc. In addition, inductive coupling utilizes appropriately spaced and oriented antennas (e.g., coils) on the sensing unit and the electronics unit to effectively transmit/receive power (e.g., current) and/or data communications therebetween. One or more coils in each sensing and electronics unit can provide the necessary power sensing and/or data transmission.
在该示例中，感测机构可以是(例如)基于导线的传感器，如参考图2A和图2B更详细地描述的并且如美国专利公开号2006/0020187中所述，或基于平面衬底的传感器，诸如在授予Say等人的美国专利号6,175,752以及授予Mastrototaro等人的美国专利号5,779,665中所述，这些专利全部均全文以引用方式并入本文。生物界面膜68可以是如本文别处更详细地描述的任何合适的生物界面，例如，多孔生物界面膜材料层、网笼等。在一个示例性示例中，生物界面膜68是多孔膜材料(诸如ePTFE)的单层片或多层片(例如袋)，其中掺入有感测机构36。In this example, the sensing mechanism can be, for example, a wire-based sensor, as described in more detail with reference to FIGS. 2A and 2B and as described in U.S. Patent Publication No. 2006/0020187, or a planar substrate-based sensor, such as described in U.S. Patent No. 6,175,752 to Say et al. and U.S. Patent No. 5,779,665 to Mastrototaro et al., all of which are incorporated herein by reference in their entirety. The biointerface membrane 68 can be any suitable biointerface as described in more detail elsewhere herein, for example, a porous biointerface membrane material layer, a mesh cage, etc. In an exemplary example, the biointerface membrane 68 is a single-layer sheet or a multi-layer sheet (e.g., a bag) of a porous membrane material (such as ePTFE) into which the sensing mechanism 36 is incorporated.
图3G是处于功能上有用的距离的植入受者组织中的电感耦合到电子单元上的植入传感器的一个示例的侧视图。图3G展示了与上文参考图3F所描述的类似的感测单元58和电子单元52，然而两者都被适当紧密接近地植入到受者皮肤下面。Fig. 3G is a side view of one example of an implanted sensor inductively coupled to an electronics unit implanted in recipient tissue at a functionally useful distance. Fig. 3G shows a sensing unit 58 and electronics unit 52 similar to those described above with reference to Fig. 3F, however both are implanted in appropriately close proximity beneath the recipient's skin.
一般来讲，据信当承载可植入设备的大部分质量的电子单元52与感测单元58分离时，在感测单元周围将发生较小的异物反应(例如，与较大质量的设备(例如，包括某些电子器件和/或电源的设备)相比)。因此，包括生物界面膜和/或生物活性物质释放膜的感测单元的配置可被优化以最小化和/或改变受者的组织反应，例如具有如在别处更详细地描述的最小质量。In general, it is believed that when the electronics unit 52, which carries most of the mass of the implantable device, is separated from the sensing unit 58, less foreign body reaction will occur around the sensing unit (e.g., compared to a larger mass device (e.g., a device that includes certain electronics and/or a power source)). Therefore, the configuration of the sensing unit including the biointerface membrane and/or the bioactive substance release membrane can be optimized to minimize and/or alter the tissue reaction of the recipient, such as having a minimal mass as described in more detail elsewhere.
生物界面膜/层Biointerface Film/Layer
在一个示例中，传感器包括设置在其一些部分上的多孔材料，该多孔材料改变受者组织对传感器的反应。在一些示例中，传感器周围的多孔材料通过减缓或减少细胞向传感器迁移和相关联的劣化，有利地增强传感器性能并延长传感器寿命，其中该劣化在传感器直接暴露于体内环境的情况下原本会由细胞侵袭引起。另选地，多孔材料可以长期经由组织向内生长到多孔材料中来提供对传感器的稳定。合适的多孔材料包括有机硅；聚四氟乙烯；膨胀型聚四氟乙烯；聚乙烯-共-四氟乙烯；聚烯烃；聚酯；聚碳酸烷基酯；聚碳酸酯；生物稳定的聚四氟乙烯；聚氨酯的均聚物、共聚物、三元共聚物；聚丙烯(PP)；聚氯乙烯(PVC)；聚偏二氟乙烯(PVDF)；聚乙烯醇(PVA)；聚对苯二甲酸丁二醇酯(PBT)；聚甲基丙烯酸甲酯(PMMA)；聚醚醚酮(PEEK)；聚酰胺；聚氨酯；聚氨酯脲共聚物；纤维素聚合物；聚(环氧乙烷)、聚(环氧丙烷)以及它们的共聚物和共混物；聚砜及其嵌段共聚物，包括例如二嵌段、三嵌段、交替、无规和接枝共聚物；以及金属、陶瓷、纤维素、水凝胶聚合物、聚乙烯乙酸乙烯酯(EVA)、聚(2-羟乙基甲基丙烯酸酯)(pHEMA)、甲基丙烯酸羟乙酯(HEMA)、聚丙烯腈-聚氯乙烯(PAN-PVC)、高密度聚乙烯、丙烯酸共聚物、尼龙、聚二氟乙烯、聚酸酐、聚(l-赖氨酸)、聚(L-乳酸)、甲基丙烯酸羟乙酯、羟磷灰石(hydroxyapeptite)、氧化铝、氧化锆、碳纤维、铝、磷酸钙、钛、钛合金、镍钛诺、不锈钢和CoCr合金等，诸如2004年5月10日提交的名称为“BIOINTERFACE MEMBRANES INCORPORATING BIOACTIVE AGENTS”的美国专利号7,875,293和2003年8月22日提交的名称为“POROUS MEMBRANES FOR USE WITH IMPLANTABLEDEVICES”的美国专利号7,192,450中所述。In one example, the sensor includes a porous material disposed on portions thereof that alters the response of the recipient tissue to the sensor. In some examples, the porous material surrounding the sensor advantageously enhances sensor performance and extends sensor life by slowing or reducing cell migration into the sensor and associated degradation that would otherwise be caused by cell invasion if the sensor were directly exposed to the in vivo environment. Alternatively, the porous material can provide long-term stabilization of the sensor via tissue ingrowth into the porous material. Suitable porous materials include silicones; polytetrafluoroethylene; expanded polytetrafluoroethylene; polyethylene-co-tetrafluoroethylene; polyolefins; polyesters; polyalkyl carbonates; polycarbonates; biostable polytetrafluoroethylene; homopolymers, copolymers, terpolymers of polyurethanes; polypropylene (PP); polyvinyl chloride (PVC); polyvinylidene fluoride (PVDF); polyvinyl alcohol (PVA); polybutylene terephthalate (PBT); polymethyl methacrylate (PMMA); polyetheretherketone (PEEK); polyamides; polyurethanes; polyurethane urea copolymers; cellulosic polymers; poly(ethylene oxide), poly(propylene oxide) and copolymers and blends thereof; polysulfones and block copolymers thereof, including, for example, diblock, triblock, alternating , random and graft copolymers; and metals, ceramics, cellulose, hydrogel polymers, polyethylene vinyl acetate (EVA), poly(2-hydroxyethyl methacrylate) (pHEMA), hydroxyethyl methacrylate (HEMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC), high density polyethylene, acrylic copolymers, nylon, polyvinylidene fluoride, polyanhydrides, poly(l-lysine), poly(L-lactic acid), hydroxyethyl methacrylate, hydroxyapeptite, alumina, zirconia, carbon fiber, aluminum, calcium phosphate, titanium, titanium alloys, nitinol, stainless steel and CoCr alloys, etc., such as described in U.S. Patent No. 7,875,293, entitled "BIOINTERFACE MEMBRANES INCORPORATING BIOACTIVE AGENTS" filed on May 10, 2004 and U.S. Patent No. 7,192,450, entitled "POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES" filed on August 22, 2003.
在一些示例中，围绕传感器的多孔材料提供体内(例如，1天至14天)的独特优点，这些优点可以用于增强传感器性能并延长传感器寿命。然而，此类材料也可以提供长期(例如，大于14天)的优点。特别地，传感器的体内部分(传感器被植入受者组织中的那部分)被(部分地或完全地)包在多孔材料中。多孔材料可以包裹在传感器周围(例如，通过将多孔材料包裹在传感器周围，或者通过将传感器插入多孔材料的大小被确定成接纳该传感器的区段中)。另选地，多孔材料可以沉积在传感器上(例如，通过在其上直接电纺聚合物)。在还有其他另选示例中，将传感器插入多孔生物材料的选定区段中。如本领域技术人员将理解的，还可使用用多孔材料包围传感器的体内部分的其他方法。In some examples, the porous material surrounding the sensor provides unique advantages in vivo (e.g., 1 day to 14 days), which can be used to enhance sensor performance and extend sensor life. However, such materials can also provide long-term (e.g., greater than 14 days) advantages. In particular, the in vivo portion of the sensor (the portion where the sensor is implanted in the recipient tissue) is (partially or completely) wrapped in a porous material. The porous material can be wrapped around the sensor (e.g., by wrapping the porous material around the sensor, or by inserting the sensor into a section of the porous material that is sized to receive the sensor). Alternatively, the porous material can be deposited on the sensor (e.g., by electrospinning a polymer directly thereon). In other alternative examples, the sensor is inserted into a selected section of a porous biomaterial. As will be appreciated by those skilled in the art, other methods of surrounding the in vivo portion of the sensor with a porous material can also be used.
包围传感器的多孔材料有利地减缓或减少细胞向传感器迁移和相关联的劣化，该劣化在传感器直接暴露于体内环境的情况下原本会由细胞侵袭引起。也就是说，多孔材料提供使细胞向传感器的迁移更曲折并因此更慢的屏障。据信，这减少或减缓了通常随时间推移观察到的灵敏度损失。The porous material surrounding the sensor advantageously slows or reduces cell migration to the sensor and associated degradation that would otherwise be caused by cell invasion if the sensor were directly exposed to the in vivo environment. That is, the porous material provides a barrier that makes cell migration to the sensor more tortuous and therefore slower. It is believed that this reduces or slows the sensitivity loss typically observed over time.
在其中多孔材料是高氧溶解度材料(诸如多孔有机硅)的示例中，该高氧溶解度多孔材料包围传感器体内部分的一部分或全部。在一些示例中，较低的氧-葡萄糖比率可能足以通过使用高氧可溶性域(例如，基于有机硅或碳氟化合物的材料)来提供过量的氧，以增强氧向酶膜和/或电活性表面的供应/转运。据信，常规传感器通常遭遇的一些信号噪声可以归因于缺氧。有机硅具有高透氧性，因此促进氧向酶层转运。例如，通过使用有机硅组合物来增强氧供应，葡萄糖浓度可以不再是限制因素。换句话讲，如果向酶和/或电化学活性表面供应更多的氧，则也可向酶供应更多的葡萄糖，而不产生氧速率限制过量。尽管不受任何特定理论的束缚，但据信，有机硅材料在与其他聚合物材料(诸如聚氨酯)相比时，提供增强的生物稳定性。In the example where the porous material is a high oxygen solubility material (such as porous organosilicon), the high oxygen solubility porous material surrounds part or all of the sensor body. In some examples, a lower oxygen-glucose ratio may be sufficient to provide excess oxygen by using a high oxygen soluble domain (e.g., a material based on organosilicon or fluorocarbon) to enhance the supply/transport of oxygen to the enzyme membrane and/or electroactive surface. It is believed that some signal noises commonly encountered by conventional sensors can be attributed to hypoxia. Organosilicon has high oxygen permeability, so it promotes oxygen transport to the enzyme layer. For example, by using an organosilicon composition to enhance oxygen supply, glucose concentration may no longer be a limiting factor. In other words, if more oxygen is supplied to the enzyme and/or electrochemically active surface, more glucose can also be supplied to the enzyme without generating an excessive oxygen rate limit. Although not bound by any particular theory, it is believed that organosilicon materials provide enhanced biostability when compared with other polymeric materials (such as polyurethane).
在另一个示例中，多孔材料还包含在插入时释放的生物活性剂。在示例中，多孔结构为葡萄糖渗透提供途径，同时允许生物活性剂释放/洗脱。在示例中，当生物活性剂从多孔结构释放/洗脱时，葡萄糖转运可增加，例如以便抵消来自前述免疫应答因子的葡萄糖转运的任何衰减。In another example, the porous material further comprises a bioactive agent that is released upon insertion. In an example, the porous structure provides a pathway for glucose penetration while allowing the bioactive agent to be released/eluted. In an example, when the bioactive agent is released/eluted from the porous structure, glucose transport may be increased, for example, to offset any attenuation of glucose transport from the aforementioned immune response factors.
当在本文中使用时，术语“膜”和“基质”意在可互换使用。在这些示例中，前述多孔材料是包括第一域的生物界面膜，该第一域包括改变受者的组织反应的，该构造包括空腔尺寸、配置和/或总体厚度，例如，通过产生流体囊、促进血管化组织向内生长、破坏组织向下挛缩、抵抗邻近设备的纤维组织生长，以及/或者阻碍屏障细胞形成。在示例中，生物界面膜至少覆盖传感器的感测机构，并且可具有任何形状或尺寸，包括均匀地、不对称地或轴对称地覆盖或围绕感测机构或传感器。As used herein, the terms "membrane" and "matrix" are intended to be used interchangeably. In these examples, the aforementioned porous material is a biointerface membrane including a first domain that includes a configuration that alters the tissue response of the recipient, including cavity size, configuration, and/or overall thickness, for example, by creating fluid pockets, promoting vascularized tissue ingrowth, disrupting tissue contraction downward, resisting fibrous tissue growth adjacent to the device, and/or hindering barrier cell formation. In examples, the biointerface membrane covers at least the sensing mechanism of the sensor and can have any shape or size, including uniformly, asymmetrically, or axisymmetrically covering or surrounding the sensing mechanism or sensor.
任选地提供不可渗透细胞和/或细胞过程的生物界面膜第二域。任选地提供掺入第一域、第二域、感测膜或可植入设备的其他部分中的至少一者中的生物活性剂，其中该生物活性剂被配置为改变受者的组织反应。在示例中，生物界面包括生物活性剂，该生物活性剂被掺入生物界面膜的第一域和第二域中的至少一个域中，或者掺入设备中并且适于扩散通过第一域和/或第二域，以便改变受者对膜的组织反应。Optionally, a second domain of the biointerface membrane is provided that is impermeable to cells and/or cellular processes. Optionally, a bioactive agent is provided that is incorporated into at least one of the first domain, the second domain, the sensing membrane, or other portions of the implantable device, wherein the bioactive agent is configured to alter a tissue response of a recipient. In an example, the biointerface includes a bioactive agent that is incorporated into at least one of the first domain and the second domain of the biointerface membrane, or is incorporated into the device and adapted to diffuse through the first domain and/or the second domain so as to alter a tissue response of a recipient to the membrane.
由于本公开的传感器(感测机构)的小尺寸，多孔膜形成和/或多孔膜粘附的一些常规方法不适于在如本文所述的传感器上形成生物界面膜。因此，以下示例举例说明了用于在如本文所定义的有小结构的传感器上形成和/或粘附生物界面膜的系统和方法。例如，可以使用诸如电纺、模制、编织、直写、冻干、包裹等技术在传感器上形成本公开的生物界面膜或释放膜。Due to the small size of the sensor (sensing mechanism) of the present disclosure, some conventional methods of porous membrane formation and/or porous membrane adhesion are not suitable for forming a biointerface membrane on the sensor as described herein. Therefore, the following examples illustrate systems and methods for forming and/or adhering a biointerface membrane on a sensor with small structures as defined herein. For example, the biointerface membrane or release membrane of the present disclosure can be formed on the sensor using techniques such as electrospinning, molding, weaving, direct writing, freeze drying, wrapping, etc.
在其中生物界面被直写到传感器上的示例中，分配器使用具有阀的喷嘴等分配聚合物溶液，例如如美国专利公开号2004/0253365中所述。一般来讲，可以使用多种喷嘴和/或分配器来分配聚合物材料以形成生物界面膜的织造或非织造纤维。In the example where the biointerface is written directly onto the sensor, the dispenser dispenses the polymer solution using a nozzle with a valve, etc., such as described in U.S. Patent Publication No. 2004/0253365. In general, a variety of nozzles and/or dispensers can be used to dispense polymer materials to form woven or nonwoven fibers of the biointerface membrane.
生物活性物质释放膜/层-炎症反应控制Bioactive substance release membrane/layer-inflammatory response control
一般来讲，对生物材料植入物的炎症反应可以分为两个阶段。第一阶段由肥大细胞的动员和随后主要的多形核(PMN)细胞的浸润组成。该阶段被称为急性炎症阶段。在数天至数周的过程中，包含第二阶段炎症的慢性细胞类型替代了PMN。巨噬细胞和淋巴细胞在该阶段期间占优势。虽然不希望受任何特定理论所束缚，但据信限制血管舒张和/或阻断促炎信号传导、短期刺激血管形成或短期抑制瘢痕形成或屏障细胞层形成提供了对瘢痕组织形成的保护和/或减少了急性炎症，从而例如为持续维持改变的异物反应提供稳定的平台。Generally speaking, the inflammatory response to biomaterial implants can be divided into two stages. The first stage is composed of the mobilization of mast cells and the subsequent infiltration of polymorphonuclear (PMN) cells. This stage is called the acute inflammatory stage. In the process of several days to several weeks, the chronic cell type comprising the second stage inflammation replaces PMN. Macrophages and lymphocytes are dominant during this stage. Although it is not desired to be bound by any particular theory, it is believed that limiting vasodilation and/or blocking proinflammatory signaling, short-term stimulation of angiogenesis or short-term inhibition of scar formation or barrier cell layer formation provides protection to scar tissue formation and/or reduces acute inflammation, thereby, for example, providing a stable platform for the foreign body reaction to continue to maintain changes.
因此，生物活性干预可以改变在异物囊形成的早期数周内的异物反应，并且改变异物囊的延长行为。附加地，据信在一些情况下，本公开的生物界面膜可受益于生物活性干预以克服膜对植入物程序的敏感性、植入物的运动或已知原本引起炎症、瘢痕形成和阻碍设备体内功能的其他因素。Thus, bioactive interventions can alter the foreign body response in the early weeks of foreign body capsule formation and alter the extended behavior of the foreign body capsule. Additionally, it is believed that in some cases, the biointerface membranes of the present disclosure may benefit from bioactive interventions to overcome the sensitivity of the membrane to implant procedures, implant movement, or other factors known to otherwise cause inflammation, scarring, and impede device function in vivo.
一般来讲，认为改变组织反应的生物活性剂包括抗炎剂、抗感染剂、抗增殖剂、抗组胺剂、麻醉剂、炎性剂、生长因子、血管生成(生长)因子、佐剂、免疫抑制剂、抗血小板剂、抗凝血剂、ACE抑制剂、细胞毒性剂、抗屏障细胞化合物、血管形成化合物、反义分子等。在一些示例中，优选的生物活性剂包括S1P(鞘氨醇-1-磷酸酯)、单丁酸甘油酯、环孢菌素A、抗凝血酶敏感蛋白2、雷帕霉素(及其衍生物)、NLRP3炎性小体抑制剂(诸如MCC950)和地塞米松。然而，可以将其他生物活性剂、生物材料(例如，蛋白质)或甚至非生物活性物质掺入本公开的膜中。In general, it is believed that bioactive agents that alter tissue responses include anti-inflammatory agents, anti-infective agents, antiproliferative agents, antihistamines, anesthetics, inflammatory agents, growth factors, angiogenic (growth) factors, adjuvants, immunosuppressants, antiplatelet agents, anticoagulants, ACE inhibitors, cytotoxic agents, anti-barrier cell compounds, angiogenic compounds, antisense molecules, etc. In some examples, preferred bioactive agents include S1P (sphingosine-1-phosphate), monobutyrin, cyclosporin A, antithrombin 2, rapamycin (and its derivatives), NLRP3 inflammasome inhibitors (such as MCC950) and dexamethasone. However, other bioactive agents, biomaterials (e.g., proteins) or even non-bioactive substances can be incorporated into the membranes of the present disclosure.
适合用于本公开的生物活性剂被松散地组织成两组：抗屏障细胞剂和血管形成剂。这些命名反映了被认为提供通过本发明所公开的传感器的一个或多个膜的短期溶质转运并且附加地延长健康血管床的寿命并因此延长体内长期通过该一个或多个膜的溶质转运的功能。然而，不是所有的生物活性剂都可以清楚地分类为上述组中的一种或另一种。相反，生物活性剂通常包含用于改变组织反应的一种或多种变化机制，并且通常可以分类为上述类别中的一种或两种。Bioactive agents suitable for use in the present disclosure are loosely organized into two groups: anti-barrier cell agents and angiogenic agents. These nomenclatures reflect the function of being believed to provide short-term solute transport through one or more membranes of the sensor disclosed herein and additionally extend the life of healthy vascular beds and thus extend long-term solute transport through the one or more membranes in vivo. However, not all bioactive agents can be clearly classified into one or another of the above groups. Instead, bioactive agents generally contain one or more mechanisms of change for altering tissue responses and can generally be classified into one or both of the above categories.
抗屏障细胞剂Anti-barrier cell agents
通常，抗屏障细胞剂包括表现出对巨噬细胞和异物巨细胞(FBGC)的作用的化合物。据信，抗屏障细胞剂防止对由巨噬细胞提供的溶质转运的屏障的闭合以及在FBC成熟期间在设备-组织界面处的FBGC。Generally, anti-barrier cellular agents include compounds that exhibit effects on macrophages and foreign body giant cells (FBGCs). It is believed that anti-barrier cellular agents prevent the closure of the barrier to solute transport provided by macrophages and FBGCs at the device-tissue interface during FBC maturation.
抗屏障细胞剂通常包括抑制异物巨细胞和/或闭塞性细胞层的机制。例如，将超氧化物歧化酶(SOD)模拟物掺入优选示例的生物界面膜或释放膜中，该超氧化物歧化酶模拟物利用卟啉样分子内的锰催化中心来模拟天然SOD并长时间有效地去除超氧化物，从而抑制在体内的生物材料表面的FBGC形成。Anti-barrier cell agents generally include mechanisms that inhibit foreign giant cells and/or occlusive cell layers. For example, a superoxide dismutase (SOD) mimetic is incorporated into a preferred example of a biointerface membrane or release membrane, which utilizes a manganese catalytic center within a porphyrin-like molecule to mimic natural SOD and effectively remove superoxide for a long time, thereby inhibiting the formation of FBGC on the surface of biomaterials in vivo.
抗屏障细胞剂可以包括影响早期FBC形成的抗炎和/或免疫抑制机制。可将刺激生物材料周围非常高水平的新血管形成的环孢菌素掺入优选示例的生物界面膜(参见授予Martinson等人的美国专利号5,569,462)或释放膜中。Anti-barrier cell agents may include anti-inflammatory and/or immunosuppressive mechanisms that affect early FBC formation. Cyclosporine, which stimulates very high levels of neovascularization around biomaterials, may be incorporated into a preferred exemplary biointerface membrane (see US Pat. No. 5,569,462 to Martinson et al.) or release membrane.
在示例中，将例如减弱在设备-组织界面处的FBC反应的强度的地塞米松、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松)掺入生物活性物质释放膜70中。在另一示例中，将地塞米松和醋酸地塞米松的组合掺入生物活性物质释放膜70中。在另一示例中，将地塞米松和/或醋酸地塞米松与一种或多种其他抗炎剂和/或免疫抑制剂的组合掺入生物活性物质释放膜70中。另选地，雷帕霉素作为一些巨噬细胞炎症功能的有效特异性抑制剂可被单独地或与地塞米松、地塞米松盐、地塞米松衍生物(特别是醋酸地塞米松)组合掺入释放膜中。In an example, dexamethasone, a dexamethasone salt, or a dexamethasone derivative (particularly dexamethasone acetate), which, for example, reduces the intensity of the FBC reaction at the device-tissue interface, is incorporated into the bioactive substance release membrane 70. In another example, a combination of dexamethasone and dexamethasone acetate is incorporated into the bioactive substance release membrane 70. In another example, a combination of dexamethasone and/or dexamethasone acetate and one or more other anti-inflammatory agents and/or immunosuppressants is incorporated into the bioactive substance release membrane 70. Alternatively, rapamycin, as an effective specific inhibitor of some macrophage inflammatory functions, may be incorporated into the release membrane alone or in combination with dexamethasone, a dexamethasone salt, a dexamethasone derivative (particularly dexamethasone acetate).
可将其他合适的药物、药物组合物、治疗剂或其他所需的物质掺入本公开的生物活性物质释放膜70中，包括但不限于抗炎剂、抗感染剂、坏死剂(necrosing agent)和麻醉剂。Other suitable drugs, pharmaceutical compositions, therapeutic agents or other desired substances may be incorporated into the bioactive substance release membrane 70 of the present disclosure, including but not limited to anti-inflammatory agents, anti-infective agents, necrosing agents and anesthetics.
通常，抗炎剂减少邻近植入物的急性和/或慢性炎症，以便减少FBC囊的形成，从而减少或防止屏障细胞层形成。合适的抗炎剂包括但不限于例如非类固醇抗炎药物(NSAID)，诸如对乙酰氨基酚、氨基水杨酸、阿司匹林、塞来考昔、三水杨酸胆碱镁、双氯芬酸钾、双氯芬酸钠、二氟尼柳、依托度酸、非诺洛芬、氟比洛芬、布洛芬、吲哚美辛、白介素(IL)-10、IL-6突变蛋白、抗IL-6iNOS抑制剂(例如，L-NAME或L-NMDA)、干扰素、酮洛芬、酮咯酸、来氟米特、甲芬那酸、霉酚酸、咪唑立宾、萘丁美酮、萘普生、萘普生钠、奥沙普秦、吡罗昔康、罗非考昔、双水杨酯、舒林酸和托美汀；以及皮质类固醇，诸如可的松、氢化可的松、甲泼尼龙、泼尼松、泼尼松龙、倍他米松、二丙酸倍氯米松、布地奈德、地塞米松磷酸钠、氟尼缩松、丙酸氟替卡松、紫杉醇、他克莫司、曲尼司特、曲安奈德、倍他米松、氟轻松、氟轻松醋酸酯、二丙酸倍他米松、戊酸倍他米松、地奈德、去羟米松、氟轻松、曲安西龙、曲安奈德、丙酸氯倍他索、NLRP3炎性小体抑制剂(诸如MCC950)、地塞米松和醋酸地塞米松。Typically, anti-inflammatory agents reduce acute and/or chronic inflammation adjacent to implants to reduce the formation of FBC capsules, thereby reducing or preventing barrier cell layer formation. Suitable anti-inflammatory agents include, but are not limited to, for example, nonsteroidal anti-inflammatory drugs (NSAIDs), such as acetaminophen, aminosalicylic acid, aspirin, celecoxib, choline magnesium trisalicylate, diclofenac potassium, diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, interleukin (IL) -10, IL-6 mutant proteins, anti-IL-6 iNOS inhibitors (e.g., L-NAME or L-NMDA), interferon, ketoprofen, ketorolac, leflunomide, mefenamic acid, mycophenolic acid, mizoribine, nabumetone, naproxen, naproxen sodium, oxaprozin, pyro and corticosteroids such as cortisone, hydrocortisone, methylprednisolone, prednisone, prednisolone, betamethasone, beclomethasone dipropionate, budesonide, dexamethasone sodium phosphate, flunisolide, fluticasone propionate, paclitaxel, tacrolimus, tranilast, triamcinolone acetonide, betamethasone, fluocinolone acetonide, fluocinolone acetonide, betamethasone dipropionate, betamethasone valerate, desonide, desoximetasone, fluocinolone acetonide, triamcinolone acetonide, triamcinolone acetonide, clobetasol propionate, NLRP3 inflammasome inhibitors (such as MCC950), dexamethasone and dexamethasone acetate.
通常，免疫抑制剂和/或免疫调节剂直接干扰炎症反应中涉及不同细胞元件所必需的几种关键机制。合适的免疫抑制剂和/或免疫调节剂包括抗增殖细胞周期抑制剂(例如，紫杉醇(例如，西罗莫司)、细胞松弛素D、英夫利西单抗)、紫杉醇、放线菌素、丝裂霉素、thospromote VEGF、雌二醇、NO供体、QP-2、他克莫司、曲尼司特、放线菌素、依维莫司、甲氨蝶呤、霉酚酸、血管肽素、长春新碱、丝裂霉素、他汀类、C MYC反义物、西罗莫司(和类似物)、RestenASE、2-氯-脱氧腺苷、PCNA核酶、巴马司他、脯氨酰羟化酶抑制剂、PPARγ配体(例如，曲格列酮、罗格列酮、吡格列酮)、常山酮、C-蛋白酶抑制剂、普罗布考、BCP671、EPC抗体、儿茶素、糖化剂、内皮素抑制剂(例如，安贝生坦、替索生坦(Tesosentan)、波生坦)、他汀类(例如，西立伐他汀)、大肠杆菌(E.coli)热不稳定肠毒素和高级包衣。Typically, immunosuppressants and/or immunomodulators directly interfere with several key mechanisms necessary for the involvement of different cellular elements in the inflammatory response. Suitable immunosuppressants and/or immunomodulators include antiproliferative cell cycle inhibitors (e.g., paclitaxel (e.g., sirolimus), cytochalasin D, infliximab), paclitaxel, actinomycin, mitomycin, thospromote VEGF, estradiol, NO donors, QP-2, tacrolimus, tranilast, actinomycin, everolimus, methotrexate, mycophenolic acid, angiopeptide, vincristine, mitomycin, statins, C MYC antisense, sirolimus (and analogs), RestenASE, 2-chloro-deoxyadenosine, PCNA ribozyme, batimastat, prolyl hydroxylase inhibitors, PPARγ ligands (e.g., troglitazone, rosiglitazone, pioglitazone), halofuginone, C-proteinase inhibitors, probucol, BCP671, EPC antibodies, catechins, glycating agents, endothelin inhibitors (e.g., ambrisentan, tesosentan, bosentan), statins (e.g., cerivastatin), E. coli heat-labile enterotoxin, and advanced coatings.
通常，抗感染剂是能够通过抑制感染源的扩散或通过彻底杀死感染源而起抗感染作用的物质，其可以用于减少免疫应答而在植入部位没有炎症反应。抗感染源包括但不限于驱肠虫剂(甲苯咪唑)；抗生素，包括氨基糖苷类(庆大霉素、新霉素、妥布霉素)、抗真菌抗生素(两性霉素B、氟康唑、灰黄霉素、伊曲康唑、酮康唑、制霉菌素、咪康唑、托萘酯)、头孢菌素类(头孢克洛、头孢唑啉、头孢噻肟、头孢他啶、头孢曲松、头孢呋辛、头孢氨苄)、β-内酰胺抗生素(头孢替坦、美罗培南)、氯霉素、大环内酯类(阿奇霉素、克拉霉素、红霉素)、青霉素类(青霉素G钠盐、阿莫西林、氨苄西林、双氯西林、萘夫西林、哌拉西林、替卡西林)、四环素类(强力霉素、米诺环素、四环素)、杆菌肽；克林霉素；多粘菌素E甲磺酸钠；硫酸多粘菌素B；万古霉素；抗病毒药，包括阿昔洛韦、金刚烷胺、去羟肌苷、依法韦仑、膦甲酸、更昔洛韦、茚地那韦、拉米夫定、奈非那韦、利托那韦、沙奎那韦、银、司他夫定、伐昔洛韦、缬更昔洛韦、齐多夫定；喹诺酮类(环丙沙星、左氧氟沙星)；磺酰胺(磺胺嘧啶、磺胺异噁唑)；砜(氨苯砜)；呋喃唑酮；甲硝唑；喷他脒；灭菌结晶磺胺；加替沙星；和磺胺甲噁唑/甲氧苄啶。Generally, anti-infective agents are substances that can play an anti-infective role by inhibiting the spread of the source of infection or by completely killing the source of infection, which can be used to reduce the immune response without an inflammatory reaction at the implant site. Anti-infective sources include, but are not limited to, anthelmintics (mebendazole); antibiotics, including aminoglycosides (gentamicin, neomycin, tobramycin), antifungal antibiotics (amphotericin B, fluconazole, griseofulvin, itraconazole, ketoconazole, nystatin, miconazole, tolnaftate), cephalosporins (cefaclor, cefazolin, cefotaxime, ceftazidime, ceftriaxone, cefuroxime, cephalexin), β-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, cefadroxil), cephalosporins (cefadroxil, cefuroxime, ceftazidime, ceftriaxone, cefuroxime, cefalexin), β-lactam antibiotics (cefotetan, meropenem), chloramphenicol, macrolides (azithromycin, clarithromycin, erythromycin), penicillins (penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin, nafcillin, piperacillin, cefadroxil), cefadroxil, ... oxazolidinone), tetracyclines (doxycycline, minocycline, tetracycline), bacitracin; clindamycin; polymyxin E mesylate sodium; polymyxin B sulfate; vancomycin; antivirals, including acyclovir, amantadine, didanosine, efavirenz, foscarnet, ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, silver, stavudine, valacyclovir, valganciclovir, zidovudine; quinolones (ciprofloxacin, levofloxacin); sulfonamides (sulfadiazine, sulfisoxazole); sulfones (dapsone); furazolidone; metronidazole; pentamidine; sterile crystalline sulfonamides; gatifloxacin; and sulfamethoxazole/trimethoprim.
通常，坏死剂是引起组织坏死或细胞死亡的任何药物。坏死剂包括顺铂、BCNU、紫杉醇或紫杉醇衍生物等。Generally, a necrotizing agent is any drug that causes tissue necrosis or cell death. Necrotic agents include cisplatin, BCNU, paclitaxel or paclitaxel derivatives, etc.
血管形成剂Angiogenic Agents
通常，血管形成剂包括具有直接或间接血管生成特性的物质。在一些情况下，血管形成剂可附加地影响体内屏障细胞的形成。间接血管生成意指可以通过炎症途径或免疫刺激途径介导血管生成。还不完全知道诱导局部血管形成的药剂如何间接抑制屏障细胞形成；然而，据信一些屏障-细胞作用可以间接由血管形成剂的作用引起。In general, angiogenic agents include substances with direct or indirect angiogenic properties. In some cases, angiogenic agents can additionally affect the formation of barrier cells in vivo. Indirect angiogenesis means that angiogenesis can be mediated through inflammatory pathways or immune stimulation pathways. It is not fully known how agents that induce local angiogenesis indirectly inhibit barrier cell formation; however, it is believed that some barrier-cell effects can be indirectly caused by the action of angiogenic agents.
血管形成剂包括通过增加靠近设备-组织界面的血管形成来促进膜周围的新血管形成和/或最小化缺血周期的机制。鞘氨醇-1-磷酸酯(S1P)作为具有有效的血管生成活性的磷脂被掺入优选示例的生物界面膜或释放膜中。单丁酸甘油酯作为脂肪细胞的有效血管扩张剂和血管生成脂质产物被掺入优选示例的生物界面膜或释放膜中。在另一个示例中，将增加血管形成的反义分子(例如，凝血酶敏感蛋白2反义物)掺入生物界面膜或释放膜中。Angiogenic agents include mechanisms that promote neovascularization around the membrane and/or minimize ischemic periods by increasing vascularization near the device-tissue interface. Sphingosine-1-phosphate (S1P) is incorporated into the preferred example biointerface membrane or release membrane as a phospholipid with effective angiogenic activity. Monobutyric acid glyceride is incorporated into the preferred example biointerface membrane or release membrane as an effective vasodilator and angiogenic lipid product of adipocytes. In another example, an antisense molecule that increases angiogenesis (e.g., thrombospondin 2 antisense) is incorporated into the biointerface membrane or release membrane.
血管形成剂可包括促进炎症的机制，其被认为在体内引起加速的新血管形成。在一个示例中，通过其外源性质引起免疫应答的异种载体(例如牛胶原)刺激新血管形成，并且被掺入本公开的生物界面膜或释放膜中。在另一个示例中，脂多糖作为有效的免疫刺激剂被掺入生物界面膜或释放膜中。在另一个示例中，将已知调节组织中的骨愈合的蛋白质(例如骨形态发生蛋白(BMP))掺入优选示例的生物界面膜或释放膜中。Angiogenic agents may include mechanisms that promote inflammation, which are believed to cause accelerated neovascularization in vivo. In one example, a xenogeneic carrier (e.g., bovine collagen) that causes an immune response through its exogenous properties stimulates neovascularization and is incorporated into the biointerface membrane or release membrane of the present disclosure. In another example, lipopolysaccharide is incorporated into the biointerface membrane or release membrane as an effective immunostimulant. In another example, a protein known to regulate bone healing in tissues (e.g., bone morphogenetic protein (BMP)) is incorporated into the biointerface membrane or release membrane of a preferred example.
通常，血管生成剂是能够刺激新血管形成的物质，其可以加速和维持设备-组织界面处的血管化组织床的发育。血管生成剂包括但不限于铜离子、铁离子三十二烷基甲基氯化铵、碱性成纤维细胞生长因子(bFGF)(也称为肝素结合生长因子II和成纤维细胞生长因子II)、酸性成纤维细胞生长因子(aFGF)(也称为肝素结合生长因子I和成纤维细胞生长因子I)、血管内皮生长因子(VEGF)、血小板源性内皮细胞生长因子BB(PDEGF-BB)、血管生成素-1、转化生长因子β(TGF-β)、转化生长因子α(TGF-α)、肝细胞生长因子、肿瘤坏死因子-α(TNF-α)、胎盘生长因子(PLGF)、血管生成素、白介素-8(IL-8)、低氧诱导因子-I(HIF-1)、血管紧张素转化酶(ACE)抑制剂喹那普利拉、血管趋向素(Angiotropin)、血小板反应蛋白、肽KGHK、低氧张力、乳酸、胰岛素、硫酸铜、雌二醇、前列腺素、cox抑制剂、内皮细胞结合剂(例如，核心蛋白聚糖或波形蛋白)、京尼平(glenipin)、过氧化氢、尼古丁和生长激素。Generally, angiogenic agents are substances that can stimulate the formation of new blood vessels, which can accelerate and maintain the development of a vascularized tissue bed at the device-tissue interface. Angiogenic agents include, but are not limited to, copper ions, iron ions, tridodecylmethylammonium chloride, basic fibroblast growth factor (bFGF) (also known as heparin-binding growth factor II and fibroblast growth factor II), acidic fibroblast growth factor (aFGF) (also known as heparin-binding growth factor I and fibroblast growth factor I), vascular endothelial growth factor (VEGF), platelet-derived endothelial growth factor BB (PDEGF-BB), angiopoietin-1, transforming growth factor beta (TGF-β), transforming growth factor alpha (TGF-α), hepatocyte growth factor , tumor necrosis factor-α (TNF-α), placental growth factor (PLGF), angiogenin, interleukin-8 (IL-8), hypoxia-inducible factor-I (HIF-1), angiotensin-converting enzyme (ACE) inhibitor quinaprilat, angiotropin, thrombospondin, peptide KGHK, low oxygen tension, lactate, insulin, copper sulfate, estradiol, prostaglandins, cox inhibitors, endothelial cell binding agents (e.g., decorin or vimentin), glenipin, hydrogen peroxide, nicotine, and growth hormone.
通常，促炎剂是能够刺激受者组织中的免疫应答的物质，其可以加速或维持成熟血管化组织床的形成。例如，促炎剂通常是在植入部位诱导慢性炎症和慢性颗粒反应的刺激物或其他物质。虽然不希望受理论所束缚，但据信高组织颗粒化的形成诱导血管向设备-组织界面提供足够或丰富的分析物供应。促炎剂包括但不限于异种载体、脂多糖、金黄色葡萄球菌(S.aureus)肽聚糖和蛋白质。Typically, proinflammatory agents are substances that can stimulate an immune response in recipient tissues, which can accelerate or maintain the formation of mature vascularized tissue beds. For example, proinflammatory agents are typically stimulants or other substances that induce chronic inflammation and chronic particle reactions at the implant site. Although not wishing to be bound by theory, it is believed that the formation of high tissue granulation induces blood vessels to provide sufficient or abundant analyte supply to the device-tissue interface. Proinflammatory agents include, but are not limited to, xenogeneic carriers, lipopolysaccharides, Staphylococcus aureus (S. aureus) peptidoglycans, and proteins.
可以掺入本公开的膜中的其他物质包括各种药理学药剂、赋形剂和药物制剂领域熟知的其他物质。Other substances that may be incorporated into the films of the present disclosure include various pharmacological agents, excipients, and other substances well known in the art of pharmaceutical formulation.
尽管在一些示例中将生物活性剂掺入生物界面膜或释放膜和/或可植入设备中，但在一些示例中，可以在设备植入的同时、之前或之后全身施用(例如通过口服施用)或局部施用(例如通过在植入部位附近皮下注射)生物活性剂。在某些示例中，掺入生物界面膜中的生物活性剂与局部施用和/或全身施用的生物活性剂的组合可能是优选的。Although in some examples the bioactive agent is incorporated into the biointerface membrane or release membrane and/or the implantable device, in some examples the bioactive agent may be systemically administered (e.g., by oral administration) or locally administered (e.g., by subcutaneous injection near the implantation site) simultaneously with, before, or after the device is implanted. In some examples, a combination of a bioactive agent incorporated into the biointerface membrane and a bioactive agent that is locally and/or systemically administered may be preferred.
在一个示例中，生物活性物质释放膜70用作生物界面膜。在另一示例中，生物活性物质释放膜70在化学上不同于生物界面膜68，或者不使用生物界面膜68。在此类示例中，将一种或多种生物活性剂掺入生物活性物质释放膜70中或者掺入生物界面膜68和生物活性物质释放膜70两者中。In one example, the bioactive substance release membrane 70 is used as a biointerface membrane. In another example, the bioactive substance release membrane 70 is chemically different from the biointerface membrane 68, or the biointerface membrane 68 is not used. In such examples, one or more bioactive agents are incorporated into the bioactive substance release membrane 70 or into both the biointerface membrane 68 and the bioactive substance release membrane 70.
通常，许多变量可以影响生物活性剂释放的药代动力学。本公开的生物活性剂可以被优化用于短期释放和/或延长释放。在一些示例中，本公开的生物活性剂被设计成帮助或克服与异物反应的短期效应(例如，急性炎症)相关的因素，该短期效应可以早在植入的时候就开始并且延长到在植入后至多约一个月。在一些示例中，本公开的生物活性剂被设计成帮助或克服与延长效应相关的因素，例如慢性炎症、屏障细胞层形成或异物反应的纤维化组织的积聚，该延长效应可以早在植入后约一周开始并且延长到植入物的寿命，例如数月至数年。在一些示例中，本公开的生物活性剂组合了短期释放和延长释放以利用两者的益处。授予Shults等人的公开的美国专利公开号2005/0031689公开了用于释放生物活性剂的多种系统和方法。Generally, many variables can affect the pharmacokinetics of bioactive agent release. Bioactive agents of the present disclosure can be optimized for short-term release and/or extended release. In some examples, bioactive agents of the present disclosure are designed to help or overcome factors related to the short-term effects (e.g., acute inflammation) of foreign body reactions, which can start as early as implantation and extend to about one month after implantation. In some examples, bioactive agents of the present disclosure are designed to help or overcome factors related to extended effects, such as accumulation of fibrotic tissue of chronic inflammation, barrier cell layer formation or foreign body reactions, which can start as early as about one week after implantation and extend to the life of the implant, such as months to years. In some examples, bioactive agents of the present disclosure combine short-term release and extended release to utilize the benefits of both. The disclosed U.S. Patent Publication No. 2005/0031689 granted to Shults et al. discloses a variety of systems and methods for releasing bioactive agents.
生物活性剂加载到释放膜中的量可以取决于若干因素。例如，生物活性剂剂量和持续时间可以随释放膜的预期用途(例如，细胞移植、分析物测量设备等)而变化。受者之间生物活性剂有效剂量的差异；-加载生物活性剂的位置和方法；以及与生物活性剂和任选地它们的化学组成和/或生物活性剂负载相关的释放速率。因此，本领域技术人员将理解实现一种或多种生物活性剂的可再现和受控释放的可变性，至少由于上述原因。授予Shults等人的美国专利公开号2005/0031689公开了用于负载生物活性剂的多种系统和方法。The amount of bioactive agent loaded into the release film can depend on several factors. For example, the bioactive agent dosage and duration can vary with the intended use of the release film (e.g., cell transplantation, analyte measurement equipment, etc.). Differences in effective doses of bioactive agents between recipients; - Location and method of loading bioactive agents; and release rates associated with bioactive agents and optionally their chemical composition and/or bioactive agent loading. Therefore, those skilled in the art will appreciate the variability of achieving reproducible and controlled release of one or more bioactive agents, at least due to the above reasons. U.S. Patent Publication No. 2005/0031689 to Shults et al. discloses a variety of systems and methods for loading bioactive agents.
在示例中，采用生物活性物质释放膜的多层或离散或半离散环或带以针对预期的生命感觉特异性地定制生物活性剂的释放。因此，在示例中，多层生物活性物质释放膜的两层或更多层在一个或多个方面不同，该一个或多个方面为例如：软链段化-硬链段化聚合物或共聚物的链段的疏水性/亲水性含量或比率；每层中两种或更多种不同聚合物或共聚物或者不同聚合物和/或共聚物的共混物的组合物组成或重量％，或者它们在一层或多层中的垂直或水平分布；在每一层中的生物活性负载和/或(在涂覆的膜内垂直或纵向)分布；每一层的膜厚度；两种或更多种不同生物活性剂(例如，生物活性剂的中性、衍生物和/或盐形式或初级形式和衍生物形式)的组成和负载量；用于流延或沉积或浸涂单个生物活性物质释放膜层的溶剂体系；和生物活性物质释放膜层沿着传感器长度的相对位置(连续、半连续或非连续定位)。In an example, multiple layers or discrete or semi-discrete rings or bands of bioactive substance release membranes are used to specifically tailor the release of bioactive agents for the expected life sensation. Therefore, in an example, two or more layers of the multilayer bioactive substance release membrane differ in one or more aspects, such as: the hydrophobicity/hydrophilicity content or ratio of the segments of the soft-segmented-hard-segmented polymer or copolymer; the composition composition or weight % of the blend of two or more different polymers or copolymers or different polymers and/or copolymers in each layer, or their vertical or horizontal distribution in one or more layers; the bioactive load in each layer and/or (vertically or longitudinally within the coated membrane) distribution; the membrane thickness of each layer; the composition and loading of two or more different bioactive agents (e.g., neutral, derivative and/or salt form or primary and derivative forms of the bioactive agent); the solvent system used for casting or depositing or dip coating a single bioactive substance release membrane layer; and the relative position of the bioactive substance release membrane layer along the length of the sensor (continuous, semi-continuous or non-continuous positioning).
在传感器上形成生物活性物质释放膜/层Formation of bioactive substance release film/layer on the sensor
本文所公开的膜系统适合用于与生物流体接触的可植入设备。例如，膜系统可以与可植入设备(诸如用于监测和确定生物流体中分析物水平的设备，例如用于监测患有糖尿病的个体的葡萄糖水平的设备)一起使用。在一些示例中，分析物测量设备是连续式设备。分析物测量设备可以采用任何合适的感测元件来提供原始信号，包括但不限于涉及酶元件、化学元件、物理元件、电化学元件、分光光度元件、偏振元件、电位元件、比色元件、辐射元件、免疫化学元件或类似元件的那些感测元件。The membrane system disclosed herein is suitable for implantable devices in contact with biological fluids. For example, the membrane system can be used with an implantable device (such as a device for monitoring and determining the level of analyte in a biological fluid, for example, a device for monitoring the glucose level of an individual with diabetes). In some examples, the analyte measuring device is a continuous device. The analyte measuring device can use any suitable sensing element to provide a raw signal, including but not limited to those sensing elements involving enzyme elements, chemical elements, physical elements, electrochemical elements, spectrophotometric elements, polarization elements, potential elements, colorimetric elements, radiation elements, immunochemical elements or similar elements.
尽管下面的一些描述涉及葡萄糖测量设备，包括所描述的膜系统及其使用方法，但这些膜系统不限于用于测量或监测葡萄糖的设备中。这些膜系统适合用于多种设备中的任一种中，该设备包括例如检测和定量生物流体中存在的其他分析物(例如胆固醇、氨基酸、醇、半乳糖和乳酸盐)的设备、细胞移植设备(参见例如，美国专利号6,015,572、美国专利号5,964,745和美国专利号6,083,523)、药物递送设备(参见例如，美国专利号5,458,631、美国专利号5,820,589和美国专利号5,972,369)等，所述专利出于它们对膜系统的教导全文以引用方式并入本文。Although some of the following descriptions relate to glucose measuring devices, including the described membrane systems and methods of use thereof, these membrane systems are not limited to devices for measuring or monitoring glucose. These membrane systems are suitable for use in any of a variety of devices, including, for example, devices for detecting and quantifying other analytes present in biological fluids (e.g., cholesterol, amino acids, alcohols, galactose, and lactate), cell transplantation devices (see, e.g., U.S. Patent No. 6,015,572, U.S. Patent No. 5,964,745, and U.S. Patent No. 6,083,523), drug delivery devices (see, e.g., U.S. Patent No. 5,458,631, U.S. Patent No. 5,820,589, and U.S. Patent No. 5,972,369), etc., which are incorporated herein by reference in their entirety for their teachings of membrane systems.
合适的生物活性物质释放膜是从插入传感器开始并且在传感器的整个寿命期间提供治疗有效量和释放速率的生物活性剂的那些膜。在一个示例中，当与包括生物活性物质释放膜而没有生物活性剂的等同传感器相比(或与没有生物活性物质释放膜和生物活性剂相比)时，生物活性物质释放膜与一定量的生物活性剂组合提供了延长的传感器使用寿命。如本文所用，生物活性剂的治疗有效量是能够诱导预期治疗效果的量。预期治疗效果是可以使用常规诊断方法容易地确定的治疗效果。例如，预期治疗效果涵盖抑制对植入物(异物)的不想要的异物反应，包括但不限于炎症和/或纤维囊形成。Suitable bioactive substance release membranes are those membranes of bioactive agents that provide therapeutically effective amounts and release rates starting from the insertion of the sensor and during the entire life of the sensor. In one example, when compared with an equivalent sensor including a bioactive substance release membrane without a bioactive agent (or compared with no bioactive substance release membrane and a bioactive agent), the bioactive substance release membrane and a certain amount of bioactive agent combination provide an extended sensor service life. As used herein, the therapeutically effective amount of a bioactive agent is an amount that can induce an expected therapeutic effect. The expected therapeutic effect is a therapeutic effect that can be easily determined using conventional diagnostic methods. For example, the expected therapeutic effect covers suppression of unwanted foreign body reactions to implants (foreign bodies), including but not limited to inflammation and/or fibrous capsule formation.
在一些示例中，可以通过在含表面活性基团的聚合物、含官能团的聚合物、具有两性离子基团的聚合物(或其前体或衍生物)以及它们的组合之间产生共价交联来调节和/或控制膜的润湿特性(以及通过延伸传感器表现出的传感器漂移的程度)。交联可以对膜结构具有显著影响，这进而又可以影响膜的表面润湿特性。交联也可以影响膜的拉伸强度、机械强度、吸水速率和其他特性。In some examples, the wetting properties of the membrane (and the degree of sensor drift exhibited by the extended sensor) can be adjusted and/or controlled by creating covalent crosslinks between polymers containing surface active groups, polymers containing functional groups, polymers having zwitterionic groups (or their precursors or derivatives), and combinations thereof. Crosslinking can have a significant effect on the membrane structure, which in turn can affect the surface wetting properties of the membrane. Crosslinking can also affect the tensile strength, mechanical strength, water absorption rate, and other properties of the membrane.
交联的聚合物可以具有不同的交联密度。在某些示例中，使用交联剂来促进各层之间的交联。在其他示例中，代替(或除此之外)上述交联技术，使用热来形成交联。例如，在一些示例中，由于高温，可以在两种聚合物之间形成酰亚胺和酰胺键。在一些示例中，进行光交联以在聚阳离子层和聚阴离子层之间形成共价键。光交联的一个主要优点是它提供了模式化的可能性。在某些示例中，使用光交联进行模式化以改变膜结构并因此调节膜的润湿特性。Crosslinked polymers can have different crosslink densities. In some examples, a crosslinking agent is used to promote crosslinking between the layers. In other examples, instead of (or in addition to) the above-mentioned crosslinking techniques, heat is used to form crosslinks. For example, in some examples, due to high temperature, imide and amide bonds can be formed between two polymers. In some examples, photocrosslinking is performed to form covalent bonds between the polycationic layer and the polyanionic layer. A major advantage of photocrosslinking is that it provides the possibility of patterning. In some examples, patterning is performed using photocrosslinking to change the film structure and thus adjust the wetting properties of the film.
可以通过本领域已知的方法制备具有被官能化以允许交联的域或链段的聚合物。例如，具有含亲电子官能团(例如，羰基、醛、酸酐、酯、酰胺、异氰基、环氧基、烯丙基或卤代基团)的芳族链段或脂族链段的聚氨酯脲聚合物可以与具有多个亲核基团(例如，羟基、胺、脲、氨基甲酸酯或硫代基团)的交联剂进行交联。在另外的示例中，具有含亲核官能团的芳族链段或脂族链段的聚氨酯脲聚合物可以与具有多个亲电子基团的交联剂进行交联。还另外，具有含亲核官能团或亲电子官能团的亲水性链段的聚氨酯脲聚合物可以与具有多个亲电子官能团或亲核基团的交联剂进行交联。聚氨酯脲上的不饱和官能团也可以通过与多价自由基试剂反应而用于交联。合适的交联剂的非限制性示例包括异氰酸酯、碳二亚胺、戊二醛、氮丙啶、硅烷或其他醛、环氧、丙烯酸酯、基于自由基的试剂、乙二醇二缩水甘油醚(EGDE)、聚(乙二醇)二缩水甘油醚(PEGDE)或过氧化二枯基(DCP)。在示例中，相对于在共混交联剂和聚合物时添加的这些成分的总干重，添加约0.1重量％至约15重量％的交联剂(在示例中，约1重量％至约10重量％)，包括其间的所有范围和子范围。在固化过程期间，认为基本上所有的交联剂发生反应，在最终的膜中基本上没有留下可检测到的未反应的交联剂。Polymers having domains or segments functionalized to allow crosslinking can be prepared by methods known in the art. For example, polyurethane urea polymers having aromatic segments or aliphatic segments containing electrophilic functional groups (e.g., carbonyl, aldehyde, anhydride, ester, amide, isocyano, epoxy, allyl or halo groups) can be crosslinked with a crosslinking agent having multiple nucleophilic groups (e.g., hydroxyl, amine, urea, carbamate or thio group). In another example, polyurethane urea polymers having aromatic segments or aliphatic segments containing nucleophilic functional groups can be crosslinked with a crosslinking agent having multiple electrophilic groups. In addition, polyurethane urea polymers having hydrophilic segments containing nucleophilic functional groups or electrophilic functional groups can be crosslinked with a crosslinking agent having multiple electrophilic functional groups or nucleophilic groups. Unsaturated functional groups on polyurethane urea can also be used for crosslinking by reacting with multivalent free radical reagents. Non-limiting examples of suitable crosslinking agents include isocyanates, carbodiimides, glutaraldehyde, aziridine, silanes or other aldehydes, epoxies, acrylates, free radical-based agents, ethylene glycol diglycidyl ether (EGDE), poly (ethylene glycol) diglycidyl ether (PEGDE) or dicumyl peroxide (DCP). In examples, about 0.1 wt % to about 15 wt % of the crosslinking agent is added (in examples, about 1 wt % to about 10 wt %), including all ranges and sub-ranges therebetween, relative to the total dry weight of these ingredients added when blending the crosslinking agent and the polymer. During the curing process, it is believed that substantially all of the crosslinking agent reacts, leaving substantially no detectable unreacted crosslinking agent in the final film.
本文所公开的聚合物可以被配制成混合物，该混合物可以使用本领域已知的任何方法(例如，喷涂、涂抹、浸涂、气相沉积、模塑、3-D印刷、平版印刷技术(例如，光刻法)、微米和纳米移液印刷技术、丝网印刷等)拉伸成膜或施加到表面上。然后可将混合物在高温(例如，50℃-150℃)下固化。其他合适的固化方法可以包括例如紫外辐射或γ辐射。The polymers disclosed herein can be formulated into a mixture that can be stretched into a film or applied to a surface using any method known in the art (e.g., spraying, painting, dipping, vapor deposition, molding, 3-D printing, lithography (e.g., photolithography), micro- and nano-pipette printing, screen printing, etc.). The mixture can then be cured at an elevated temperature (e.g., 50° C.-150° C.). Other suitable curing methods may include, for example, ultraviolet radiation or gamma radiation.
在一个示例中，与传感器相关联的生物活性剂的量为1μL-120μL、2μL-110μL、3μL-100μL、4μL-90μL、5μL-80μL、6μL-70μL、7μL-60μL、8μL-50μL、9μL-40μL或10μL-30μL。在另一个示例中，与传感器相关联的两种或更多种生物活性剂的量独立地或共同地为1μL-120μL、2μL-110μL、3μL-100μL、4μL-90μL、5μL-80μL、6μL-70μL、7μL-60μL、8μL-50μL、9μL-40μL或10μL-30μL。In one example, the amount of the bioactive agent associated with the sensor is 1 μL-120 μL, 2 μL-110 μL, 3 μL-100 μL, 4 μL-90 μL, 5 μL-80 μL, 6 μL-70 μL, 7 μL-60 μL, 8 μL-50 μL, 9 μL-40 μL, or 10 μL-30 μL. In another example, the amount of two or more bioactive agents associated with the sensor is independently or collectively 1 μL-120 μL, 2 μL-110 μL, 3 μL-100 μL, 4 μL-90 μL, 5 μL-80 μL, 6 μL-70 μL, 7 μL-60 μL, 8 μL-50 μL, 9 μL-40 μL, or 10 μL-30 μL.
在一个示例中，生物活性物质释放膜70中生物活性剂的重量百分比负载为约10重量％至约90重量％。在示例中，生物活性物质释放膜70中生物活性剂的重量百分比负载为生物活性物质释放膜加上生物活性剂(作为传感器上的沉积膜)的总重量的10％、20％、30％、40％、50％、60％、70％、80％或90％。在示例中，生物活性物质释放膜70中生物活性剂的重量百分比负载为生物活性物质释放膜加上生物活性剂(作为传感器上的沉积膜)的总重量的30％、40％、50％或60％。根据生物活性物质释放膜的性质，例如疏水性/亲水性软链段的比率，基于生物活性剂与生物活性物质释放膜的溶解度/混溶性/分散以及用于将生物活性物质释放膜和生物活性剂分配到传感器上的任何溶剂或溶剂体系来选择生物活性剂的重量百分比。特定生物活性物质释放膜中生物活性剂的负载过高可导致生物活性剂沉淀和/或涂层质量差。生物活性物质释放膜中生物活性剂的负载过低可导致在传感器的预期寿命内的无效治疗效果，这可本身表现为初始和/或在传感器的设计寿命终止之前差的信噪比、在插入之后不久和/或在传感器的设计寿命终止之前传感器对目标分析物的灵敏度的降低或波动等。In one example, the weight percent loading of the bioactive agent in the bioactive substance release film 70 is about 10% to about 90% by weight. In an example, the weight percent loading of the bioactive agent in the bioactive substance release film 70 is 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% of the total weight of the bioactive substance release film plus the bioactive agent (as a deposited film on the sensor). In an example, the weight percent loading of the bioactive agent in the bioactive substance release film 70 is 30%, 40%, 50% or 60% of the total weight of the bioactive substance release film plus the bioactive agent (as a deposited film on the sensor). The weight percent of the bioactive agent is selected based on the solubility/miscibility/dispersion of the bioactive agent with the bioactive substance release film and any solvent or solvent system used to distribute the bioactive substance release film and the bioactive agent onto the sensor according to the properties of the bioactive substance release film, such as the ratio of hydrophobic/hydrophilic soft segments. Too high a loading of the bioactive agent in a particular bioactive substance release membrane may result in precipitation of the bioactive agent and/or poor coating quality. Too low a loading of the bioactive agent in the bioactive substance release membrane may result in ineffective therapeutic effect over the expected life of the sensor, which may manifest itself as a poor signal-to-noise ratio initially and/or before the end of the designed life of the sensor, a decrease or fluctuation in the sensitivity of the sensor to the target analyte shortly after insertion and/or before the end of the designed life of the sensor, etc.
在示例中，生物活性物质释放膜被配置为在插入之后并且直到传感器的寿命终止时按重量百分比计释放生物活性剂的初始负载的至少10％、20％、30％、40％、50％、60％、70％、80％、90％，直到并包括100％。在示例中，生物活性物质释放膜被配置为在插入之后并且直到传感器寿命终止时释放60重量％至90重量％的生物活性剂。在另一示例中，生物活性物质释放膜被配置为在插入之后并且直到传感器寿命终止时释放75重量％至85重量％的生物活性剂。In an example, the bioactive substance release membrane is configured to release at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, up to and including 100% of the initial load of the bioactive agent by weight percentage after insertion and until the end of the life of the sensor. In an example, the bioactive substance release membrane is configured to release 60% to 90% by weight of the bioactive agent after insertion and until the end of the life of the sensor. In another example, the bioactive substance release membrane is configured to release 75% to 85% by weight of the bioactive agent after insertion and until the end of the life of the sensor.
在一个示例中，本公开的生物活性物质释放膜提供与生物活性剂的推注量相称的从生物活性物质释放膜的生物活性剂释放。在另一示例中，本公开的生物活性物质释放膜提供与生物活性剂的治疗有效量相称的从生物活性物质释放膜的生物活性剂释放。在示例中，本公开的生物活性物质释放膜提供与非治疗有效量相称的从生物活性物质释放膜的生物活性剂释放，其中该非治疗有效量在释放推注量或治疗量的生物活性剂中的一者或多者之后。In one example, the bioactive substance release membrane of the present disclosure provides a release of the bioactive agent from the bioactive substance release membrane commensurate with the bolus amount of the bioactive agent. In another example, the bioactive substance release membrane of the present disclosure provides a release of the bioactive agent from the bioactive substance release membrane commensurate with the therapeutically effective amount of the bioactive agent. In an example, the bioactive substance release membrane of the present disclosure provides a release of the bioactive agent from the bioactive substance release membrane commensurate with a non-therapeutically effective amount, wherein the non-therapeutically effective amount is after releasing one or more of the bolus amount or the therapeutic amount of the bioactive agent.
在示例中，本公开的生物活性物质释放膜在传感器插入到受试者的软组织中后基本上立即提供生物活性剂的推注释放，持续第一时间段或范围(例如，数分钟、数小时、数天、数周等)，该第一时间段或范围在第一时间点(例如，一秒或更短时间)开始。在示例中，本公开的生物活性物质释放膜提供在传感器插入到受试者的软组织中后基本上立即释放推注量的生物活性剂，持续在第一时间点开始的第一时间段，随后在第二时间点开始释放治疗有效量的生物活性剂，持续第二时间段，该第二时间段与第一时间段重叠或在第一时间段之后。在示例中，第二时间点在第一时间点之后至少10秒、30秒、1分钟、5分钟、10分钟或更长时间。在一个示例中，本公开的生物活性物质释放膜提供在传感器插入到受试者的软组织中后基本上立即释放推注量的生物活性剂，持续在第一时间点开始的第一时间段，随后在第二时间点开始释放治疗有效量的生物活性剂，持续第二时间段，该第二时间段与第一时间段重叠或在第一时间段之后，随后在第三时间点开始释放非治疗有效量的生物活性剂，持续第三时间段，该第三时间段与第二时间段重叠或在第二时间段之后。在示例中，第三时间点在第二时间点之后至少10秒、30秒、1分钟、5分钟、10分钟或更长时间。In an example, the bioactive substance release film of the present disclosure provides a bolus release of the bioactive agent substantially immediately after the sensor is inserted into the soft tissue of the subject, for a first time period or range (e.g., minutes, hours, days, weeks, etc.), which starts at a first time point (e.g., one second or less). In an example, the bioactive substance release film of the present disclosure provides a bolus release of the bioactive agent substantially immediately after the sensor is inserted into the soft tissue of the subject, for a first time period starting at the first time point, followed by a therapeutically effective amount of the bioactive agent starting at a second time point, for a second time period, which overlaps with the first time period or is after the first time period. In an example, the second time point is at least 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes, or more after the first time point. In one example, the bioactive substance release film of the present disclosure provides for releasing a bolus amount of a bioactive agent substantially immediately after the sensor is inserted into the soft tissue of a subject, for a first time period starting at a first time point, followed by release of a therapeutically effective amount of the bioactive agent starting at a second time point, for a second time period, the second time period overlapping with the first time period or after the first time period, followed by release of a non-therapeutically effective amount of the bioactive agent starting at a third time point, for a third time period, the third time period overlapping with the second time period or after the second time period. In an example, the third time point is at least 10 seconds, 30 seconds, 1 minute, 5 minutes, 10 minutes or more after the second time point.
在示例中，生物活性物质的推注释放与非活性药物成分(非API)诸如亲水性物质(两性离子物质、水凝胶颗粒或球体)的释放组合，以便改变由于传感器体积的存在而在组织中产生的环境。虽然不希望受理论所束缚，但据信亲水性物质将流体吸引到环境中，这可减轻生物淤积、减缓生物活性物质的代谢分解和/或增加生物活性物质到细胞中的摄取。此类非API的释放可促进异物反应的延迟和/或促进生物活性物质从生物活性物质释放膜的释放，以及其他益处。In an example, a bolus release of a bioactive substance is combined with the release of an inactive pharmaceutical ingredient (non-API) such as a hydrophilic substance (zwitterionic substance, hydrogel particles or spheres) to change the environment created in the tissue due to the presence of the sensor volume. While not wishing to be bound by theory, it is believed that the hydrophilic substance attracts fluid into the environment, which can reduce biofouling, slow metabolic breakdown of the bioactive substance, and/or increase the uptake of the bioactive substance into cells. The release of such non-APIs can promote the delay of foreign body reactions and/or promote the release of the bioactive substance from the bioactive substance release membrane, among other benefits.
在上述第一时间段、第二时间段或第三时间段的任一时间段中，生物活性剂的释放速率可以相同或不同。例如，通过改变膜的化学性质、结构和/或形态、生物活性剂的负载、生物活性物质化学性质中的一种或多种，可以将在上述第一时间段、第二时间段或第三时间段中的任一时间段中的生物活性剂的释放速率配置为以基本上恒定的速率或可变的速率(间歇的、周期性的和/或随机的)发生。例如，通过改变膜的化学性质、结构和/或形态、生物活性剂负载、生物活性物质化学性质中的一种或多种，可以将在任何前述时间段中生物活性剂的释放速率(随时间推移释放的生物活性物质的浓度或量)被配置为在植入后随时间推移而变化。In any time period of the above-mentioned first time period, the second time period or the third time period, the release rate of the bioactive agent can be the same or different. For example, by changing one or more of the chemical properties, structure and/or morphology of the film, the load of the bioactive agent, the chemical properties of the bioactive substance, the release rate of the bioactive agent in any time period of the above-mentioned first time period, the second time period or the third time period can be configured to occur at a substantially constant rate or a variable rate (intermittent, periodic and/or random). For example, by changing one or more of the chemical properties, structure and/or morphology of the film, the load of the bioactive agent, the chemical properties of the bioactive substance, the release rate of the bioactive agent in any of the aforementioned time periods (the concentration or amount of the bioactive substance released over time) can be configured to change over time after implantation.
在一个示例中，初始或在第一时间段期间生物活性剂从生物活性物质释放膜的释放速率大于初始或在第二时间段期间生物活性剂从生物活性物质释放膜的释放速率。在一个示例中，初始或在第二时间段期间生物活性剂从生物活性物质释放膜的释放速率大于初始或在第三时间段期间生物活性剂从生物活性物质释放膜的释放速率。在一个示例中，初始或在第一时间段期间生物活性剂从生物活性物质释放膜的释放速率大于初始或在第二时间段期间生物活性剂从生物活性物质释放膜的释放速率，并且初始或在第二时间段期间生物活性剂从生物活性物质释放膜的释放速率大于初始或在第三时间段期间生物活性剂从生物活性物质释放膜的释放速率。In one example, the release rate of the bioactive agent from the bioactive substance release film initially or during the first time period is greater than the release rate of the bioactive agent from the bioactive substance release film initially or during the second time period. In one example, the release rate of the bioactive agent from the bioactive substance release film initially or during the second time period is greater than the release rate of the bioactive agent from the bioactive substance release film initially or during the third time period. In one example, the release rate of the bioactive agent from the bioactive substance release film initially or during the first time period is greater than the release rate of the bioactive agent from the bioactive substance release film initially or during the second time period, and the release rate of the bioactive agent from the bioactive substance release film initially or during the second time period is greater than the release rate of the bioactive agent from the bioactive substance release film initially or during the third time period.
能够具有前述释放速率和释放量的生物活性剂的合适的本公开的生物活性物质释放膜可选自有机硅聚合物；聚四氟乙烯；膨胀型聚四氟乙烯；聚乙烯-共-四氟乙烯；聚烯烃；聚酯；聚烷基酯；聚碳酸烷基酯；聚碳酸酯；生物稳定的聚四氟乙烯；聚氨酯的均聚物、共聚物、三元共聚物；聚丙烯(PP)；聚氯乙烯(PVC)；聚偏二氟乙烯(PVDF)；聚乙烯醇(PVA)；聚乙烯乙酸乙烯酯(EVA)；聚对苯二甲酸丁二醇酯(PBT)；聚甲基丙烯酸甲酯(PMMA)；聚醚醚酮(PEEK)；聚酰胺；聚氨酯及其共聚物和共混物；聚氨酯脲聚合物及其共聚物和共混物；纤维素聚合物及其共聚物和共混物；聚(环氧乙烷)及其共聚物和共混物；聚(环氧丙烷)及其共聚物和共混物；聚砜及其嵌段共聚物，包括例如二嵌段、三嵌段、交替、无规和接枝共聚物；纤维素；水凝胶聚合物；聚(2-羟乙基甲基丙烯酸酯)(pHEMA)及其共聚物和共混物；甲基丙烯酸羟乙酯(HEMA)及其共聚物和共混物；聚丙烯腈-聚氯乙烯(PAN-PVC)及其共聚物和共混物；丙烯酸共聚物及其共聚物和共混物；尼龙及其共聚物和共混物；聚二氟乙烯；聚酸酐；聚(l-赖氨酸)；聚(L-乳酸)；甲基丙烯酸羟乙酯及其共聚物和共混物；以及羟磷灰石及其共聚物和共混物。Suitable bioactive material release membranes of the present disclosure capable of having the aforementioned release rates and amounts of bioactive agents can be selected from silicone polymers; polytetrafluoroethylene; expanded polytetrafluoroethylene; polyethylene-co-tetrafluoroethylene; polyolefins; polyesters; polyalkyl esters; polyalkyl carbonates; polycarbonates; biostable polytetrafluoroethylene; homopolymers, copolymers, terpolymers of polyurethane; polypropylene (PP); polyvinyl chloride (PVC); polyvinylidene fluoride (PVDF); polyvinyl alcohol (PVA); polyethylene vinyl acetate (EVA); polybutylene terephthalate (PBT); polymethyl methacrylate (PMMA); polyetheretherketone (PEEK); polyamides; polyurethanes and copolymers and blends thereof; polyurethaneurea polymers and copolymers and blends thereof; cellulose polymers and copolymers and blends thereof; poly(ethylene oxide) and copolymers and blends thereof; poly(propylene oxide) and copolymers and blends thereof; polysulfones and block copolymers thereof, including, for example, diblock, triblock, alternating, random and graft copolymers; cellulose; hydrogel polymers; poly(2-hydroxyethyl methacrylate) (pHEMA) and copolymers and blends thereof; hydroxyethyl methacrylate (HEMA) and copolymers and blends thereof; polyacrylonitrile-polyvinyl chloride (PAN-PVC) and copolymers and blends thereof; acrylic acid copolymers and copolymers and blends thereof; nylon and copolymers and blends thereof; polyvinylidene fluoride; polyanhydrides; poly(l-lysine); poly(L-lactic acid); hydroxyethyl methacrylate and copolymers and blends thereof; and hydroxyapatite and copolymers and blends thereof.
合适的生物活性物质释放膜是聚氨酯或聚醚聚氨酯脲。聚氨酯是通过二异氰酸酯和双官能含羟基材料的缩合反应制备的聚合物。聚氨酯脲是通过二异氰酸酯和双官能含胺材料的缩合反应制备的聚合物。示例性二异氰酸酯包括含有约4个至约8个亚甲基单元的脂族二异氰酸酯。含有脂环族部分的二异氰酸酯也可用于制备本公开的生物活性物质释放膜的聚合物和共聚物组分。形成生物活性物质释放膜或其域的疏水性基质的基础的材料可以是本领域已知的适于用作连续分析物传感器设备中的膜的那些材料中的任一种材料。在一个示例中，生物活性物质释放膜与传感器系统的其他膜的不同之处在于，生物活性物质释放膜对相关化合物的渗透性不足以例如允许葡萄糖分子通过膜。Suitable bioactive substance release membranes are polyurethanes or polyether polyurethane ureas. Polyurethanes are polymers prepared by the condensation reaction of diisocyanates and difunctional hydroxyl-containing materials. Polyurethane ureas are polymers prepared by the condensation reaction of diisocyanates and difunctional amine-containing materials. Exemplary diisocyanates include aliphatic diisocyanates containing about 4 to about 8 methylene units. Diisocyanates containing alicyclic moieties can also be used to prepare polymer and copolymer components of the bioactive substance release membrane of the present disclosure. The material forming the basis of the hydrophobic matrix of the bioactive substance release membrane or its domain can be any of those materials known in the art that are suitable for use as a membrane in a continuous analyte sensor device. In one example, the difference between the bioactive substance release membrane and other membranes of the sensor system is that the permeability of the bioactive substance release membrane to the related compound is not enough to allow, for example, glucose molecules to pass through the membrane.
可用于制备非聚氨酯型生物活性物质释放膜的其他材料的示例包括乙烯基聚合物、聚乙烯乙酸乙烯酯、聚乙烯乙酸乙烯酯共聚物、聚醚、聚酯、聚烷基酯、聚酰胺、聚有机硅、聚(二烷基硅氧烷)、聚(烷基芳基硅氧烷)、聚(二芳基硅氧烷)、聚碳硅氧烷、聚碳酸烷基酯、聚碳酸酯、天然聚合物(诸如纤维素和蛋白质基材料)，以及它们与或不与前述聚氨酯或聚醚聚氨酯脲聚合物的混合物、共聚物或组合。Examples of other materials that can be used to prepare non-polyurethane bioactive substance release membranes include vinyl polymers, polyethylene vinyl acetate, polyethylene vinyl acetate copolymers, polyethers, polyesters, polyalkyl esters, polyamides, polysilicones, poly(dialkylsiloxanes), poly(alkylarylsiloxanes), poly(diarylsiloxanes), polycarbosiloxanes, polyalkyl carbonates, polycarbonates, natural polymers (such as cellulose and protein-based materials), and mixtures, copolymers or combinations thereof with or without the aforementioned polyurethane or polyether polyurethane urea polymers.
在示例中，生物活性物质释放膜包括软链段和硬链段，该硬链段包括氨基甲酸酯基团、脲基团或氨基甲酸酯基团与脲基团的组合。软链段可以是两种或更多种不同的聚合物链段。软链段可包括疏水性嵌段和亲水性嵌段。软链段可包括聚硅氧烷、聚烷基醚、聚烷基酯、聚碳酸烷基酯、聚碳酸酯或聚硅氧烷-聚烷基醚链段化嵌段。In an example, the bioactive substance release film includes a soft segment and a hard segment, and the hard segment includes a carbamate group, a urea group or a combination of a carbamate group and a urea group. The soft segment can be two or more different polymer segments. The soft segment can include a hydrophobic block and a hydrophilic block. The soft segment can include a polysiloxane, a polyalkyl ether, a polyalkyl ester, a polyalkyl carbonate, a polycarbonate or a polysiloxane-polyalkyl ether segmented block.
在示例中，软链段独立地包括疏水性部分/亲水性部分的组合，诸如多元醇(聚环氧乙烷“PEO”、聚乙烯环氧丙烷、聚四氢呋喃或聚四亚甲基氧化物、聚醚、聚硅氧烷、聚胺、聚硅氧烷胺、聚酯、聚烷基酯、聚碳酸烷基酯、聚碳酸酯)，并且一种或多种独立的硬链段为例如脂族或芳族二异氰酸酯，诸如降冰片烷二异氰酸酯(NBDI)、异佛尔酮二异氰酸酯(IPDI)、甲苯二异氰酸酯(TDI)、1,3-亚苯基二异氰酸酯(MPDI)、反式-1,3-双(异氰酸甲基)环己烷(1,3-H6XDI)、双环己基甲烷-4,4'-二异氰酸酯(HMDI)、4,4'-二苯基甲烷二异氰酸酯(MDI)、反式-1,4-双(异氰酸甲基)环己烷(1,4-H6XDI)、1,4-环己基二异氰酸酯(CHDI)、1,4-亚苯基二异氰酸酯(PPDI)、3,3'-二甲基-4,4'-联苯二异氰酸酯(TODI)、1,6-六亚甲基二异氰酸酯(HDI)或它们的组合。In an example, the soft segments independently include a hydrophobic/hydrophilic portion combination such as a polyol (polyethylene oxide "PEO", polyethylene propylene oxide, polytetramethylene oxide or polytetramethylene oxide, polyether, polysiloxane, polyamine, polysiloxane amine, polyester, polyalkyl ester, polyalkyl carbonate, polycarbonate), and one or more independent hard segments are, for example, an aliphatic or aromatic diisocyanate such as norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), polyisocyanate (PEO ... ), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI) or a combination thereof.
在示例中，生物活性物质释放膜还可包括扩链剂。扩链剂例如可以是二醇、二胺、硅-氢化物或多官能环氧化物。示例性二醇包括脂族或芳族低分子量二醇，例如二醇、丙二醇、二甘醇和1,4-丁二醇，并且其他示例性扩链剂包括二烷基胺，例如乙二胺、1,6-六亚甲基二胺、4,4'-二氨基二苯基甲烷、三亚乙基二胺、腐胺和二氨基丙烷或羟胺。In an example, the bioactive substance release film may further include a chain extender. The chain extender may be, for example, a diol, a diamine, a silicon-hydride, or a multifunctional epoxide. Exemplary diols include aliphatic or aromatic low molecular weight diols, such as diol, propylene glycol, diethylene glycol, and 1,4-butanediol, and other exemplary chain extenders include dialkylamines, such as ethylenediamine, 1,6-hexamethylenediamine, 4,4'-diaminodiphenylmethane, triethylenediamine, putrescine, and diaminopropane or hydroxylamine.
在其他示例中，生物活性物质释放膜还包括选自由以下各项组成的组的一个或多个两性离子重复单元：椰油酰胺丙基甜菜碱、油酰胺丙基甜菜碱、辛基磺基甜菜碱、癸基磺基甜菜碱、月桂基磺基甜菜碱、肉豆蔻基磺基甜菜碱、棕榈基磺基甜菜碱、硬脂酰基磺基甜菜碱、甜菜碱(三甲基甘氨酸)、辛基甜菜碱、磷脂酰胆碱、甘氨酸甜菜碱、聚(羧基甜菜碱)、聚(磺基甜菜碱)以及它们的衍生物。在另一方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜不包括仅在聚合物链末端处的两性离子基团。In other examples, the bioactive substance release film also includes one or more zwitterionic repeating units selected from the group consisting of: cocamidopropyl betaine, oleamidopropyl betaine, octyl sulfobetaine, decyl sulfobetaine, lauryl sulfobetaine, myristyl sulfobetaine, palmityl sulfobetaine, stearoyl sulfobetaine, betaine (trimethylglycine), octyl betaine, phosphatidylcholine, glycine betaine, poly (carboxy betaine), poly (sulfobetaine) and their derivatives. On the other hand, alone or in combination with any of the foregoing aspects, the bioactive substance release film does not include zwitterionic groups only at the ends of the polymer chains.
在示例中，一个或多个两性离子重复单元衍生自选自由以下各项组成的组的单体：In an example, the one or more zwitterionic repeating units are derived from a monomer selected from the group consisting of:
以及 as well as
其中Z是支链或直链烷基、杂烷基、环烷基、环杂烷基、芳基或杂芳基；R1是H、烷基、杂烷基、环烷基、杂环烷基、芳基或杂芳基；并且R2、R3和R4独立地选自烷基、杂烷基、环烷基、杂环烷基、芳基或杂芳基；并且其中R1、R2、R3、R4和Z中的一者或多者被聚合基团取代，用作生物活性物质释放膜的至少一部分。wherein Z is a branched or straight chain alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl; R1 is H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and R2, R3 and R4 are independently selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and wherein one or more ofR1 ,R2 ,R3 ,R4 and Z are substituted with a polymeric group, for use as at least a portion of a bioactive substance release membrane.
在示例中，聚合基团选自烯烃、炔烃、环氧化物、内酯、胺、羟基、异氰酸酯、羧酸、酸酐、硅烷、卤化物、醛和碳二亚胺。在另一个示例中，基于聚合物的总重量，该一个或多个两性离子重复单元为至少约1重量％。In an example, the polymeric group is selected from olefins, alkynes, epoxides, lactones, amines, hydroxyls, isocyanates, carboxylic acids, anhydrides, silanes, halides, aldehydes, and carbodiimides. In another example, the one or more zwitterionic repeating units are at least about 1 wt % based on the total weight of the polymer.
在一个示例中，至少一种生物活性剂与生物活性物质释放膜共价缔合。在另一示例中，至少一种生物活性剂与生物活性物质释放膜离子缔合。在另一个示例中，该生物活性剂是缀合物。In one example, at least one bioactive agent is covalently associated with the bioactive substance release membrane. In another example, at least one bioactive agent is ionically associated with the bioactive substance release membrane. In another example, the bioactive agent is a conjugate.
在另一个示例中，该至少一种生物活性剂是一氧化氮(NO)释放分子、聚合物或寡聚物。在另一方面，单独地或与前述方面中的任一方面组合地，一氧化氮释放分子选自N-二醇二氮烯鎓和S-亚硝基硫醇。在示例中，一氧化氮释放分子与聚合物或寡聚物共价或非共价偶联。在示例中，N-二醇二氮烯鎓具有以下结构：RR'N-N2O2，其中R和R'独立地是烷基、芳基、苯基、烷基芳基、烷基苯基或官能化的N-烷基氨基三烷氧基硅烷。在示例中，具有以下结构RR'N-N2O2的N-二醇二氮烯鎓的R和R'基团中的至少一者具有足够的亲脂性以保留在生物活性物质释放膜的疏水性区域中，同时向插入部位提供一氧化氮源。在示例中，R和R'中的至少一者被充分官能化以与生物活性物质释放膜偶联，同时向插入部位提供一氧化氮源。在示例中，S-亚硝基硫醇是S-亚硝基-谷胱甘肽(GSNO)或青霉胺的S-亚硝基硫醇衍生物。In another example, the at least one bioactive agent is a nitric oxide (NO) releasing molecule, polymer or oligomer. On the other hand, alone or in combination with any of the foregoing aspects, the nitric oxide releasing molecule is selected from N-diazenium diolate and S-nitrosothiol. In an example, the nitric oxide releasing molecule is covalently or non-covalently coupled to a polymer or oligomer. In an example, the N-diazenium diolate has the following structure: RR'N-N2O2, wherein R and R' are independently alkyl, aryl, phenyl, alkylaryl, alkylphenyl or functionalized N-alkylaminotrialkoxysilane. In an example, at least one of the R and R' groups of the N-diazenium diolate having the following structure RR'N-N2O2 has sufficient lipophilicity to be retained in the hydrophobic region of the bioactive substance release membrane while providing a nitric oxide source to the insertion site. In an example, at least one of R and R' is fully functionalized to couple with the bioactive substance release membrane while providing a nitric oxide source to the insertion site. In examples, the S-nitrosothiol is S-nitroso-glutathione (GSNO) or an S-nitrosothiol derivative of penicillamine.
在另一个示例中，生物活性剂是硼酸酯或硼酸盐。在一个示例中，生物活性剂-硼酸酯或硼酸盐与生物活性物质释放膜共价偶联。在另一示例中，生物活性剂-硼酸酯或硼酸盐与生物活性物质释放膜非共价偶联。在一个示例中，生物活性剂-硼酸酯或硼酸盐与生物活性剂共价偶联，并且与生物活性物质释放膜共价偶联。在另一示例中，生物活性剂-硼酸酯或硼酸盐与生物活性剂共价偶联，并且与生物活性物质释放膜非共价偶联。在另一个示例中，生物活性剂是地塞米松的硼酸酯或硼酸盐、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松或醋酸地塞米松盐)。In another example, the bioactive agent is a borate or borate. In one example, the bioactive agent-borate or borate is covalently coupled to the bioactive substance release film. In another example, the bioactive agent-borate or borate is non-covalently coupled to the bioactive substance release film. In one example, the bioactive agent-borate or borate is covalently coupled to the bioactive agent and covalently coupled to the bioactive substance release film. In another example, the bioactive agent-borate or borate is covalently coupled to the bioactive agent and non-covalently coupled to the bioactive substance release film. In another example, the bioactive agent is a borate or borate of dexamethasone, a dexamethasone salt or a dexamethasone derivative (particularly dexamethasone acetate or dexamethasone acetate salt).
在另一个示例中，生物活性剂是缀合物，该缀合物包含至少一个通过皮下刺激可裂解的连接子。在另一个示例中，生物活性剂是地塞米松、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松或醋酸地塞米松盐)的缀合物，其包含至少一个通过皮下刺激可裂解的连接子。例如，在将分析物传感器插入受者的皮下域中之后，包含至少一个可裂解连接子的生物活性剂缀合物通过皮下刺激被裂解。在一个示例中，皮下刺激是由锌内肽酶(metzincin)超家族的一个或多个成员、基质金属蛋白酶(MMP)、或基质金属肽酶或基质蛋白酶(matrixin)或任何其他蛋白酶的化学攻击。在示例中，MMP是钙或锌依赖性内肽酶、蛇毒蛋白酶(adamalysin)、虾红素或粘质沙雷氏菌酶(serralysin)。In another example, the bioactive agent is a conjugate comprising at least one linker that can be cleaved by subcutaneous stimulation. In another example, the bioactive agent is a conjugate of dexamethasone, a dexamethasone salt or a dexamethasone derivative (particularly dexamethasone acetate or dexamethasone acetate salt), which comprises at least one linker that can be cleaved by subcutaneous stimulation. For example, after the analyte sensor is inserted into the subcutaneous domain of the recipient, the bioactive agent conjugate comprising at least one cleavable linker is cleaved by subcutaneous stimulation. In one example, subcutaneous stimulation is a chemical attack by one or more members of the zinc endopeptidase (metzincin) superfamily, a matrix metalloproteinase (MMP), or a matrix metalloproteinase or a matrix protease (matrixin) or any other protease. In an example, MMP is a calcium or zinc-dependent endopeptidase, an adamalysin, astaxanthin or serralysin.
在另一示例中，包括生物活性剂(单独地或作为缀合物或与生物活性物质释放膜缔合)的生物活性物质释放膜包括亲水性水凝胶，其中该亲水性水凝胶至少部分地交联并且能够溶解于生物流体中。在另一示例中，包括生物活性剂(单独地或作为缀合物)的生物活性物质释放膜包括与地塞米松、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松或醋酸地塞米松盐)缔合或偶联的亲水性水凝胶，其中该亲水性水凝胶至少部分地交联并且能够溶解于生物流体中，并且提供地塞米松、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松或醋酸地塞米松盐)的释放。In another example, the bioactive substance release membrane comprising a bioactive agent (alone or as a conjugate or associated with a bioactive substance release membrane) comprises a hydrophilic hydrogel, wherein the hydrophilic hydrogel is at least partially cross-linked and can be dissolved in a biological fluid. In another example, the bioactive substance release membrane comprising a bioactive agent (alone or as a conjugate) comprises a hydrophilic hydrogel associated or coupled with dexamethasone, a dexamethasone salt or a dexamethasone derivative (particularly dexamethasone acetate or a dexamethasone acetate salt), wherein the hydrophilic hydrogel is at least partially cross-linked and can be dissolved in a biological fluid, and provides release of dexamethasone, a dexamethasone salt or a dexamethasone derivative (particularly dexamethasone acetate or a dexamethasone acetate salt).
在示例中，亲水性水凝胶在6小时、12小时、24小时、2天、3天、4天、5天、6天、7天或更长时间内至少部分地溶解于生物流体中，并且提供地塞米松、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松或醋酸地塞米松盐)的连续、半连续或推注释放。在示例中，亲水性水凝胶包括通过二乙烯基砜或聚乙二醇二乙烯基砜交联的透明质酸(HA)。在示例中，亲水性水凝胶包括地塞米松、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松或醋酸地塞米松盐)的水凝胶缀合物。In an example, the hydrophilic hydrogel is at least partially dissolved in a biological fluid within 6 hours, 12 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days or longer, and provides a continuous, semi-continuous or bolus release of dexamethasone, a dexamethasone salt or a dexamethasone derivative (particularly dexamethasone acetate or a dexamethasone acetate salt). In an example, the hydrophilic hydrogel includes hyaluronic acid (HA) cross-linked by divinyl sulfone or polyethylene glycol divinyl sulfone. In an example, the hydrophilic hydrogel includes a hydrogel conjugate of dexamethasone, a dexamethasone salt or a dexamethasone derivative (particularly dexamethasone acetate or a dexamethasone acetate salt).
在另一方面，生物活性物质释放膜包括银纳米颗粒或纳米凝胶单独地作为生物活性剂或与地塞米松、地塞米松盐或地塞米松衍生物或其混合物(特别是醋酸地塞米松或醋酸地塞米松盐)组合作为生物活性剂。在一个示例中，纳米颗粒是可生物降解的。例如，可生物降解聚合物纳米颗粒包括含有至少一种生物活性剂的PLA、PLGA、PCL、PVL、PLLA、PDLA、PEO-b-PLA嵌段共聚物、聚磷酸酯或PEO-b-多肽。在示例中，生物活性物质释放膜包括铜和/或锌纳米颗粒或纳米凝胶作为生物活性剂。银、铜或锌纳米颗粒/纳米凝胶可在整个生物活性物质释放膜中空间分布或分散，其中该空间分布或分散可以是均匀的或不均匀的，和/或以某个梯度垂直和/或水平变化。On the other hand, the bioactive substance release film includes silver nanoparticles or nanogels as bioactive agents alone or in combination with dexamethasone, dexamethasone salts or dexamethasone derivatives or their mixtures (particularly dexamethasone acetate or dexamethasone acetate salts) as bioactive agents. In one example, the nanoparticles are biodegradable. For example, biodegradable polymer nanoparticles include PLA, PLGA, PCL, PVL, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphates or PEO-b-polypeptides containing at least one bioactive agent. In an example, the bioactive substance release film includes copper and/or zinc nanoparticles or nanogels as bioactive agents. Silver, copper or zinc nanoparticles/nanogels can be spatially distributed or dispersed in the entire bioactive substance release film, wherein the spatial distribution or dispersion can be uniform or inhomogeneous, and/or vertically and/or horizontally changed with a certain gradient.
在示例中，具有银、锌或铜的自组装纳米颗粒/纳米凝胶的细菌纤维素用作生物活性物质释放膜，并且提供单独地或与本文所公开的聚氨酯/聚氨酯脲膜中的任一种膜一起的地塞米松、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松或醋酸地塞米松盐)的释放。在另一示例中，壳寡糖/聚(乙烯醇)纳米颗粒/纳米凝胶或银、锌或铜的纳米纤维用作生物活性物质释放膜，并且提供地塞米松、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松或醋酸地塞米松盐)的释放。In an example, bacterial cellulose with self-assembled nanoparticles/nanogels of silver, zinc or copper is used as a bioactive substance release membrane, and provides release of dexamethasone, dexamethasone salts or dexamethasone derivatives (particularly dexamethasone acetate or dexamethasone acetate salts) alone or together with any of the polyurethane/polyurethaneurea membranes disclosed herein. In another example, chitosan oligosaccharide/poly(vinyl alcohol) nanoparticles/nanogels or nanofibers of silver, zinc or copper are used as bioactive substance release membranes, and provide release of dexamethasone, dexamethasone salts or dexamethasone derivatives (particularly dexamethasone acetate or dexamethasone acetate salts).
在示例中，生物活性物质释放膜包括选自以下各项的可生物降解聚合物纳米颗粒：PLA、PLGA、PCL、PVL、PLLA、PDLA、PEO-b-PLA嵌段共聚物、聚磷酸酯、PEO-b-多肽，其中该聚合物纳米颗粒/纳米凝胶包括共价或非共价缔合的地塞米松、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松或醋酸地塞米松盐)。In an example, the bioactive substance releasing membrane comprises biodegradable polymer nanoparticles selected from the group consisting of PLA, PLGA, PCL, PVL, PLLA, PDLA, PEO-b-PLA block copolymers, polyphosphates, PEO-b-polypeptides, wherein the polymer nanoparticles/nanogels comprise covalently or non-covalently associated dexamethasone, a dexamethasone salt or a dexamethasone derivative (particularly dexamethasone acetate or a dexamethasone acetate salt).
在另一示例中，生物活性物质释放膜包括提供地塞米松、地塞米松盐或地塞米松衍生物(特别是醋酸地塞米松或醋酸地塞米松盐)的释放的有机和/或无机溶胶-凝胶或有机-无机复合溶胶-凝胶或基于泊洛沙姆的载体。在另一示例中，生物活性物质释放膜包括热敏性控释水凝胶或泊洛沙姆，例如聚(ε-己内酯)-聚(乙二醇)-聚(ε-己内酯)水凝胶。In another example, the bioactive substance release film includes an organic and/or inorganic sol-gel or organic-inorganic composite sol-gel or poloxamer-based carrier that provides release of dexamethasone, dexamethasone salt or dexamethasone derivative (particularly dexamethasone acetate or dexamethasone acetate salt). In another example, the bioactive substance release film includes a thermosensitive controlled release hydrogel or poloxamer, such as poly (ε-caprolactone) -poly (ethylene glycol) -poly (ε-caprolactone) hydrogel.
在一个示例中，前述生物活性物质释放膜包括包封在生物活性物质释放膜中的至少一种生物活性剂和与生物活性物质释放膜共价偶联的至少一种生物活性剂的组合。在另一示例中，如本文所公开，生物活性物质释放膜包括作为缀合物或与生物活性物质释放膜缔合的至少一种生物活性剂的空间远侧药物贮库。In one example, the aforementioned bioactive substance release membrane includes a combination of at least one bioactive agent encapsulated in the bioactive substance release membrane and at least one bioactive agent covalently coupled to the bioactive substance release membrane. In another example, as disclosed herein, the bioactive substance release membrane includes a spatial distal drug reservoir of at least one bioactive agent as a conjugate or associated with the bioactive substance release membrane.
在另一示例中，生物活性物质释放膜包括含有至少一种生物活性剂的可水解降解生物聚合物。在一个示例中，可水解降解的生物聚合物包含能够水解成水杨酸和己二酸的水杨酸聚酸酐酯(结构I)。In another example, the bioactive substance release membrane includes a hydrolytically degradable biopolymer containing at least one bioactive agent. In one example, the hydrolytically degradable biopolymer includes salicylic acid polyanhydride ester (Structure I) that can be hydrolyzed into salicylic acid and adipic acid.
在一个示例中，合适的生物活性物质释放膜70是硬链段化-软链段化聚合物。参考图4A，描绘了示例性硬链段化-软链段化共聚物，其具有其中存在提供结晶性或晶体样结构的聚合物链段的紧密缔合的硬链段72和提供无定形或无定形样结构的软链段74。在一个示例中，本公开的生物活性物质释放膜70是硬链段化-软链段化共聚物71，其中软链段74包括亲水性聚合物或亲水性聚合物链段。在一个示例中，本公开的生物活性物质释放膜70是硬链段化-软链段化共聚物71，其中软链段74包括亲水性聚合物或亲水性聚合物链段与疏水性聚合物或疏水性聚合物链段的组合。参考图4B、图4C，硬链段化-软链段化共聚物(其中软链段74包括亲水性聚合物或亲水性聚合物链段与疏水性聚合物或疏水性聚合物链段的组合)示意性地示出为感测膜32的生物活性物质释放膜70的三维体积4C，其描绘了疏水性域76和亲水性域78的布置。根据每个域的相对浓度以及是否存在非化学计量量或化学计量量的每个域，设想了疏水性域和亲水性域的各种确认和分布。在示例中，生物活性物质释放膜70的软链段包括重量百分比不为0％的亲水性链段和重量百分比包括0％在内的疏水性链段。In one example, a suitable bioactive substance release film 70 is a hard segmented-soft segmented polymer. Referring to FIG4A, an exemplary hard segmented-soft segmented copolymer is depicted, which has a hard segment 72 in which there are polymer segments providing a crystalline or crystal-like structure and a soft segment 74 providing an amorphous or amorphous-like structure. In one example, the bioactive substance release film 70 of the present disclosure is a hard segmented-soft segmented copolymer 71, wherein the soft segment 74 includes a hydrophilic polymer or a hydrophilic polymer segment. In one example, the bioactive substance release film 70 of the present disclosure is a hard segmented-soft segmented copolymer 71, wherein the soft segment 74 includes a combination of a hydrophilic polymer or a hydrophilic polymer segment and a hydrophobic polymer or a hydrophobic polymer segment. Referring to FIG. 4B and FIG. 4C , a hard segmented-soft segmented copolymer (wherein the soft segment 74 includes a combination of a hydrophilic polymer or a hydrophilic polymer segment and a hydrophobic polymer or a hydrophobic polymer segment) is schematically shown as a three-dimensional volume 4C of a bioactive substance release membrane 70 of a sensing membrane 32, which depicts the arrangement of a hydrophobic domain 76 and a hydrophilic domain 78. Various identifications and distributions of hydrophobic domains and hydrophilic domains are envisioned, depending on the relative concentration of each domain and whether there is a non-stoichiometric amount or a stoichiometric amount of each domain. In the example, the soft segment of the bioactive substance release membrane 70 includes a hydrophilic segment having a weight percentage not being 0% and a hydrophobic segment having a weight percentage including 0%.
在一个示例中，生物活性物质释放膜70包括硬链段化-软链段化聚氨酯共聚物。在另一示例中，生物活性物质释放膜70包括硬链段化-软链段化聚氨酯脲共聚物。在示例中，本公开的生物活性物质释放膜70是硬链段化-软链段化聚氨酯或聚氨酯脲共聚物，其中软链段74包括亲水性聚合物或亲水性聚合物链段与疏水性聚合物或疏水性聚合物链段的组合。在示例中，本公开的生物活性物质释放膜70是硬链段化-软链段化聚氨酯或聚氨酯脲共聚物共混物，其中聚合物共混物的单独聚合物中的至少一种聚合物包括软链段74，其包括亲水性聚合物或亲水性聚合物链段与疏水性聚合物或疏水性聚合物链段的组合。在示例中，本公开的生物活性物质释放膜70是硬链段化-软链段化聚氨酯或聚氨酯脲共聚物共混物，其中聚合物共混物的单独聚合物中的至少一种聚合物包括仅含有亲水性聚合物链段的软链段74，并且聚合物共混物的至少一种聚合物包括含有亲水性聚合物链段与疏水性聚合物或疏水性聚合物链段的组合的软链段。In one example, the bioactive substance release film 70 includes a hard segmented-soft segmented polyurethane copolymer. In another example, the bioactive substance release film 70 includes a hard segmented-soft segmented polyurethane urea copolymer. In an example, the bioactive substance release film 70 of the present disclosure is a hard segmented-soft segmented polyurethane or polyurethane urea copolymer, wherein the soft segment 74 includes a hydrophilic polymer or a hydrophilic polymer segment and a combination of a hydrophobic polymer or a hydrophobic polymer segment. In an example, the bioactive substance release film 70 of the present disclosure is a hard segmented-soft segmented polyurethane or polyurethane urea copolymer blend, wherein at least one polymer of the individual polymers of the polymer blend includes a soft segment 74, which includes a hydrophilic polymer or a hydrophilic polymer segment and a combination of a hydrophobic polymer or a hydrophobic polymer segment. In an example, the bioactive substance release membrane 70 of the present disclosure is a hard-segmented-soft-segmented polyurethane or polyurethaneurea copolymer blend, wherein at least one of the individual polymers of the polymer blend includes a soft segment 74 containing only a hydrophilic polymer segment, and at least one polymer of the polymer blend includes a soft segment containing a combination of a hydrophilic polymer segment and a hydrophobic polymer or a hydrophobic polymer segment.
在示例中，生物活性物质释放膜70包括硬链段化-软链段化聚氨酯共聚物或聚氨酯脲共聚物，其包括药物量的生物活性物质并提供具有释放曲线(推注、推注然后控释等)的生物活性物质的释放。生物活性物质可以是地塞米松((11β,16α)-9-氟-11,17,21-三羟基-16-甲基孕甾-1,4-二烯-3,20-二酮)、地塞米松盐(例如，磷酸钠)或地塞米松衍生物(或类似物)，特别是醋酸地塞米松；醋酸地塞米松盐；地塞米松17-丙酸酯；地塞米松烯醇-丙酮醛；(Z)-2-((8S,9R,10S,11S,13S,14S,16R)-9-氟-11-羟基-10,13,16-三甲基-3-氧代-3,6,7,8,9,10,11,12,13,14,15,16-十二氢-17H-环戊二烯并[a]菲-17-亚基)-2-羟基乙醛；2-((10R,13S,16S,17R)-11,17-二羟基-10,13,16-三甲基-4,9,10,11,12,13,14,15,16,17-十氢螺[环戊二烯并[a]菲-3,2'-[1,3]二氧戊环]-17-基)-2-氧代乙酸乙酯；(8S,9R,10R,11S,13S,14S,16R,17R)-9-氟-1,11,17-三羟基-17-(2-羟基乙酰基)-10,13,16-三甲基-1,2,6,7,8,9,10,11,12,13,14,15,16,17-十四氢-3H-环戊二烯并[a]菲-3-酮；地塞米松乙二醛；或2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-氟-11,17-二羟基-10,13,16-三甲基-3-氧代-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊二烯并[a]菲-17-基)-2-氧代乙酸。In an example, the bioactive substance release membrane 70 includes a hard segmented-soft segmented polyurethane copolymer or a polyurethane urea copolymer, which includes a pharmaceutical amount of a bioactive substance and provides release of the bioactive substance with a release profile (bolus injection, bolus injection followed by controlled release, etc.). The bioactive substance can be dexamethasone ((11β, 16α)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), a dexamethasone salt (e.g., sodium phosphate) or a dexamethasone derivative (or analog), in particular dexamethasone acetate; dexamethasone acetate salt; dexamethasone 17-propionate; dexamethasone enol-methylglyoxal; (Z)-2-((8S,9R,10S,11S,13S,14 S,16R)-9-fluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-3,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthrene-17-ylidene)-2-hydroxyacetaldehyde; 2-((10R,13S,16S,17R)-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-3,6,7,8,9,10,11,12,13,14,15,16-dodecahydro-17H-cyclopenta[a]phenanthrene-17-ylidene)-2-hydroxyacetaldehyde; 15,16,17-decahydrospiro[cyclopenta[a]phenanthrene-3,2'-[1,3]dioxolane]-17-yl)-2-oxoacetic acid ethyl ester; (8S,9R,10R,11S,13S,14S,16R,17R)-9-fluoro-1,11,17-trihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16, 17-tetradecahydro-3H-cyclopenta[a]phenanthrene-3-one; dexamethasone glyoxal; or 2-((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-yl)-2-oxoacetic acid.
在一些示例中，共聚物的硬链段可具有约160道尔顿(DA)至约10,000DA或约200DA至约2,000DA的平均分子量或数均分子量，包括其间的所有范围和子范围。在一些示例中，软链段的平均分子量或数均分子量可为约200DA至约100,000DA，或约500DA至约500,000DA，或约5,000DA至约20,000DA，包括其间的所有范围和子范围。In some examples, the hard segments of the copolymer may have an average molecular weight or number average molecular weight of about 160 Daltons (DA) to about 10,000 DA, or about 200 DA to about 2,000 DA, including all ranges and sub-ranges therebetween. In some examples, the average molecular weight or number average molecular weight of the soft segments may be about 200 DA to about 100,000 DA, or about 500 DA to about 500,000 DA, or about 5,000 DA to about 20,000 DA, including all ranges and sub-ranges therebetween.
在一些示例中，生物活性物质释放膜的基础聚合物具有约200DA至约10,000DA、约10,000DA至约50,000DA、约50,000DA至约100,000DA、约100,000DA至约150,000DA、约150,000DA至约250,000DA或约250,000DA至约500,000DA的平均分子量或数均分子量，包括其间的所有范围和子范围。In some examples, the base polymer of the bioactive substance release membrane has an average molecular weight or number average molecular weight of about 200 DA to about 10,000 DA, about 10,000 DA to about 50,000 DA, about 50,000 DA to about 100,000 DA, about 100,000 DA to about 150,000 DA, about 150,000 DA to about 250,000 DA, or about 250,000 DA to about 500,000 DA, including all ranges and subranges therebetween.
在示例中，使用脂族或芳族二异氰酸酯制备生物活性物质释放膜70的硬链段72。在示例中，用于提供生物活性物质释放膜70的硬链段72的脂族或芳族二异氰酸酯是降冰片烷二异氰酸酯(NBDI)、异佛尔酮二异氰酸酯(IPDI)、甲苯二异氰酸酯(TDI)、1,3-亚苯基二异氰酸酯(MPDI)、反式-1,3-双(异氰酸甲基)环己烷(1,3-H6XDI)、双环己基甲烷-4,4'-二异氰酸酯(HMDI)、4,4'-二苯基甲烷二异氰酸酯(MDI)、反式-1,4-双(异氰酸甲基)环己烷(1,4-H6XDI)、1,4-环己基二异氰酸酯(CHDI)、1,4-亚苯基二异氰酸酯(PPDI)、3,3'-二甲基-4,4'-联苯二异氰酸酯(TODI)、1,6-六亚甲基二异氰酸酯(HDI)或它们的组合。In an example, the hard segment 72 of the bioactive substance releasing membrane 70 is prepared using an aliphatic or aromatic diisocyanate. In an example, the aliphatic or aromatic diisocyanate used to provide the hard segment 72 of the bioactive substance releasing membrane 70 is norbornane diisocyanate (NBDI), isophorone diisocyanate (IPDI), toluene diisocyanate (TDI), 1,3-phenylene diisocyanate (MPDI), trans-1,3-bis(isocyanatomethyl)cyclohexane (1,3-H6XDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), 4,4'-diphenylmethane diisocyanate (MDI), trans-1,4-bis(isocyanatomethyl)cyclohexane (1,4-H6XDI), 1,4-cyclohexyl diisocyanate (CHDI), 1,4-phenylene diisocyanate (PPDI), 3,3'-dimethyl-4,4'-biphenyl diisocyanate (TODI), 1,6-hexamethylene diisocyanate (HDI), or a combination thereof.
在示例中，硬链段化-软链段化聚氨酯或聚氨酯脲共聚物的软链段74包括聚硅氧烷或其共聚物。在示例中，硬链段化-软链段化聚氨酯或聚氨酯脲共聚物的软链段74包括聚(二烷基)硅氧烷、聚(二苯基)硅氧烷、聚(烷基苯基)硅氧烷或它们的共聚物。在示例中，硬链段化-软链段化聚氨酯或聚氨酯脲共聚物的软链段74包括聚(烷基)氧基聚合物、聚(亚烷基)氧化物或它们的共聚物。在示例中，硬链段化-软链段化聚氨酯或聚氨酯脲共聚物的软链段74包括聚(烷基)氧化物、聚(氧化乙烯)、聚(氧化丙烯)、聚(氧化乙烯-氧化丙烯)、聚(四亚烷基)氧化物、聚(四亚甲基)氧化物聚合物或它们的共聚物或共混物。软链段可包括例如聚亚烷基二醇、聚碳酸烷基酯、聚碳酸酯、聚酯、聚醚、聚乙烯醇、聚乙烯吡咯烷酮、聚噁唑啉等的亲水性和/或疏水性寡聚物。In an example, the soft segment 74 of the hard segmented-soft segmented polyurethane or polyurethane urea copolymer includes polysiloxane or a copolymer thereof. In an example, the soft segment 74 of the hard segmented-soft segmented polyurethane or polyurethane urea copolymer includes poly(dialkyl)siloxane, poly(diphenyl)siloxane, poly(alkylphenyl)siloxane, or a copolymer thereof. In an example, the soft segment 74 of the hard segmented-soft segmented polyurethane or polyurethane urea copolymer includes poly(alkyl)oxy polymer, poly(alkylene) oxide, or a copolymer thereof. In an example, the soft segment 74 of the hard segmented-soft segmented polyurethane or polyurethane urea copolymer includes poly(alkyl) oxide, poly(ethylene oxide), poly(propylene oxide), poly(ethylene oxide-propylene oxide), poly(tetraalkylene) oxide, poly(tetramethylene) oxide polymer, or a copolymer or blend thereof. The soft segments may include hydrophilic and/or hydrophobic oligomers such as polyalkylene glycols, polyalkyl carbonates, polycarbonates, polyesters, polyethers, polyvinyl alcohols, polyvinyl pyrrolidones, polyoxazolines, and the like.
在示例中，硬链段化-软链段化聚氨酯或聚氨酯脲共聚物的软链段74包括聚硅氧烷或其共聚物和聚(亚烷基)氧基聚合物或其共聚物。在示例中，硬链段化-软链段化聚氨酯或聚氨酯脲共聚物的软链段74包括聚(二烷基)硅氧烷、聚(二苯基)硅氧烷、聚(烷基苯基)硅氧烷或共聚物和聚(烷基)氧化物、聚(氧化乙烯)、聚(氧化丙烯)、聚(氧化乙烯-氧化丙烯)、聚(四亚烷基)氧化物、聚(四亚甲基)氧化物聚合物或它们的共聚物或共混物。In an example, the soft segment 74 of the hard segmented-soft segmented polyurethane or polyurethane urea copolymer includes polysiloxane or a copolymer thereof and a poly(alkylene)oxy polymer or a copolymer thereof. In an example, the soft segment 74 of the hard segmented-soft segmented polyurethane or polyurethane urea copolymer includes poly(dialkyl)siloxane, poly(diphenyl)siloxane, poly(alkylphenyl)siloxane or a copolymer and poly(alkyl)oxide, poly(ethylene oxide), poly(propylene oxide), poly(ethylene oxide-propylene oxide), poly(tetraalkylene)oxide, poly(tetramethylene)oxide polymer or a copolymer or blend thereof.
在一个示例中，生物活性物质释放膜70具有静态接触角大于90度的亲水性链段。在一个示例中，生物活性物质释放膜70具有静态接触角小于90度的疏水性链段。适合用于生物活性物质释放膜70的软链段的至少一部分以便提供90度或更大的静态接触角的亲水性聚合物的示例包括但不限于聚乙烯吡咯烷酮、聚乙烯基吡啶、蛋白质、纤维素、聚醚、聚醚亚胺。适合用于生物活性物质释放膜70的软链段的至少一部分以便提供小于90度的静态接触角的疏水性聚合物的示例包括但不限于聚氨酯、有机硅、聚氨酯脲、聚酯、聚酰胺、聚碳酸烷基酯、聚碳酸酯以及它们的共聚物。In one example, the bioactive substance release film 70 has a hydrophilic segment with a static contact angle greater than 90 degrees. In one example, the bioactive substance release film 70 has a hydrophobic segment with a static contact angle less than 90 degrees. Examples of hydrophilic polymers suitable for at least a portion of the soft segment of the bioactive substance release film 70 to provide a static contact angle of 90 degrees or greater include, but are not limited to, polyvinyl pyrrolidone, polyvinyl pyridine, protein, cellulose, polyether, polyetherimide. Examples of hydrophobic polymers suitable for at least a portion of the soft segment of the bioactive substance release film 70 to provide a static contact angle less than 90 degrees include, but are not limited to, polyurethane, silicone, polyurethane urea, polyester, polyamide, polyalkyl carbonate, polycarbonate, and copolymers thereof.
生物界面/生物活性物质释放膜的表面的至少一部分可以是疏水的，如通过接触角所测量的。例如，生物界面/生物活性物质释放膜可具有约90°至约160°、约95°至约155°、约100°至约150°、约105°至约145°、约110°至约140°、至少约100°、至少约110°或至少约120°的接触角，包括其间的所有范围和子范围。在示例中，动态接触角，即在生物界面/生物活性物质释放膜的表面的润湿(前进角)或去润湿(后退角)过程中出现的接触角具有约100°至约150°的前进接触角。在另一示例中，动态接触角，即在生物界面/生物活性物质释放膜的表面的润湿(前进角)或去润湿(后退角)过程中出现的接触角具有约105°至约130°或110°至约120°的前进接触角，包括其间的所有范围和子范围。在又一示例中，动态接触角，即在生物界面/生物活性物质释放膜的表面的润湿(前进角)或去润湿(后退角)过程中出现的接触角具有约40°至约80°的后退接触角。在另一示例中，动态接触角，即在生物界面/生物活性物质释放膜的表面的润湿(前进角)或去润湿(后退角)过程中出现的接触角具有约45°至约75°的后退接触角。在又一示例中，动态接触角，即在生物界面/生物活性物质释放膜的表面的润湿(前进角)或去润湿(后退角)过程中出现的接触角具有约50°至约70°的后退接触角。在一些示例中，放置在分析物传感器上之后和灭菌之后在生物活性物质释放膜上的动态接触角测量和表面粗糙度(与接触角滞后相关，该接触角滞后由表面的化学和形貌异质性、吸附在表面上的溶液杂质或溶剂对表面的溶胀、重排或改变引起)可使用Sigma 701力张力计并且执行前进接触角测量、后退接触角测量、滞后测量以及它们的组合中的一者或多者来进行。力张力计测量影响天平的质量，并且计算并自动减去浮力和探针重量的影响，使得由天平测量的仅有的剩余力是润湿力。At least a portion of the surface of the biointerface/bioactive substance release film can be hydrophobic, as measured by the contact angle. For example, the biointerface/bioactive substance release film can have a contact angle of about 90° to about 160°, about 95° to about 155°, about 100° to about 150°, about 105° to about 145°, about 110° to about 140°, at least about 100°, at least about 110°, or at least about 120°, including all ranges and sub-ranges therebetween. In an example, the dynamic contact angle, i.e., the contact angle that occurs during the wetting (advancing angle) or dewetting (receding angle) process of the surface of the biointerface/bioactive substance release film, has an advancing contact angle of about 100° to about 150°. In another example, the dynamic contact angle, i.e., the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface/bioactive substance release film, has an advancing contact angle of about 105° to about 130° or 110° to about 120°, including all ranges and sub-ranges therebetween. In yet another example, the dynamic contact angle, i.e., the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface/bioactive substance release film, has a receding contact angle of about 40° to about 80°. In another example, the dynamic contact angle, i.e., the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface/bioactive substance release film, has a receding contact angle of about 45° to about 75°. In yet another example, the dynamic contact angle, i.e., the contact angle that occurs during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface/bioactive substance release film, has a receding contact angle of about 50° to about 70°. In some examples, dynamic contact angle measurements and surface roughness (related to contact angle hysteresis, which is caused by chemical and topographic heterogeneity of the surface, swelling, rearrangement or modification of the surface by solution impurities adsorbed on the surface or solvent) on the bioactive substance release membrane after placement on the analyte sensor and after sterilization can be performed using a Sigma 701 force tensiometer and performing one or more of advancing contact angle measurements, receding contact angle measurements, hysteresis measurements, and combinations thereof. The force tensiometer measures the mass affecting the balance and calculates and automatically subtracts the effects of buoyancy and probe weight so that the only remaining forces measured by the balance are wetting forces.
在示例中，生物活性物质释放膜70具有约20％至60％、30％至50％或35％至45％的硬链段的重量百分比含量以便实现70A-55D硬度计硬度。在另一示例中，生物活性物质释放膜70具有约20％至60％、30％至50％或35％至45％的硬链段的重量百分比含量以便实现目标模量。在一个示例中，生物活性物质释放膜70的硬度计硬度和/或模量由单一共聚物或共聚物的共混物提供。In an example, the bioactive substance release film 70 has a hard segment weight percentage content of about 20% to 60%, 30% to 50%, or 35% to 45% to achieve a 70A-55D durometer hardness. In another example, the bioactive substance release film 70 has a hard segment weight percentage content of about 20% to 60%, 30% to 50%, or 35% to 45% to achieve a target modulus. In one example, the durometer hardness and/or modulus of the bioactive substance release film 70 is provided by a single copolymer or a blend of copolymers.
在一个示例中，生物活性物质释放膜70包括软链段-硬链段共聚物，其包括重量百分比小于70％但不为0％的软链段。在一个示例中，释放膜包含软链段-硬链段共聚物，该软链段-硬链段共聚物包含软链段-硬链段聚氨酯或聚氨酯脲共聚物，其包含重量百分比小于70％但不为0％的软链段。In one example, the bioactive substance release film 70 includes a soft segment-hard segment copolymer, which includes a soft segment with a weight percentage of less than 70% but not 0%. In one example, the release film includes a soft segment-hard segment copolymer, which includes a soft segment-hard segment polyurethane or polyurethane urea copolymer, which includes a soft segment with a weight percentage of less than 70% but not 0%.
在一个示例中，生物活性物质释放膜包括软链段-硬链段共聚物，该软链段-硬链段共聚物包括的亲水性链段的重量百分比大于其疏水性链段的重量百分比。在示例中，释放膜包括软链段-硬链段聚氨酯或聚氨酯脲共聚物，其包括的软链段-硬链段的亲水性链段的重量百分比大于其疏水性链段的重量百分比。In one example, the bioactive substance release film includes a soft segment-hard segment copolymer, wherein the weight percentage of the hydrophilic segment included in the soft segment-hard segment copolymer is greater than the weight percentage of its hydrophobic segment. In an example, the release film includes a soft segment-hard segment polyurethane or polyurethane urea copolymer, wherein the weight percentage of the hydrophilic segment of the soft segment-hard segment included in the soft segment-hard segment is greater than the weight percentage of its hydrophobic segment.
在一个示例中，软链段-硬链段共聚物的亲水性链段的重量百分比小于其疏水性链段的重量百分比。在一个示例中，软链段-硬链段聚氨酯或聚氨酯脲共聚物的亲水性链段的重量百分比小于其疏水性链段的重量百分比。In one example, the weight percentage of the hydrophilic segments of the soft segment-hard segment copolymer is less than the weight percentage of its hydrophobic segments. In one example, the weight percentage of the hydrophilic segments of the soft segment-hard segment polyurethane or polyurethane urea copolymer is less than the weight percentage of its hydrophobic segments.
在一个示例中，生物活性物质释放膜包括软链段-硬链段共聚物，其为不同软链段-硬链段共聚物的共混物。在一个示例中，生物活性物质释放膜包括软链段-硬链段聚氨酯或聚氨酯脲共聚物，其为不同软链段-硬链段共聚物的共混物。In one example, the bioactive substance release film includes a soft segment-hard segment copolymer, which is a blend of different soft segment-hard segment copolymers. In one example, the bioactive substance release film includes a soft segment-hard segment polyurethane or polyurethane urea copolymer, which is a blend of different soft segment-hard segment copolymers.
在一个示例中，生物活性物质释放膜包括不同软链段-硬链段共聚物的共混物，该共混物为包括重量百分比不为0％的亲水性链段和重量百分比包括0％在内的疏水性链段的第一软链段-硬链段共聚物与包括的亲水性链段的重量百分比大于疏水性链段的重量百分比的另一种第二软链段-硬链段共聚物的共混物。在一个示例中，生物活性物质释放膜包括不同软链段-硬链段聚氨酯或聚氨酯脲共聚物的共混物，该共混物包括含有重量百分比不为0％的亲水性链段和重量百分比包括0％在内的疏水性链段的第一软链段-硬链段共聚物与包括的亲水性链段的重量百分比大于疏水性链段的重量百分比的另一种软链段-硬链段聚氨酯或聚氨酯脲共聚物的共混物。In one example, the bioactive substance release membrane includes a blend of different soft segment-hard segment copolymers, which is a blend of a first soft segment-hard segment copolymer including a hydrophilic segment whose weight percentage is not 0% and a hydrophobic segment whose weight percentage is including 0% and another second soft segment-hard segment copolymer including a hydrophilic segment whose weight percentage is greater than the hydrophobic segment. In one example, the bioactive substance release membrane includes a blend of different soft segment-hard segment polyurethane or polyurethane urea copolymers, which includes a first soft segment-hard segment copolymer including a hydrophilic segment whose weight percentage is not 0% and a hydrophobic segment whose weight percentage is including 0% and another soft segment-hard segment polyurethane or polyurethane urea copolymer including a hydrophilic segment whose weight percentage is greater than the hydrophobic segment.
在一个示例中，生物活性物质释放膜包括含有重量百分比不为0％的亲水性链段和重量百分比包括0％在内的疏水性链段的软链段-硬链段共聚物与包括的亲水性链段的重量百分比小于疏水性链段的重量百分比的另一种软链段-硬链段共聚物的共混物。在一个示例中，生物活性物质释放膜包括含有重量百分比不为0％的亲水性链段和重量百分比包括0％在内的疏水性链段的软链段-硬链段聚氨酯或聚氨酯脲共聚物与包括的亲水性链段的重量百分比小于疏水性链段的重量百分比的另一种软链段-硬链段聚氨酯或聚氨酯脲共聚物的共混物。In one example, the bioactive substance release membrane includes a blend of a soft segment-hard segment copolymer containing a hydrophilic segment not 0% by weight and a hydrophobic segment including 0% by weight, and another soft segment-hard segment copolymer including a hydrophilic segment whose weight percentage is less than the hydrophobic segment. In one example, the bioactive substance release membrane includes a blend of a soft segment-hard segment polyurethane or polyurethaneurea copolymer containing a hydrophilic segment not 0% by weight and a hydrophobic segment including 0% by weight, and another soft segment-hard segment polyurethane or polyurethaneurea copolymer including a hydrophilic segment whose weight percentage is less than the hydrophobic segment.
在一个示例中，生物活性物质释放膜包括软链段-硬链段共聚物和软链段-硬链段共聚物，它们各自包括重量百分比小于70％但不为0％的软链段并且它们各自包括重量百分比不为0％的亲水性链段和重量百分比包括0％在内的疏水性链段。在一个示例中，生物活性物质释放膜包括软链段-硬链段聚氨酯或聚氨酯脲共聚物和另一种不同的软链段-硬链段聚氨酯或聚氨酯脲共聚物，它们各自包括重量百分比小于70％但不为0％的软链段并且它们各自包括重量百分比不为0％的亲水性链段和重量百分比包括0％在内的疏水性链段。In one example, the bioactive substance release film includes a soft segment-hard segment copolymer and a soft segment-hard segment copolymer, each of which includes a soft segment with a weight percentage of less than 70% but not 0% and each of which includes a hydrophilic segment with a weight percentage of not 0% and a hydrophobic segment with a weight percentage of 0%. In one example, the bioactive substance release film includes a soft segment-hard segment polyurethane or polyurethane urea copolymer and another different soft segment-hard segment polyurethane or polyurethane urea copolymer, each of which includes a soft segment with a weight percentage of less than 70% but not 0% and each of which includes a hydrophilic segment with a weight percentage of not 0% and a hydrophobic segment with a weight percentage of 0%.
在一个示例中，生物活性物质释放膜包括与疏水性聚合物和/或亲水性聚合物共混的软链段-硬链段共聚物。在一个示例中，生物活性物质释放膜包括与疏水性聚合物和/或亲水性聚合物共混的软链段-硬链段聚氨酯或聚氨酯脲共聚物。In one example, the bioactive substance release membrane includes a soft segment-hard segment copolymer blended with a hydrophobic polymer and/or a hydrophilic polymer. In one example, the bioactive substance release membrane includes a soft segment-hard segment polyurethane or polyurethane urea copolymer blended with a hydrophobic polymer and/or a hydrophilic polymer.
在一个示例中，生物活性物质释放膜70基本上不能渗透分析物转运穿过其中。在另一示例中，与感测膜32的干扰膜44相比，生物活性物质释放膜70对分析物的渗透性较低。在此类示例中，生物活性物质释放膜70沉积在邻近传感器的电化学活性部分但不覆盖传感器的电化学活性部分的传感器部分上。In one example, the bioactive substance releasing membrane 70 is substantially impermeable to the analyte transported therethrough. In another example, the bioactive substance releasing membrane 70 is less permeable to the analyte than the interfering membrane 44 of the sensing membrane 32. In such examples, the bioactive substance releasing membrane 70 is deposited on a portion of the sensor adjacent to but not covering the electrochemically active portion of the sensor.
在一个示例中，生物活性物质释放膜70在沉积到传感器34和/或感测膜32上之前负载有生物活性剂。在一个示例中，生物活性剂溶解于与生物活性物质释放膜70可混溶的一种或多种溶剂中。可使用温和加热来促进生物活性物质释放膜70中的生物活性剂的溶解、分布或分散。合适的溶剂包括THF、醇、酮、醚、乙酸酯、NMP、二氯甲烷、庚烷、己烷以及它们的组合。In one example, the bioactive substance release film 70 is loaded with a bioactive agent before being deposited on the sensor 34 and/or the sensing film 32. In one example, the bioactive agent is dissolved in one or more solvents that are miscible with the bioactive substance release film 70. Mild heating can be used to promote the dissolution, distribution or dispersion of the bioactive agent in the bioactive substance release film 70. Suitable solvents include THF, alcohols, ketones, ethers, acetates, NMP, dichloromethane, heptane, hexane, and combinations thereof.
在一个示例中，将生物活性物质释放膜70沉积到感测膜32的至少一部分上。在另一示例中，生物活性物质释放膜70邻近但不直接沉积到感测膜32上。在示例中，沉积生物活性物质释放膜以便提供约0.05微米或更大至约50微米或更小的膜厚度，包括其间的所有范围和子范围。在另一示例中，沉积生物活性物质释放膜以便提供约0.5微米至50微米、1微米至50微米、2微米至50微米、3微米至50微米、4微米至50微米、5微米至50微米、6微米至50微米、7微米至50微米、8微米至50微米、9微米至50微米、10微米至50微米、10微米至40微米、10微米至30微米、10微米、11微米、12微米、13微米、14微米、15微米、16微米、17微米、18微米、19微米、20微米、21微米、22微米、23微米、24微米、25微米、26微米、27微米、28微米、29微米或30微米的膜厚度，包括其间的所有范围和子范围。In one example, the bioactive substance releasing film 70 is deposited onto at least a portion of the sensing film 32. In another example, the bioactive substance releasing film 70 is deposited adjacent to but not directly onto the sensing film 32. In an example, the bioactive substance releasing film is deposited to provide a film thickness of about 0.05 microns or more to about 50 microns or less, including all ranges and sub-ranges therebetween. In another example, the bioactive substance releasing film is deposited so as to provide a film thickness of about 0.5 microns to 50 microns, 1 micron to 50 microns, 2 microns to 50 microns, 3 microns to 50 microns, 4 microns to 50 microns, 5 microns to 50 microns, 6 microns to 50 microns, 7 microns to 50 microns, 8 microns to 50 microns, 9 microns to 50 microns, 10 microns to 50 microns, 10 microns to 40 microns, 10 microns to 30 microns, 10 microns, 11 microns, 12 microns, 13 microns, 14 microns, 15 microns, 16 microns, 17 microns, 18 microns, 19 microns, 20 microns, 21 microns, 22 microns, 23 microns, 24 microns, 25 microns, 26 microns, 27 microns, 28 microns, 29 microns, or 30 microns, including all ranges and subranges therebetween.
在示例中，通过喷涂、刷涂、移印或浸涂将生物活性物质释放膜70沉积到酶域上。在某些示例中，使用喷涂和/或浸涂沉积生物活性物质释放膜70。在示例中，通过移印约1重量％至约80重量％的聚合物/药物组合和约20重量％至约99重量％的溶剂的混合物(包括其间的所有范围和子范围)，将生物活性物质释放膜70沉积到感测膜32上。In an example, the bioactive substance release film 70 is deposited onto the enzyme domain by spraying, brushing, pad printing, or dipping. In some examples, spraying and/or dipping are used to deposit the bioactive substance release film 70. In an example, the bioactive substance release film 70 is deposited onto the sensing film 32 by pad printing a mixture of about 1 wt % to about 80 wt % of the polymer/drug combination and about 20 wt % to about 99 wt % of the solvent (including all ranges and sub-ranges therebetween).
在将生物活性物质释放膜72的溶液(包括溶剂)接触到感测膜上时，期望减轻或显著减少移印混合物中可使酶域的基础酶失活的任何溶剂与酶的任何接触。四氢呋喃(THF)是一种单独地或与一种或多种醇组合在喷涂时对酶域中的酶影响最小或可忽略不计的溶剂。如本领域技术人员所理解的，其他溶剂也可能适用。When the solution (including solvent) of the bioactive substance release film 72 is contacted to the sensing film, it is desirable to mitigate or significantly reduce any contact of any solvent in the pad printing mixture that may inactivate the base enzyme of the enzyme domain with the enzyme. Tetrahydrofuran (THF) is a solvent that has minimal or negligible effect on the enzyme in the enzyme domain when sprayed alone or in combination with one or more alcohols. As will be appreciated by those skilled in the art, other solvents may also be suitable.
在示例中，通过喷涂约1重量％至约50重量％的聚合物和约50重量％至约99重量％的溶剂的溶液(包括其间的所有范围和子范围)，将生物活性物质释放膜70沉积到感测膜32上。在将生物活性物质释放膜72的溶液(包括溶剂)喷涂到感测膜上时，期望减轻或显著减少喷雾溶液中可使酶域的基础酶失活的任何溶剂与酶的任何接触。四氢呋喃(THF)是一种单独地或与一种或多种醇组合在喷涂时对酶域中的酶影响最小或可忽略不计的溶剂。如本领域技术人员所理解的，其他溶剂也可能适用。In an example, a solution of about 1 wt % to about 50 wt % of a polymer and about 50 wt % to about 99 wt % of a solvent (including all ranges and sub-ranges therebetween) is sprayed onto the sensing film 32 to deposit the bioactive substance release film 70. When the solution (including solvent) of the bioactive substance release film 72 is sprayed onto the sensing film, it is desirable to mitigate or significantly reduce any contact of any solvent with the enzyme that can inactivate the basic enzyme of the enzyme domain in the spray solution. Tetrahydrofuran (THF) is a solvent that has minimal or negligible effect on the enzyme in the enzyme domain when sprayed alone or in combination with one or more alcohols. As will be appreciated by those skilled in the art, other solvents may also be applicable.
生物活性物质释放膜/层组合物-生物活性剂释放曲线Bioactive Substance Release Film/Layer Composition - Bioactive Agent Release Profile
本公开提供生物活性剂从生物活性物质释放膜的释放的控制，或提供生物活性剂从生物活性物质释放膜的释放曲线。举例来说，使用示例性生物活性剂/生物活性物质释放膜系统，例如，地塞米松和/或醋酸地塞米松盐/软链段-硬链段聚氨酯脲共聚物或共混物，然而，设想了生物活性剂和生物活性物质释放膜的其他组合。The present disclosure provides control of the release of a bioactive agent from a bioactive material release membrane, or provides a release profile of a bioactive agent from a bioactive material release membrane. For example, using an exemplary bioactive agent/bioactive material release membrane system, for example, dexamethasone and/or dexamethasone acetate salt/soft segment-hard segment polyurethane urea copolymer or blend, however, other combinations of bioactive agents and bioactive material release membranes are contemplated.
参考图5A，使用示例性生物活性物质释放膜70示出了醋酸地塞米松的示例性体外生物活性物质释放曲线。醋酸地塞米松的累积释放百分比可以使用HPLC确定，例如使用Phenomenex Kinetex 5μEVO C18(50×3.0mm)柱，保持在25℃，具有254nm UV检测器，洗脱梯度为A：含0.1％甲酸的水/B：含0.1％甲酸的乙腈(体积/体积)，其中从时间0至2分钟的梯度为90％A/10％B；从2分钟至5分钟的梯度为10％A/90％B；以及从5分钟起的梯度为90％A/10％B。制备浓度为约0.1-20ug/mL的醋酸地塞米松和地塞米松HPLC标准品。5A, an exemplary in vitro bioactive substance release profile of dexamethasone acetate is shown using an exemplary bioactive substance release membrane 70. The cumulative release percentage of dexamethasone acetate can be determined using HPLC, for example, using a Phenomenex Kinetex 5μEVO C18 (50 x 3.0 mm) column maintained at 25°C with a 254 nm UV detector and an elution gradient of A: 0.1% formic acid in water/B: 0.1% formic acid in acetonitrile (volume/volume) with a gradient of 90% A/10% B from time 0 to 2 minutes; 10% A/90% B from 2 minutes to 5 minutes; and 90% A/10% B from 5 minutes onwards. Dexamethasone acetate and dexamethasone HPLC standards were prepared at concentrations of approximately 0.1-20 ug/mL.
图5A示出了在15天时间段内本发明所公开的生物活性物质释放膜70中醋酸地塞米松的体外释放77和体内释放79之间的相互关系，其证明了本发明所公开的系统的体外数据用于近似估计体内数据的能力。FIG. 5A shows the correlation between the in vitro release 77 and in vivo release 79 of dexamethasone acetate from the bioactive substance releasing membrane 70 disclosed in the present invention over a 15-day period, demonstrating the ability of the in vitro data of the disclosed system to approximate in vivo data.
参考图5B，示出了初始或在第一时间段期间生物活性剂(醋酸地塞米松)从生物活性物质释放膜70的释放速率大于初始或在第二时间段期间生物活性剂从生物活性物质释放膜的释放速率，以及初始或在第二时间段期间生物活性剂从生物活性物质释放膜的释放速率大于初始或在第三时间段期间生物活性剂从生物活性物质释放膜的释放速率的实验数据。5B , experimental data are shown showing that the release rate of the bioactive agent (dexamethasone acetate) from the bioactive substance release membrane 70 initially or during the first time period is greater than the release rate of the bioactive agent from the bioactive substance release membrane initially or during the second time period, and the release rate of the bioactive agent from the bioactive substance release membrane initially or during the second time period is greater than the release rate of the bioactive agent from the bioactive substance release membrane initially or during the third time period.
因此，图5B描绘了图5A的示例性体外生物活性物质释放曲线，其示出了具有指示为对应于与传感器插入相关联并且延长大约2天或更长时间的时间段的第一释放速率(例如，推注)，随后是指示为对应于与大约在约2天时开始并且向前延长传感器插入后15天的时间相关联的第二时间段的第二释放速率(例如，治疗范围内的量，或“持续治疗量”)。在传感器插入后大约18天或更长时间并持续直至传感器寿命终点结束的时间期间释放小于治疗量的量，例如非治疗量(数据未示出)。从图5B的图表数据可看出，第一释放速率对应于在大约两天时间段内大约50％的醋酸地塞米松初始负载的推注释放，随后第二释放速率对应于在约13天的时间跨度内大约40％的醋酸地塞米松初始负载的释放。随后的第三释放速率对应于在16-35天的时间跨度内剩余量的醋酸地塞米松(大约10％)的释放。Thus, FIG. 5B depicts the exemplary in vitro bioactive material release profile of FIG. 5A , which shows a first release rate (e.g., a bolus) indicated as corresponding to a time period associated with sensor insertion and extending about 2 days or more, followed by a second release rate (e.g., an amount within the therapeutic range, or a "sustained therapeutic amount") indicated as corresponding to a second time period associated with a time period beginning about 2 days and extending forward to 15 days after sensor insertion. An amount less than the therapeutic amount, such as a non-therapeutic amount (data not shown), is released during a time period of about 18 days or more after sensor insertion and continuing until the end of the sensor life end. As can be seen from the data in the graph of FIG. 5B , the first release rate corresponds to a bolus release of about 50% of the initial load of dexamethasone acetate over a period of about two days, followed by a second release rate corresponding to the release of about 40% of the initial load of dexamethasone acetate over a time span of about 13 days. The subsequent third release rate corresponds to the release of the remaining amount of dexamethasone acetate (about 10%) over a time span of 16-35 days.
因此，在50μg至100μg醋酸地塞米松(DexAc)/传感器的初始负载的情况下，例如，在目标为每天治疗有效量或更多的释放的情况下，本发明所公开的生物活性物质释放膜70可在插入后立即提供DexAc的推注治疗量的释放(大约3μg至20μg/传感器/天、4μg至18μg/传感器/天、5μg至16μg/传感器/天、6μg至14μg/传感器/天)并且之后持续一段时间，随后是DexAc的延长的治疗量的释放(大约0.5μg至10μg/传感器/天、0.6μg至9μg/传感器/天、0.4μg至7μg/传感器/天、0.5μg至8μg/传感器/天)，随后是DexAc的延长的非治疗量的释放(大约小于0.5μg/传感器/天)直到传感器的寿命终止。Thus, with an initial load of 50 μg to 100 μg dexamethasone acetate (DexAc)/sensor, for example, where the goal is a release of a therapeutically effective amount per day or more, the bioactive substance release membrane 70 disclosed in the present invention can provide a bolus therapeutic amount of DexAc release immediately after insertion (approximately 3 μg to 20 μg/sensor/day, 4 μg to 18 μg/sensor/day, 5 μg to 16 μg/sensor/day, 6 μg to 14 μg/sensor/day) and thereafter for a period of time, followed by an extended therapeutic amount of DexAc release (approximately 0.5 μg to 10 μg/sensor/day, 0.6 μg to 9 μg/sensor/day, 0.4 μg to 7 μg/sensor/day, 0.5 μg to 8 μg/sensor/day), followed by an extended non-therapeutic amount of DexAc release (approximately less than 0.5 μg/sensor/day) until the end of the life of the sensor.
参考图5C，呈现了不同的生物活性物质释放膜的初始和持续生物活性物质释放速率。如图所示，在软链段中具有约10重量％至约40重量％范围内的不同量的聚硅氧烷组分的聚氨酯聚合物膜示例(示例中的每一个示例具有40重量％至55重量％的硬链段)证明了在初始10小时至48小时的时间段内醋酸地塞米松的独特释放速率以及在长达15天的延长时间段内不同的总释放量，总结如下：样品120-10重量％的聚硅氧烷:50重量％的硬链段；样品121-22重量％的聚硅氧烷:55重量％的硬链段；样品122-25重量％的聚硅氧烷:50重量％的硬链段；样品123-27重量％的聚硅氧烷:45重量％的硬链段；样品124-30重量％的聚硅氧烷:40重量％的硬链段；样品125-30重量％的聚硅氧烷:45重量％的硬链段；样品126-30重量％的聚硅氧烷:50重量％的硬链段；样品127-40重量％的聚硅氧烷:40重量％的硬链段。例如，含10重量％的聚硅氧烷的膜提供快速的初始释放速率和持续的高总释放速率，相比之下，含35重量％的聚硅氧烷的膜提供更类似线性的释放速率和持续的低总释放速率。图5C的数据进一步证明了硬链段重量％与含聚硅氧烷的膜的组合对定制初始和持续时间内的生物活性物质释放速率的作用。因此，通过改变生物活性物质释放膜70的化学组成，可获得与生物活性治疗方案相称的所需或目标生物活性物质释放曲线。With reference to Figure 5C, the initial and sustained bioactive release rates of different bioactive release films are presented. As shown, polyurethane polymer film examples with different amounts of polysiloxane components in the range of about 10 wt % to about 40 wt % in the soft segment (each example in the example has a hard segment of 40 wt % to 55 wt %) demonstrate the unique release rate of dexamethasone acetate in the initial 10 to 48 hour period and the different total release amounts in the extended period of up to 15 days, summarized as follows: Sample 120-10 wt % polysiloxane: 50 wt % hard segment; Sample 121-22 wt % Polysiloxane: 55% by weight hard segment; Sample 122-25% by weight polysiloxane: 50% by weight hard segment; Sample 123-27% by weight polysiloxane: 45% by weight hard segment; Sample 124-30% by weight polysiloxane: 40% by weight hard segment; Sample 125-30% by weight polysiloxane: 45% by weight hard segment; Sample 126-30% by weight polysiloxane: 50% by weight hard segment; Sample 127-40% by weight polysiloxane: 40% by weight hard segment. For example, a film containing 10% by weight polysiloxane provides a fast initial release rate and a sustained high total release rate, while a film containing 35% by weight polysiloxane provides a more linear release rate and a sustained low total release rate. The data of Figure 5C further demonstrate the effect of the combination of the hard segment weight % and the polysiloxane-containing film on the release rate of the bioactive substance in the initial and duration of customization. Thus, by varying the chemical composition of the bioactive substance releasing membrane 70, a desired or targeted bioactive substance release profile commensurate with the bioactive therapeutic regimen may be achieved.
参考图6A，生物活性物质释放膜70化学物质对生物活性物质释放的影响与膜的吸水率相关。在一个示例中，生物活性物质释放膜70的至少一部分(例如，硬链段)具有比生物活性物质释放膜的另一部分(例如，软链段)更接近可释放生物活性剂的希尔德布兰德溶解度参数。例如，生物活性物质释放膜70可包括疏水性软链段、至少一种亲水性软链段和包括氨基甲酸酯基团、脲基团或氨基甲酸酯基团与脲基团的组合的硬链段，其中其硬链段具有比任一软链段部分更接近可释放生物活性剂的希尔德布兰德溶解度参数。图6A示出了具有不同硬链段部分(和不同重量％范围)和具有不同重量％范围的疏水性软链段和亲水性软链段部分的生物活性物质释放膜70的各种样品。因此，包括具有40重量％至60重量％的硬链段(例如，环状异氟尔酮二异氰酸酯(IPDI))、10重量％至30重量％的疏水性软链段部分(例如，聚硅氧烷)和20重量％至50重量％的亲水性软链段部分(例如，聚烷基醚)的聚氨酯嵌段聚合物的样品130、136和137显示出对选定的生物活性物质(例如，醋酸地塞米松)的期望释放速率。相比之下，包括具有40重量％至60重量％的硬链段(例如，线性1,6-六亚甲基二异氰酸酯(HDI))、10重量％至30重量％的疏水性软链段部分(例如，聚硅氧烷)和0重量％至50重量％的亲水性软链段部分(例如，聚烷基醚)的聚氨酯嵌段聚合物的样品131、132、133、134和135显示出对选定的生物活性物质(例如，醋酸地塞米松)的快速释放。该数据证明生物活性物质释放层的吸水率(例如，硬链段溶解度类似于可释放生物活性物质)与生物活性物质的吸水率的相关性可用于定制生物活性物质的释放速率/曲线。With reference to Fig. 6A, the influence of the chemical substance of bioactive substance release film 70 on the release of bioactive substance is related to the water absorption rate of film. In one example, at least a portion (e.g., hard segment) of bioactive substance release film 70 has a Hildebrand solubility parameter closer to the releasable bioactive agent than another portion (e.g., soft segment) of bioactive substance release film 70. For example, bioactive substance release film 70 may include a hydrophobic soft segment, at least one hydrophilic soft segment and a hard segment including a carbamate group, a urea group or a combination of a carbamate group and a urea group, wherein its hard segment has a Hildebrand solubility parameter closer to the releasable bioactive agent than any soft segment portion. Fig. 6A shows various samples of bioactive substance release film 70 with different hard segment portions (and different weight % ranges) and hydrophobic soft segments and hydrophilic soft segment portions with different weight % ranges. Thus, samples 130, 136, and 137, which include a polyurethane block polymer having 40 to 60 wt % of a hard segment (e.g., cyclic isophorone diisocyanate (IPDI)), 10 to 30 wt % of a hydrophobic soft segment portion (e.g., polysiloxane), and 20 to 50 wt % of a hydrophilic soft segment portion (e.g., polyalkyl ether), show a desired release rate for a selected bioactive substance (e.g., dexamethasone acetate). In contrast, samples 131, 132, 133, 134 and 135 of polyurethane block polymers having 40 wt % to 60 wt % hard segments (e.g., linear 1,6-hexamethylene diisocyanate (HDI)), 10 wt % to 30 wt % hydrophobic soft segments (e.g., polysiloxane) and 0 wt % to 50 wt % hydrophilic soft segments (e.g., polyalkyl ether) showed rapid release of selected bioactive substances (e.g., dexamethasone acetate). This data demonstrates that the correlation between the water absorption of the bioactive substance release layer (e.g., the hard segment solubility is similar to the releasable bioactive substance) and the water absorption of the bioactive substance can be used to tailor the release rate/profile of the bioactive substance.
在示例中，生物活性物质释放膜70化学物质包括软链段和硬链段，该硬链段包括氨基甲酸酯基团、脲基团或氨基甲酸酯基团与脲基团的组合。软链段是两种或更多种不同的聚合物链段。软链段包括疏水性嵌段和亲水性嵌段。软链段包括聚硅氧烷、聚烷基醚、聚烷基酯、聚碳酸烷基酯、聚碳酸酯或聚硅氧烷-聚烷基醚链段化嵌段。In the example, the bioactive substance release film 70 chemical substance includes a soft segment and a hard segment, and the hard segment includes a carbamate group, a urea group or a combination of a carbamate group and a urea group. The soft segment is two or more different polymer segments. The soft segment includes a hydrophobic block and a hydrophilic block. The soft segment includes a polysiloxane, a polyalkyl ether, a polyalkyl ester, a polyalkyl carbonate, a polycarbonate or a polysiloxane-polyalkyl ether segmented block.
在示例中，生物活性物质释放膜70化学物质还包括扩链剂。扩链剂包括二醇、二胺、硅-氢化物或多官能环氧化物。In an example, the chemical composition of the bioactive substance releasing membrane 70 further includes a chain extender, which includes diols, diamines, silicon-hydrides or multifunctional epoxides.
在示例中，生物活性物质释放膜70化学物质是聚氨酯脲。In an example, the bioactive substance releasing membrane 70 chemical substance is polyurethane urea.
在示例中，按生物活性物质释放膜的总重量计，生物活性物质释放膜70化学物质包括约10重量％至30重量％的聚硅氧烷和约10重量％至30重量％的聚烷基醚、40重量％至60重量％的硬链段，并且任何剩余重量％是扩链剂，硬链段包括氨基甲酸酯基团、脲基团或氨基甲酸酯基团与脲基团的组合。In an example, the chemical composition of the bioactive substance releasing membrane 70 includes about 10 wt % to 30 wt % of polysiloxane and about 10 wt % to 30 wt % of polyalkyl ether, 40 wt % to 60 wt % of hard segments, and any remaining wt % is a chain extender, based on the total weight of the bioactive substance releasing membrane, and the hard segments include carbamate groups, urea groups, or a combination of carbamate groups and urea groups.
在示例中，按生物活性物质释放膜的总重量计，生物活性物质释放膜70化学物质包括约20重量％至30重量％的聚硅氧烷、约20重量％至30重量％的聚烷基醚和约40重量％至60重量％的硬链段，并且任何剩余重量％是扩链剂。In an example, the bioactive substance releasing membrane 70 chemical composition includes about 20 wt% to 30 wt% polysiloxane, about 20 wt% to 30 wt% polyalkyl ether, and about 40 wt% to 60 wt% hard segment, based on the total weight of the bioactive substance releasing membrane, and any remaining wt% is a chain extender.
在示例中，生物活性物质释放膜70化学物质包括软链段，按生物活性物质释放膜的总重量计，软链段包括约10重量％至30重量％的聚硅氧烷、约10重量％至30重量％的聚烷基醚和约0重量％至10重量％的扩链剂。In an example, the chemical composition of the bioactive substance releasing membrane 70 includes a soft segment, which includes about 10 wt % to 30 wt % of polysiloxane, about 10 wt % to 30 wt % of polyalkyl ether, and about 0 wt % to 10 wt % of chain extender, based on the total weight of the bioactive substance releasing membrane.
在示例中，聚烷基醚由式(I)的重复单元表示：-(R5-O)-；其中R5是2至6个碳的直链或支链烷基。In an example, the polyalkyl ether is represented by a repeating unit of formula (I): -(R5-O)-; wherein R5 is a linear or branched alkyl group of 2 to 6 carbons.
参考图6B，呈现了与具有不含醋酸地塞米松(DexAc)的膜70的对照传感器84相比，在15天内，示例性实验传感器82的活体受者灵敏度数据研究，该示例性实验传感器包括具有有效量的DexAc的本发明所公开的生物活性物质释放膜70(例如，大约40重量％至50重量百分比负载:生物活性物质释放膜)。如图所示，实验传感器82在插入后15天内提供一致的归一化灵敏度可持续性，而对照传感器84在插入后大约10天后显示出归一化灵敏度的降低。Referring to FIG6B, a study of in vivo sensitivity data of an exemplary experimental sensor 82 comprising a bioactive substance release membrane 70 disclosed herein with an effective amount of DexAc (e.g., about 40 wt % to 50 wt % loading: bioactive substance release membrane) is presented, compared to a control sensor 84 having a membrane 70 without dexamethasone acetate (DexAc), over a period of 15 days. As shown, the experimental sensor 82 provides consistent normalized sensitivity sustainability over 15 days after insertion, while the control sensor 84 shows a decrease in normalized sensitivity after about 10 days after insertion.
参考图6C，呈现了与不含醋酸地塞米松(DexAc)的对照传感器85相比，在30天内，示例性实验传感器83的活体受者灵敏度数据研究，该示例性实验传感器包括具有有效量的DexAc的本发明所公开的生物活性物质释放膜70(例如，大约40重量％至50重量百分比负载:生物活性物质释放膜)。如图所示，实验传感器83在插入后30天内提供了超过60％的改进的归一化灵敏度可持续性，而对照传感器84在插入后大约20天后显示出归一化灵敏度降低至60％以下。Referring to FIG6C, a study of in vivo sensitivity data of an exemplary experimental sensor 83 including a bioactive substance release membrane 70 disclosed herein with an effective amount of DexAc (e.g., about 40 wt% to 50 wt% load: bioactive substance release membrane) is presented, compared to a control sensor 85 without dexamethasone acetate (DexAc) over a 30-day period. As shown, the experimental sensor 83 provided an improved normalized sensitivity sustainability of more than 60% within 30 days after insertion, while the control sensor 84 showed a decrease in normalized sensitivity to less than 60% after about 20 days after insertion.
在一些实施方案中，灵敏度损失可指示寿命终止。由于生理伤口愈合和传感器周围的异物机制或其他机制(包括参比电极容量、酶消耗、膜变化等)，灵敏度损失可能在传感器寿命终止时发生。In some embodiments, sensitivity loss may indicate end of life. Sensitivity loss may occur at the end of sensor life due to physiological wound healing and foreign body mechanisms around the sensor or other mechanisms including reference electrode capacity, enzyme consumption, membrane changes, etc.
在一些实施方案中，可使用未校准的传感器数据(例如，原始或过滤数据)的分析来计算传感器灵敏度。在示例中，原始计数的缓慢移动平均值或中值开始显示负趋势，传感器可能损失灵敏度。灵敏度的损失可通过计算传感器输出的短期(例如约6小时至8小时)平均值(或中值)并通过预期的长期(48小时)平均传感器灵敏度对其进行归一化来计算。如果短期灵敏度与长期灵敏度的比率小于70％，则可能存在传感器损失灵敏度的风险。灵敏度的损失可被转化为寿命终止风险因子值，例如约为1的值直到比率为约70％，在50％时降低至0.5并且在25％时<0.1。In some embodiments, the sensor sensitivity can be calculated using analysis of uncalibrated sensor data (e.g., raw or filtered data). In an example, a slow moving average or median of the raw counts begins to show a negative trend and the sensor may be losing sensitivity. The loss of sensitivity can be calculated by calculating the short-term (e.g., about 6 hours to 8 hours) average (or median) of the sensor output and normalizing it by the expected long-term (48 hours) average sensor sensitivity. If the ratio of short-term sensitivity to long-term sensitivity is less than 70%, there may be a risk of sensor loss of sensitivity. The loss of sensitivity can be converted into an end-of-life risk factor value, such as a value of about 1 until the ratio is about 70%, decreasing to 0.5 at 50% and <0.1 at 25%.
在一些实施方案中，可通过将传感器数据(例如，经校准的传感器数据)与参比血糖进行比较来计算传感器灵敏度。例如，校准算法基于传感器与参比血糖之间的系统偏差来调节葡萄糖估计。寿命终止算法可使用该偏差(称为校准误差或向下漂移)来量化或限定寿命终止症状。校准时的误差可被归一化以考虑不规律的校准时间，并被平滑以给予最近数据更多权重(例如，移动平均值或指数平滑)。在一些实施方案中，基于校准时所得到的平滑误差来确定寿命终止风险因子值。在此类实施方案中，对于校准>-0.3时的所有误差值，寿命终止风险因子值是1，并且对于校准＝-0.4时的误差降低至0.5，并且对于校准＝-0.6时的误差降低至<0.1。在一些示例中，可采用传感器灵敏度随时间推移的向下漂移、非对称、非平稳噪声的量以及噪声的持续时间中的一者或多者，例如，如共同转让的美国专利公开号2021/0209497中所公开的，该专利以引用方式并入本文。In some embodiments, the sensor sensitivity can be calculated by comparing the sensor data (e.g., calibrated sensor data) with a reference blood glucose. For example, the calibration algorithm adjusts the glucose estimate based on the systematic deviation between the sensor and the reference blood glucose. The end-of-life algorithm can use this deviation (called calibration error or downward drift) to quantify or define the end-of-life symptoms. The error during calibration can be normalized to take into account irregular calibration times and smoothed to give more weight to recent data (e.g., moving average or exponential smoothing). In some embodiments, the end-of-life risk factor value is determined based on the smoothed error obtained during calibration. In such embodiments, for all error values when calibration>-0.3, the end-of-life risk factor value is 1, and the error is reduced to 0.5 for calibration=-0.4, and reduced to <0.1 for calibration=-0.6. In some examples, one or more of the downward drift of sensor sensitivity over time, the amount of asymmetric, non-stationary noise, and the duration of the noise can be used, for example, as disclosed in the commonly assigned U.S. Patent Publication No. 2021/0209497, which is incorporated herein by reference.
在一些实施方案中，可使用未校准的传感器数据(例如，原始或过滤数据)的分析来计算传感器灵敏度。在示例中，原始计数的缓慢移动平均值或中值开始显示负趋势，传感器可能损失灵敏度。灵敏度的损失可通过计算传感器输出的短期(例如约6小时至8小时)平均值(或中值)并通过预期的长期(48小时)平均传感器灵敏度对其进行归一化来计算。如果短期灵敏度与长期灵敏度的比率小于70％，则可能存在传感器损失灵敏度的风险。灵敏度的损失可被转化为寿命终止风险因子值，例如约为1的值直到比率为约70％，在50％时降低至0.5％并且在25％时<0.1％。In some embodiments, the sensor sensitivity can be calculated using analysis of uncalibrated sensor data (e.g., raw or filtered data). In an example, a slow moving average or median of raw counts begins to show a negative trend, and the sensor may lose sensitivity. The loss of sensitivity can be calculated by calculating the short-term (e.g., about 6 hours to 8 hours) average (or median) of the sensor output and normalizing it by the expected long-term (48 hours) average sensor sensitivity. If the ratio of short-term sensitivity to long-term sensitivity is less than 70%, there may be a risk of sensor loss of sensitivity. The loss of sensitivity can be converted into an end-of-life risk factor value, such as a value of about 1 until the ratio is about 70%, decreasing to 0.5% at 50% and <0.1% at 25%.
参考图6C，连续分析物传感器90(具有生物活性物质释放膜70)相对于对照91(无膜)和传感器92(具有膜但无生物活性物质存在)的存活图。如图所示，具有生物活性物质释放膜70的传感器在至少5天表现优于仅具有膜的对照和传感器，其中小于80％的灵敏度指示显著的寿命终止(EOL)。6C, a survival graph of continuous analyte sensor 90 (with bioactive substance release membrane 70) relative to control 91 (without membrane) and sensor 92 (with membrane but no bioactive substance present). As shown, the sensor with bioactive substance release membrane 70 outperformed the control and sensor with only membrane for at least 5 days, where a sensitivity of less than 80% indicates a significant end of life (EOL).
参考图6D的存活图，通过改变生物活性物质释放膜化学物质，例如调节硬链段、软链段的重量百分比、软链段的疏水性部分的重量百分比等，以便改变生物活性物质从生物活性物质释放膜70的释放速率(通常表征为生物活性物质的快速释放、中等释放或缓慢释放，包括任何推注释放或不存在推注释放)，证明了灵敏度保持的改善。因此，图6D示出了生物活性物质(以醋酸地塞米松为例)的缓慢释放速率膜93在14天后具有小于80％的灵敏度保持，对照94(无膜)在18天后具有小于80％的灵敏度保持，中等释放速率膜95在19天后具有小于80％的灵敏度保持，并且快速释放速率膜96在20天后具有小于80％的灵敏度保持。Referring to the survival diagram of FIG6D, by changing the bioactive substance release membrane chemistry, such as adjusting the weight percentage of the hard segment, the soft segment, the weight percentage of the hydrophobic portion of the soft segment, etc., so as to change the release rate of the bioactive substance from the bioactive substance release membrane 70 (generally characterized as a rapid release, a medium release, or a slow release of the bioactive substance, including any bolus release or the absence of a bolus release), the improvement of sensitivity retention is demonstrated. Therefore, FIG6D shows that the slow release rate membrane 93 of the bioactive substance (taking dexamethasone acetate as an example) has a sensitivity retention of less than 80% after 14 days, the control 94 (no membrane) has a sensitivity retention of less than 80% after 18 days, the medium release rate membrane 95 has a sensitivity retention of less than 80% after 19 days, and the fast release rate membrane 96 has a sensitivity retention of less than 80% after 20 days.
参考图7A，呈现了与22天内不含醋酸地塞米松(DexAc)的对照传感器84和具有生物活性物质释放膜70而不含醋酸地塞米松的对比传感器87相比，示例性实验传感器86的活体受者平均绝对噪声数据研究，该示例性实验传感器包括具有有效量的DexAc的本发明所公开的生物活性物质释放膜70(例如，大约40重量％至50重量百分比负载:生物活性物质释放膜)。如图所示，实验传感器86在插入后22天内提供相对一致的平均绝对噪声可持续性，而对照传感器88和对比传感器87在插入后大约8天至10天后显示出平均绝对噪声的增加。该数据举例说明了本发明所公开的生物活性物质释放膜与生物活性剂组合在延长的时间段内使可植入传感器噪声的增加最小化的能力。Referring to FIG. 7A , a study of live recipient average absolute noise data of an exemplary experimental sensor 86 is presented, which includes a bioactive substance release membrane 70 disclosed herein with an effective amount of DexAc (e.g., approximately 40 wt % to 50 wt % load: bioactive substance release membrane) compared to a control sensor 84 without dexamethasone acetate (DexAc) and a comparative sensor 87 with a bioactive substance release membrane 70 but without dexamethasone acetate over a 22-day period. As shown, the experimental sensor 86 provides relatively consistent average absolute noise sustainability within 22 days after insertion, while the control sensor 88 and the comparative sensor 87 show an increase in average absolute noise after approximately 8 to 10 days after insertion. This data illustrates the ability of the bioactive substance release membrane disclosed herein in combination with a bioactive agent to minimize the increase in implantable sensor noise over an extended period of time.
参考图7B，呈现了连续分析物传感器90(具有生物活性物质释放膜70)相对于对照91(无膜)和传感器92(具有膜但无生物活性物质存在)的存活图。如图所示，具有生物活性物质释放膜70的传感器在至少10天表现优于仅具有膜的对照和传感器，其中小于80％的噪声指示显著的寿命终止(EOL)。Referring to Figure 7B, a survival graph of a continuous analyte sensor 90 (with a bioactive substance releasing membrane 70) relative to a control 91 (without a membrane) and a sensor 92 (with a membrane but no bioactive substance present) is presented. As shown, the sensor with the bioactive substance releasing membrane 70 outperformed the control and the sensor with only a membrane for at least 10 days, with less than 80% noise indicating a significant end of life (EOL).
参考存活图7C，通过改变生物活性物质释放膜化学物质，例如调节硬链段、软链段的重量百分比、软链段的疏水性部分的重量百分比等，以便改变生物活性物质从生物活性物质释放膜70的释放速率(通常表征为生物活性物质的快速释放、中等释放或缓慢释放，包括任何推注释放或不存在推注释放，如先前在图6D中所述)，证明了使噪声的增加最小化的改进。因此，图7C示出了生物活性物质(以醋酸地塞米松为例)的缓慢释放速率膜93在5天后具有超过80％的噪声的增加，对照94(无膜)在4天后具有超过80％的噪声的增加，中等释放速率膜95在8天后具有超过80％的噪声的增加，并且快速释放速率膜96在8天后具有超过80％的噪声的增加。该数据举例说明了相对于对照膜或非生物活性物质膜，本发明所公开的生物活性物质释放膜与生物活性剂组合在延长的时间段内使可植入传感器噪声的增加最小化的能力。Referring to FIG. 7C , by changing the bioactive substance release membrane chemistry, such as adjusting the weight percentage of the hard segment, the soft segment, the weight percentage of the hydrophobic portion of the soft segment, etc., in order to change the release rate of the bioactive substance from the bioactive substance release membrane 70 (generally characterized as a fast release, a medium release, or a slow release of the bioactive substance, including any bolus release or the absence of a bolus release, as previously described in FIG. 6D ), it is demonstrated that the improvement of minimizing the increase in noise is improved. Therefore, FIG. 7C shows that the slow release rate membrane 93 of the bioactive substance (taking dexamethasone acetate as an example) has an increase in noise of more than 80% after 5 days, the control 94 (no membrane) has an increase in noise of more than 80% after 4 days, the medium release rate membrane 95 has an increase in noise of more than 80% after 8 days, and the fast release rate membrane 96 has an increase in noise of more than 80% after 8 days. This data illustrates the ability of the bioactive substance release membrane disclosed in the present invention to minimize the increase in noise of the implantable sensor in combination with the bioactive agent over an extended period of time relative to the control membrane or the non-bioactive substance membrane.
在不同的生物活性物质释放膜组合中使用地塞米松盐进行了附加实验。例如，水溶性纤维素基聚合物中的地塞米松磷酸钠提供了推注释放曲线。掺入如本文所公开的生物界面聚合物膜中的磷酸地塞米松提供约2天的持续释放。具有0重量％疏水性软链段的硬链段-软链段聚氨酯脲共聚物中的醋酸地塞米松提供约5天的持续释放。具有大约相等重量％的疏水性链段/亲水性链段的硬链段-软链段聚氨酯脲共聚物中的醋酸地塞米松提供大约15天的持续释放。疏水性软链段的重量百分比大于亲水性软链段的重量百分比的硬链段-软链段聚氨酯脲共聚物中的醋酸地塞米松提供超过15天的缓慢的持续释放。纤维素聚合物中的醋酸地塞米松提供超过15天的缓慢的持续(连续或半连续)释放。使用前述生物活性物质释放膜的组合，生物活性剂的释放速率和/或释放曲线可针对特定传感器及其预期的寿命终点而特异性地定制，同时提供持续的灵敏度和低噪声性能。Additional experiments were performed using dexamethasone salts in different bioactive substance release film combinations. For example, dexamethasone sodium phosphate in a water-soluble cellulose-based polymer provides a bolus release curve. Dexamethasone phosphate incorporated into a biointerface polymer film as disclosed herein provides a sustained release of about 2 days. Dexamethasone acetate in a hard segment-soft segment polyurethane urea copolymer with 0 weight % hydrophobic soft segment provides a sustained release of about 5 days. Dexamethasone acetate in a hard segment-soft segment polyurethane urea copolymer with approximately equal weight % hydrophobic segment/hydrophilic segment provides a sustained release of about 15 days. Dexamethasone acetate in a hard segment-soft segment polyurethane urea copolymer with a weight percentage of hydrophobic soft segment greater than the weight percentage of hydrophilic soft segment provides a slow sustained release of more than 15 days. Dexamethasone acetate in a cellulose polymer provides a slow sustained (continuous or semi-continuous) release of more than 15 days. Using a combination of the aforementioned bioactive material release membranes, the release rate and/or release profile of the bioactive agent can be specifically tailored for a particular sensor and its expected end of life while providing sustained sensitivity and low noise performance.
该数据举例说明了本发明所公开的生物活性物质释放膜/生物活性剂组合在延长的时间段内使可植入传感器的灵敏度的衰减/降低最小化的能力。本发明所公开的生物活性物质释放膜/生物活性剂组合可被配置用于除了基于电化学的传感器系统之外的其他传感器平台，诸如基于光学的传感器系统，以及预期用于需要随后从受试者中移除的延长植入的其他医疗设备。This data illustrates the ability of the disclosed bioactive substance release membrane/bioactive agent combination to minimize the attenuation/decrease in sensitivity of implantable sensors over extended periods of time. The disclosed bioactive substance release membrane/bioactive agent combination can be configured for use in sensor platforms other than electrochemical-based sensor systems, such as optical-based sensor systems, and other medical devices intended for extended implantation that require subsequent removal from a subject.
如图3H所示，连续分析物感测设备100包括分析物传感器，该分析物传感器具有可插入部分102，该可插入部分可操作地联接到不可插入部分104，连续分析物感测设备100被配置为部署可插入部分102。可插入部分102具有可插入表面积和可插入体积中的至少一者。至少一个感测域112至少部分地围绕可插入部分102(并且因此围绕可插入表面积和/或可插入体积)定位。可插入部分102还包括形成在可插入部分102上的生物活性物质释放膜70。As shown in Fig. 3H, the continuous analyte sensing device 100 includes an analyte sensor having an insertable portion 102, which is operably connected to a non-insertable portion 104, and the continuous analyte sensing device 100 is configured to deploy the insertable portion 102. The insertable portion 102 has at least one of an insertable surface area and an insertable volume. At least one sensing domain 112 is at least partially positioned around the insertable portion 102 (and therefore around the insertable surface area and/or the insertable volume). The insertable portion 102 also includes a bioactive substance release membrane 70 formed on the insertable portion 102.
在示例中，可插入部分102具有约1mm至约20mm的长度，包括其间的所有范围和子范围。在另一示例中，可插入部分102具有约2mm至约14mm的长度。在另外的示例中，可插入部分102具有约4mm至约12mm的长度。例如，可插入部分102具有至少约以下各项中的任一者的长度：1mm、2mm、3mm、4mm、5mm、6mm、7mm、8mm、9mm、10mm、11mm、12mm、13mm、14mm、15mm、16mm、17mm、18mm和19mm和/或至多约20mm、19mm、18mm、17mm、16mm、15mm、4mm、13mm、12mm、11mm、10mm、9mm、8mm、7mm、6mm、5mm、4mm、3mm和2mm(例如，约1mm至15mm、约5mm至18mm等)。In an example, insertable portion 102 has a length of about 1mm to about 20mm, including all ranges and subranges therebetween. In another example, insertable portion 102 has a length of about 2mm to about 14mm. In another example, insertable portion 102 has a length of about 4mm to about 12mm. For example, insertable portion 102 has a length of at least about any one of the following: 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm and 19mm and/or at most about 20mm, 19mm, 18mm, 17mm, 16mm, 15mm, 4mm, 13mm, 12mm, 11mm, 10mm, 9mm, 8mm, 7mm, 6mm, 5mm, 4mm, 3mm and 2mm (for example, about 1mm to 15mm, about 5mm to 18mm, etc.).
如图3I所示，可插入部分包括生物活性物质释放膜70。在一个示例中，生物活性物质释放膜70包括设置在可插入部分102的一部分(以及因此可插入表面积和/或可插入体积的一部分)上的至少一个聚合物层。生物活性物质释放膜70包括分散在生物活性物质释放膜中的至少一种生物活性剂110。在一个示例中，生物活性物质释放膜70被配置为与至少一种生物活性剂110缔合和/或释放该至少一种生物活性剂。至少一种生物活性剂110可被配置为不可从生物活性物质释放膜释放并改变受试者的组织反应。至少一种生物活性剂110可独立地被配置为以某种形式不可释放以及可从生物活性物质释放膜释放并改变受试者的组织反应。As shown in FIG. 3I , the insertable portion includes a bioactive substance release membrane 70. In one example, the bioactive substance release membrane 70 includes at least one polymer layer disposed on a portion of the insertable portion 102 (and therefore a portion of the insertable surface area and/or the insertable volume). The bioactive substance release membrane 70 includes at least one bioactive agent 110 dispersed in the bioactive substance release membrane. In one example, the bioactive substance release membrane 70 is configured to associate with and/or release the at least one bioactive agent 110. At least one bioactive agent 110 can be configured to be non-releasable from the bioactive substance release membrane and change the tissue response of the subject. At least one bioactive agent 110 can be independently configured to be non-releasable in a certain form and to be releasable from the bioactive substance release membrane and change the tissue response of the subject.
生物活性物质释放膜70的至少一个聚合物层可包括本文先前讨论的任何合适的聚合物材料。在示例中，生物活性物质释放膜70的至少一个聚合物层包括一种或多种环氧化物、聚烯烃、聚硅氧烷、聚酰胺、聚苯乙烯、聚丙烯酸酯、聚醚、聚乙烯吡啶、聚乙烯-共-聚苯乙烯、聚乙烯咪唑、聚酯、聚烷基酯、聚碳酸烷基酯、聚碳酸酯、聚氨酯、聚氨酯脲、聚乙烯乙酸乙烯酯(EVA)、聚乙烯醇以及它们的共聚物或共混物。在另一示例中，生物活性物质释放膜70的至少一个聚合物层包括与至少一种生物活性剂缔合的一个或多个两性离子重复单元，该至少一种生物活性剂被配置为从一个或多个两性离子重复单元释放以改变受试者的组织反应。At least one polymer layer of the bioactive substance release membrane 70 may include any suitable polymer material previously discussed herein. In an example, at least one polymer layer of the bioactive substance release membrane 70 includes one or more epoxides, polyolefins, polysiloxanes, polyamides, polystyrenes, polyacrylates, polyethers, polyvinylpyridines, polyethylene-co-polystyrenes, polyvinylimidazoles, polyesters, polyalkyl esters, polyalkyl carbonates, polycarbonates, polyurethanes, polyurethane ureas, polyethylene vinyl acetate (EVA), polyvinyl alcohols, and copolymers or blends thereof. In another example, at least one polymer layer of the bioactive substance release membrane 70 includes one or more zwitterionic repeating units associated with at least one bioactive agent, the at least one bioactive agent being configured to be released from the one or more zwitterionic repeating units to alter a tissue response of a subject.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜包括聚环氧乙烷链段。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing membrane comprises polyethylene oxide segments.
在一个方面，单独地或与前述方面中的任一方面组合地，按生物活性物质释放膜的总重量计，聚环氧乙烷链段为约5重量％至约60重量％，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the polyethylene oxide segments are about 5 wt % to about 60 wt %, based on the total weight of the bioactive substance release membrane, including all ranges and subranges therebetween.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜的基础聚合物具有约10kDa至约500kDa的平均分子量，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the base polymer of the bioactive substance release membrane has an average molecular weight of about 10 kDa to about 500 kDa, including all ranges and subranges therebetween.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜具有1至约10的多分散指数，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the bioactive material releasing film has a polydispersity index of 1 to about 10, including all ranges and subranges therebetween.
在一个方面，单独地或与前述方面中的任一方面组合地，生物活性物质释放膜具有约90°至约160°的接触角，包括其间的所有范围和子范围。In one aspect, alone or in combination with any of the preceding aspects, the bioactive substance releasing film has a contact angle of about 90° to about 160°, including all ranges and subranges therebetween.
至少一种生物活性剂110包括本文先前讨论的任何合适的生物活性剂。在示例中，至少一种生物活性剂110包括抗炎化合物或组织反应调节剂。例如，在示例中，至少一种生物活性剂110包括地塞米松、地塞米松盐、地塞米松衍生物、醋酸地塞米松或它们的任何组合中的至少一者。The at least one bioactive agent 110 includes any suitable bioactive agent previously discussed herein. In an example, the at least one bioactive agent 110 includes an anti-inflammatory compound or a tissue response modifier. For example, in an example, the at least one bioactive agent 110 includes at least one of dexamethasone, a dexamethasone salt, a dexamethasone derivative, dexamethasone acetate, or any combination thereof.
在示例中，至少一种生物活性剂110以约0.1至约2的药物/聚合物重量/重量比率(包括其间的所有范围和子范围)分散在生物活性物质释放膜70的至少一个聚合物层中(并且因此分散在聚合物层体积中)。在另一示例中，至少一种生物活性剂110以约0.1至约0.3的药物/聚合物重量/重量比率分散在生物活性物质释放膜70的至少一个聚合物层中(并且因此分散在聚合物层体积中)。在另外的示例中，至少一种生物活性剂110以约0.3至约0.5的药物/聚合物重量/重量比率分散在生物活性物质释放膜70的至少一个聚合物层中(并且因此分散在聚合物层体积中)。例如，至少一种生物活性剂110以一定的药物/聚合物重量/重量比率分散在生物活性物质释放膜70的至少一个聚合物层中，该药物/聚合物重量/重量比率为从至少约以下各项中的任一者开始：0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.2、0.21、0.22、0.23、0.24、0.25、0.26、0.27、0.28、0.29、0.3、0.31、0.32、0.33、0.34、0.35、0.36、0.37、0.38、0.39、0.4、0.41、0.42、0.43、0.44、0.45、0.46、0.47、0.48和0.49和/或至多约0.5、0.49、0.48、0.47、0.46、0.45、0.44、0.43、0.42、0.41、0.4、0.39、0.38、0.37、0.36、0.35、0.34、0.33、0.32、0.31、0.3、0.29、0.28、0.27、0.26、0.25、0.24、0.23、0.22、0.21、0.2、0.19、0.18、0.17、0.16、0.15、0.14、0.13、0.12、0.11、0.1、0.09、0.08、0.07、0.06、0.05、0.04、0.03和0.02(例如，约0.19至0.49、约0.01至0.3等)。在另外的示例中，至少一种生物活性剂以约0.1:2μg/mm3至约0.2:1μg/mm3的药物/聚合物重量/体积比率(包括其间的所有范围和子范围)分散在聚合物层体积中。In an example, at least one bioactive agent 110 is dispersed in at least one polymer layer of the bioactive substance release membrane 70 (and therefore dispersed in the polymer layer volume) at a drug/polymer weight/weight ratio of about 0.1 to about 2 (including all ranges and sub-ranges therebetween). In another example, at least one bioactive agent 110 is dispersed in at least one polymer layer of the bioactive substance release membrane 70 (and therefore dispersed in the polymer layer volume) at a drug/polymer weight/weight ratio of about 0.1 to about 0.3. In another example, at least one bioactive agent 110 is dispersed in at least one polymer layer of the bioactive substance release membrane 70 (and therefore dispersed in the polymer layer volume) at a drug/polymer weight/weight ratio of about 0.3 to about 0.5. For example, at least one bioactive agent 110 is dispersed in at least one polymer layer of the bioactive substance release membrane 70 at a drug/polymer weight/weight ratio that is at least about any of the following: 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, 0.12, 0.1 3. 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.4, 0.41, 0.42, 0.43, 0 .44, 0.45, 0.46, 0.47, 0.48 and 0.49 and/or up to about 0.5, 0.49, 0.48, 0.47, 0.46, 0.45, 0.44, 0.43, 0.42, 0.41, 0.4, 0.39, 0.38, 0.37, 0.36, 0.35, 0.34, 0.33, 0.32, 0.31, 0.3, 0.29, 0.28, 0.27 , 0.26, 0.25, 0.24, 0.23, 0.22, 0.21, 0.2, 0.19, 0.18, 0.17, 0.16, 0.15, 0.14, 0.13, 0.12, 0.11, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03 and 0.02 (e.g., about 0.19 to0.49 , about 0.01 to 0.3, etc.). In another example, the at least one bioactive agent is dispersed in the polymer layer volume at a drug/polymer weight/volume ratio of about 0.1:2 μg/mm3 to about 0.2:1 μg/mm 3 (including all ranges and subranges therebetween).
在另一示例中，至少一种生物活性剂以约0.2μg/mm3至约1μg/mm3的药物/聚合物重量/体积比率(包括其间的所有范围和子范围)分散在生物活性物质释放膜70体积中。在另一示例中，至少一种生物活性剂以约1:10μg/mm3至约2:1μg/mm3的药物/聚合物重量/体积比率分散在聚合物层体积中。例如，至少一种生物活性剂以一定的药物/聚合物重量/体积比率分散在聚合物层体积中，该药物/聚合物重量/体积比率为从至少约以下各项中的任一者开始：1:10、2:10(即1:5)、3:10、4:10(即2:5)、5:10(即1:2)、6:10(即3:5)、7:10、8:10(即4:5)、9:10、10:10(即1:1)、11:10、12:10(即6:5)、13:10、14:10(即7:5)、15:10(即3:2)、16:10(即8:5)、17:10、18:10(即9:5)和19:10μg/mm3和/或至多约20:10(即2:1)、19:10、18:10(即9:5)、17:10、16:10(即8:5)、15:10(即3:2)、14:10(即7:5)、13:10、12:10(6:5)、11:10、10:10(即1:1)、9:10、8:10(即4:5)、7:10、6:10(即3:5)、5:10(即1:2)、4:10(即2:5)、3:10和2:10(即1:5)μg/mm3(例如约1:10至19:10、约7:10至17:10等)，包括其间的所有范围和子范围。先前已经在本文中更详细地讨论了至少一种生物活性剂110的负载。In another example, at least one bioactive agent is dispersed in the volume of the bioactive substance release membrane 70 at a drug/polymer weight/volume ratio of about 0.2 μg/mm3 to about 1 μg/mm3 (including all ranges and subranges therebetween). In another example, at least one bioactive agent is dispersed in the volume of the polymer layer at a drug/polymer weight/volume ratio of about 1:10 μg/mm3 to about 2:1 μg/mm3 . For example, at least one bioactive agent is dispersed in the volume of the polymer layer at a drug/polymer weight/volume ratio that is at least about any of 1:10, 2:10 (i.e., 1:5), 3:10, 4:10 (i.e., 2:5), 5:10 (i.e., 1:2), 6:10 (i.e., 3:5), 7:10, 8:10 (i.e., 4:5), 9:10, 10:10 (i.e., 1:1), 11:10, 12:10 (i.e., 6:5), 13:10, 14:10 (i.e., 7:5), 15:10 (i.e., 3:2), 16:10 (i.e., 8:5), 17:10, 18:10 (i.e., 9:5), and 19:10 μg/mm3 and/or up to about 20:10 (i.e., 2:1), 19:10, 18:10 (i.e., 9:5), 17:10, 16:10 (i.e., 8:5), 15:10 (i.e., 3:2), 14:10 (i.e., 7:5), 13:10, 12:10 (6:5), 11:10, 10:10 (i.e., 1:1), 9:10, 8:10 (i.e., 4:5), 7:10, 6:10 (i.e., 3:5), 5:10 (i.e., 1:2), 4:10 (i.e., 2:5), 3:10, and 2:10 (i.e., 1:5) μg/mm3 (e.g., about 1:10 to 19:10, about 7:10 to 17:10, etc.), including all ranges and subranges therebetween. The loading of at least one biologically active agent 110 has been previously discussed in more detail herein.
在另一示例中，并且如图3J所示，可插入部分涂层是可包括至少一个聚合物层的生物活性物质释放膜70，并且至少一种生物活性剂110包括在该膜70中。在该示例中，生物活性物质释放膜70可邻近感测膜32，并且包括邻近任何干扰物膜/域、抵抗膜/域、生物界面膜/域和电极膜/域。生物活性物质释放膜70的各种化学物质、它们的结构、生物活性负载以及本公开所设想的其他特征先前已经在本文中讨论过。In another example, and as shown in FIG3J, the insertable portion coating is a bioactive substance release membrane 70 that may include at least one polymer layer, and at least one bioactive agent 110 is included in the membrane 70. In this example, the bioactive substance release membrane 70 may be adjacent to the sensing membrane 32, and includes adjacent to any interferent membrane/domain, resist membrane/domain, biointerface membrane/domain, and electrode membrane/domain. The various chemical substances of the bioactive substance release membrane 70, their structure, bioactive load, and other features contemplated by the present disclosure have been previously discussed herein.
如本文先前所讨论的，虽然本文的一些附图(例如，图3I和图3J)展示了可具有同轴芯和圆形或椭圆形横截面的传感器，但在包括生物界面/生物活性物质释放层的传感器系统的其他示例中，传感器可以是基本上平面的传感器，如图2H中用于图示目的的横截面所示。例如，如图2H所示，连续分析物感测设备可包括基本上平面的衬底142以及以基本上平面的方式围绕平面或基本上平面的衬底142布置的干扰域144、酶域146、抵抗域148和生物界面/生物保护性域168和/或生物活性物质释放域170。As previously discussed herein, while some of the figures herein (e.g., FIG. 3I and FIG. 3J ) illustrate sensors that may have a coaxial core and a circular or elliptical cross-section, in other examples of sensor systems that include a biointerface/bioactive substance release layer, the sensor may be a substantially planar sensor, as shown in the cross-section for illustration purposes in FIG. 2H . For example, as shown in FIG. 2H , a continuous analyte sensing device may include a substantially planar substrate 142 and an interference domain 144, an enzyme domain 146, a resistance domain 148, and a biointerface/bioprotective domain 168 and/or a bioactive substance release domain 170 arranged in a substantially planar manner around the planar or substantially planar substrate 142.
如图3K和图3L所示，在一些示例中，生物活性物质释放膜70与至少一个感测域112空间分离一定距离，使得生物活性物质释放膜70不与至少一个感测域112重叠或以其他方式干扰一种或多种分析物或与对应于一种或多种分析物的量或存在的可测量信号的生成相关联的其他物质的扩散路径。以这种方式，生物活性物质释放膜70不干扰至少一个感测域112的感测能力。在示例中，距离为约1μm或更小至约250μm，包括其间的所有范围和子范围。在另一示例中，距离为约1μm或更小至约50μm。在又一示例中，距离为约15μm至约200μm。在又一示例中，距离为约50μm至约100μm。例如，距离为从至少约以下各项中的任一者开始：1μm、5μm、10μm、15μm、20μm、25μm、30μm、35μm、40μm、45μm、50μm、55μm、60μm、65μm、70μm、75μm、80μm、85μm、90μm、95μm、100μm、105μm、110μm、115μm、120μm、125μm、130μm、135μm、140μm、145μm、150μm、155μm、160μm、165μm、170μm、175μm、180μm、185μm、190μm、195μm、200μm、205μm、210μm、215μm、220μm、225μm、230μm、235μm、240μm和245μm和/或至多约250μm、245μm、240μm、235μm、230μm、225μm、220μm、215μm、210μm、205μm、200μm、195μm、190μm、185μm、180μm、175μm、170μm、165μm、160μm、155μm、150μm、145μm、140μm、135μm、130μm、125μm、120μm、115μm、110μm、105μm、100μm、95μm、90μm、85μm、80μm、75μm、70μm、65μm、60μm、55μm、50μm、45μm、40μm、35μm、30μm、25μm、20μm、15μm、10μm和5μm(例如，约5μm至220μm、约45μm至250μm等)。As shown in FIG. 3K and FIG. 3L, in some examples, the bioactive substance release film 70 is spatially separated from at least one sensing domain 112 by a distance such that the bioactive substance release film 70 does not overlap with at least one sensing domain 112 or otherwise interfere with the diffusion path of one or more analytes or other substances associated with the generation of a measurable signal corresponding to the amount or presence of one or more analytes. In this way, the bioactive substance release film 70 does not interfere with the sensing ability of at least one sensing domain 112. In an example, the distance is about 1 μm or less to about 250 μm, including all ranges and sub-ranges therebetween. In another example, the distance is about 1 μm or less to about 50 μm. In another example, the distance is about 15 μm to about 200 μm. In another example, the distance is about 50 μm to about 100 μm. For example, the distance is from at least about any of the following: 1 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm, 60 μm, 65 μm, 70 μm, 75 μm, 80 μm, 85 μm, 90 μm, 95 μm, 100 μm, 105 μm, 110 μm, 115 μm, 120 μm, 125 um, 130 μm, 135 μm, 140 μm, 145 μm, 150 μm, 155 μm, 160 μm, 165 μm, 170 μm, 175 μm, 180 μm, 185 μm, 190 μm, 195 μm, 200 μm, 205 μm, 210 μm, 215 μm, 220 μm, 225 μm, 230 μm, 235 μm, 240 μm and 245 μm and/or up to about 2 50μm, 245μm, 240μm, 235μm, 230μm, 225μm, 220μm, 215μm, 210μm, 205μm, 200μm, 195μm, 190μm, 185μm, 180μm, 175μm, 170μm, 165μm, 160μm, 155μm, 150μm, 145μm, 140μm, 135μm, 130μm, 125μ m, 120μm, 115μm, 110μm, 105μm, 100μm, 95μm, 90μm, 85μm, 80μm, 75μm, 70μm, 65μm, 60μm, 55μm, 50μm, 45μm, 40μm, 35μm, 30μm, 25μm, 20μm, 15μm, 10μm and 5μm (for example, about 5μm to 220μm, about 45μm to 250μm, etc.).
在示例中，并且如图3K所展示的，生物活性物质释放膜70设置在可插入部分表面上(并且因此设置在可插入部分表面积上)并且不与至少一个感测域112接触。在一些示例中，生物活性物质释放膜70延伸直到可插入部分102的整个长度，但与至少一个感测域112接触的区域除外。在另一示例中，如图3L所展示的，生物活性物质释放膜70仅设置在可插入部分102的远侧端部109处(例如，可插入部分102不设置在至少一个感测域112、可插入部分102的近侧端部107、可插入部分102的剩余部分等上或与其接触)。如图3L进一步所示，可插入部分102具有远侧端部109，并且在如图所示的一个示例中，远侧端部109与至少一个感测域112空间分离。In an example, and as illustrated in FIG. 3K , the bioactive substance release film 70 is disposed on the surface of the insertable portion (and therefore disposed on the surface area of the insertable portion) and is not in contact with the at least one sensing domain 112. In some examples, the bioactive substance release film 70 extends up to the entire length of the insertable portion 102, except for the area in contact with the at least one sensing domain 112. In another example, as illustrated in FIG. 3L , the bioactive substance release film 70 is disposed only at the distal end 109 of the insertable portion 102 (e.g., the insertable portion 102 is not disposed on or in contact with the at least one sensing domain 112, the proximal end 107 of the insertable portion 102, the remaining portion of the insertable portion 102, etc.). As further shown in FIG. 3L , the insertable portion 102 has a distal end 109, and in one example as shown, the distal end 109 is spatially separated from the at least one sensing domain 112.
还如图3K所示，在一个示例中，可插入部分102是不连续的或分段的，例如跨越感测域112。在另一示例中，并且还如图3L所展示的，可插入部分102是连续的。如本领域普通技术人员所理解的，可连续地和/或不连续地使用适合于涂覆可插入部分的任何形状(例如，可插入部分涂层可以是连续的、不连续的或半连续的)。示例性涂层形状包括但不限于一个或多个圆柱形、圆形、椭圆形、正方形、矩形、三角形、菱形、泪珠形、螺旋形、盘旋形、叶形(例如，三叶草形、花形、蝴蝶形、心形等)等。As also shown in FIG. 3K , in one example, the insertable portion 102 is discontinuous or segmented, such as spanning the sensing domain 112. In another example, and as also shown in FIG. 3L , the insertable portion 102 is continuous. As will be appreciated by one of ordinary skill in the art, any shape suitable for coating the insertable portion may be used continuously and/or discontinuously (e.g., the insertable portion coating may be continuous, discontinuous, or semi-continuous). Exemplary coating shapes include, but are not limited to, one or more cylindrical, circular, oval, square, rectangular, triangular, diamond, teardrop, spiral, spiral, leaf (e.g., clover, flower, butterfly, heart, etc.), etc.
可插入部分102具有可插入表面积和/或可插入体积，并且生物活性物质释放膜70具有表面积和/或体积。在一个示例中，生物活性物质释放膜70表面积小于或等于可插入表面积。在另外的示例中，生物活性物质释放膜70体积与可插入体积相同或不同(例如，小于或等于可插入体积)。The insertable portion 102 has an insertable surface area and/or an insertable volume, and the bioactive substance releasing membrane 70 has a surface area and/or a volume. In one example, the surface area of the bioactive substance releasing membrane 70 is less than or equal to the insertable surface area. In another example, the volume of the bioactive substance releasing membrane 70 is the same as or different from the insertable volume (e.g., less than or equal to the insertable volume).
参考图3M、图3N和图3O，呈现了类似于图3K、图3L所描绘的那些传感器的传感器，这些传感器示出了生物活性物质释放膜70靠近传感器衬底的远侧顶端，而没有覆盖感测域112的感测膜32(例如，包括电极、干扰、抵抗、生物界面膜/域)的关系。图3M示出了围绕远侧顶端，而没有覆盖导线或平面或基本上平面的衬底的切单部29的生物活性物质释放膜70。图3N示出了生物活性物质释放膜70覆盖直接邻近切单部29的端帽40的另选构造。图3O描绘了另一种配置，其中端帽40直接邻近切单部29并且生物活性物质释放膜70围绕可插入部分102的远侧顶端定位而不覆盖端帽40。Referring to FIGS. 3M, 3N, and 3O, sensors similar to those depicted in FIGS. 3K, 3L are presented that illustrate the relationship of a bioactive substance release membrane 70 proximate the distal tip of the sensor substrate without covering the sensing membrane 32 (e.g., including electrodes, interference, resistance, biointerface membrane/domain) of the sensing domain 112. FIG. 3M illustrates a bioactive substance release membrane 70 surrounding the distal tip without covering the singulation portion 29 of the wire or planar or substantially planar substrate. FIG. 3N illustrates an alternative configuration in which the bioactive substance release membrane 70 covers the end cap 40 directly adjacent to the singulation portion 29. FIG. 3O depicts another configuration in which the end cap 40 is directly adjacent to the singulation portion 29 and the bioactive substance release membrane 70 is positioned around the distal tip of the insertable portion 102 without covering the end cap 40.
参考图3P和图3Q，具有位于远侧顶端处的生物活性物质释放膜70的传感器(例如，“顶端涂覆的”生物活性物质释放膜传感器)的生物活性物质释放提供了生物活性物质释放曲线以及在长期使用(例如，14天、21天、30天或更长时间)期间在灵敏度保持和噪声降低方面与本文所述的其他本发明所公开的构建体等效的改善。除了其他优点之外，具有顶端涂覆的具有生物活性物质的生物活性物质释放膜的传感器还提供了易于制造、所需总生物活性物质减少以及在创伤点处靶向递送生物活性物质的优点，例如，在初始插入部位处插入传感器时基本上立即呈现生物活性物质、将API递送到最接近需要的位置(即感测区域)、进一步物理保护免于顶端破坏和/或将API递送到最接近由针尖与传感器顶端之间的空间产生的伤口体积。顶端涂层的自然表面张力形成圆形表面，从而保护组织免受穿刺损伤，并且整体弯曲的几何形状据信有助于生物相容性。可将顶端涂覆的生物活性物质释放膜添加到传感器中，而不会极大地改变整个传感器的机械性质。制造具有顶端涂覆的生物活性物质释放膜的传感器可通过浸涂完成，这可以是快速并廉价的制造步骤。传感器的可插入部分102的组织学照片的示例在图8A和图8B中示出，其中在图8A中，染色组织成像的切片机切片描绘了在传感器的可插入部分102在延长的持续时间后已经导致免疫系统的异物反应之后的受者组织的皮下切片。脂肪组织150和纤维组织152与纤维化包封154和可能的细胞入口156一起被描绘。相比之下，图8B描绘了传感器的可插入部分102的染色组织成像的切片机切片，该可插入部分在受者组织中插入了延长持续时间，该可插入部分具有本公开的生物活性物质的生物活性物质释放层。脂肪组织150和纤维组织152被描绘为没有类似的可观察到的纤维化包封或细胞入口的迹象。Referring to FIG. 3P and FIG. 3Q , the bioactive substance release of the sensor having a bioactive substance release membrane 70 located at the distal tip (e.g., a "tip-coated" bioactive substance release membrane sensor) provides a bioactive substance release profile and an improvement in sensitivity retention and noise reduction during long-term use (e.g., 14 days, 21 days, 30 days or more) equivalent to other constructs disclosed herein. In addition to other advantages, the sensor having a tip-coated bioactive substance release membrane with a bioactive substance also provides the advantages of ease of manufacture, reduction in total bioactive substances required, and targeted delivery of bioactive substances at the wound site, for example, substantially immediate presentation of the bioactive substance upon insertion of the sensor at the initial insertion site, delivery of the API to the closest location to the need (i.e., the sensing area), further physical protection from tip damage, and/or delivery of the API to the closest wound volume created by the space between the needle tip and the sensor tip. The natural surface tension of the tip coating forms a rounded surface, thereby protecting the tissue from puncture damage, and the overall curved geometry is believed to contribute to biocompatibility. The bioactive substance release film of top coating can be added to the sensor without greatly changing the mechanical properties of the whole sensor. The sensor with the bioactive substance release film of top coating can be completed by dip coating, which can be a fast and cheap manufacturing step. The example of the histological photo of the insertable part 102 of the sensor is shown in Figure 8A and Figure 8B, wherein in Figure 8A, the slicer section of the dyed tissue imaging depicts the subcutaneous slice of the recipient tissue after the insertable part 102 of the sensor has caused the foreign body reaction of the immune system after the extended duration. Fatty tissue 150 and fibrous tissue 152 are depicted together with fibrotic encapsulation 154 and possible cell entrance 156. In contrast, Figure 8B depicts the slicer section of the dyed tissue imaging of the insertable part 102 of the sensor, which has been inserted into the recipient tissue for an extended duration, and the insertable part has a bioactive substance release layer of the bioactive substance of the present disclosure. Fatty tissue 150 and fibrous tissue 152 are depicted as having no similar observable signs of fibrotic encapsulation or cell entrance.
虽然不希望受理论所束缚，但据信由于传感器插入，位于传感器末端处的组织遭受最大程度的组织创伤。通过在传感器的顶端处提供生物活性剂，靠近传感器顶端的组织中的异物反应减少，因为生物活性剂的局部浓度在该周围环境中是最大的。这也允许在生物活性物质释放膜70内使用较少的生物活性剂。如果生物活性物质释放膜被放置在顶端附近，则由于生物活性剂通过组织的转运而发生的任何时间延迟被最小化。而且，通过用生物活性物质释放膜70涂覆传感器的顶端，与将大量生物活性剂放置在传感器顶端附近相比，减小了传感器和生物活性剂的总体插入深度。传感器顶端附近的大量生物活性剂可能在插入前或插入后不经意地与传感器顶端分离，导致治疗效果的损失。在一个示例中，具有生物活性物质的生物活性物质释放膜70直接接触并涂覆存在于传感器设备的可插入顶端部分的外表面上的感测膜。在一个示例中，具有生物活性剂的生物活性物质释放膜70仅存在于可插入部分的传感器的外表面上。外表面可包括先前公开的电极域、干扰膜、抵抗膜和酶膜中的任一者和全部，并且具有生物活性剂的生物活性物质释放膜70可比这些域或膜中的任一者更远离电极表面。在一个示例中，具有生物活性剂的生物活性物质释放膜70比电极域、干扰膜、抵抗膜和酶膜离电极表面最远。在一个示例中，扩散调节膜73更远离具有生物活性剂的扩散生物活性物质释放膜70。在一个示例中，具有生物活性剂的生物活性物质释放膜70仅存在于直接邻近可插入部分102的远侧端部109的可插入部分的传感器(例如，顶端涂覆的传感器，如图2E、图3H至图3O所示)的外表面上。Although not wishing to be bound by theory, it is believed that due to the insertion of the sensor, the tissue at the end of the sensor suffers the greatest degree of tissue trauma. By providing a bioactive agent at the top of the sensor, the foreign body reaction in the tissue near the top of the sensor is reduced, because the local concentration of the bioactive agent is the largest in this surrounding environment. This also allows the use of less bioactive agents in the bioactive substance release film 70. If the bioactive substance release film is placed near the top, any time delay that occurs due to the transport of the bioactive agent through the tissue is minimized. Moreover, by coating the top of the sensor with the bioactive substance release film 70, compared with placing a large amount of bioactive agents near the top of the sensor, the overall insertion depth of the sensor and the bioactive agent is reduced. A large amount of bioactive agents near the top of the sensor may be inadvertently separated from the top of the sensor before or after insertion, resulting in the loss of therapeutic effect. In one example, the bioactive substance release film 70 with bioactive substances directly contacts and is coated with a sensing film on the outer surface of the insertable top part of the sensor device. In one example, the bioactive substance release film 70 with bioactive agents is only present on the outer surface of the sensor of the insertable part. The outer surface may include any one or all of the previously disclosed electrode domains, interference membranes, resistance membranes, and enzyme membranes, and the bioactive substance release membrane 70 with a bioactive agent may be further away from the electrode surface than any of these domains or membranes. In one example, the bioactive substance release membrane 70 with a bioactive agent is farthest from the electrode surface than the electrode domain, interference membrane, resistance membrane, and enzyme membrane. In one example, the diffusion regulating membrane 73 is further away from the diffusion bioactive substance release membrane 70 with a bioactive agent. In one example, the bioactive substance release membrane 70 with a bioactive agent is present only on the outer surface of the sensor of the insertable portion (e.g., a sensor coated at the top, as shown in Figures 2E, 3H to 3O) directly adjacent to the distal end 109 of the insertable portion 102.
在示例中，可插入表面积为约2mm2至约200mm2，包括其间的所有范围和子范围。在另一示例中，可插入表面积为约5mm2至约150mm2。在另外的示例中，可插入表面积为约25mm2至约100mm2。例如，可插入表面积为从至少约以下各项中的任一者开始：2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32、34、36、38、40、42、44、46、48、50、52、54、56、58、60、62、64、66、68、70、72、74、76、78、80、82、84、86、88、90、92、94、96、98、100、102、104、106、108、110、112、114、116、118、120、122、124、126、128、130、132、134、136、138、140、142、144、146、148、150、152、154、156、158、160、162、164、166、168、170、172、174、176、178、180、182、184、186、188、190、192、194、196和198mm2和/或至多约200、198、196、194、192、190、188、186、184、182、180、178、176、174、172、170、168、166、164、162、160、158、156、154、152、150、148、146、144、142、140、138、136、134、132、130、128、126、124、122、120、118、116、114、112、110、108、106、104、102、100、98、96、94、92、90、88、86、84、82、80、78、76、74、72、70、68、66、64、62、60、58、56、54、52、50、48、46、44、42、40、38、36、34、32、30、28、26、24、22、20、18、16、14、12、10、8、6和4mm2(例如，约30mm2至172mm2、约2mm2至198mm2等)。In an example, the insertable surface area is about 2 mm2 to about 200 mm2 , including all ranges and subranges therebetween. In another example, the insertable surface area is about 5 mm2 to about 150 mm2 . In an additional example, the insertable surface area is about 25 mm2 to about 100 mm2 . For example, the insertable surface area is from at least about any of the following: 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 122, 124, 126, 128, 130, 132, 134, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196 and 198 mm2 and/or up to about 200, 198, 196, 194, 192, 190, 188, 186, 184, 182, 180, 178, 176, 174, 172, 170, 168, 166, 164, 162, 160, 158, 156, 154, 152, 150, 148, 146, 144, 142, 140, 138, 136, 134, 132, 130, 128, 126, 124, 122, 120, 118, 1 6, 14, 12, 10, 8,6 , and 4 mm2 (e.g., about30 to 172mm2 , about2 to 198mm2 , etc.).
在示例中，可插入体积为约5mm3至约500mm3，包括其间的所有范围和子范围。在另一示例中，可插入体积为约10mm3至约250mm3。在另外的示例中，可插入体积为约25mm3至约150mm3。例如，可插入体积为从至少约以下各项中的任一者开始：5、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、145、150、155、160、165、170、175、180、185、190、195、200、205、210、215、220、225、230、235、240、245、250、255、260、265、270、275、280、285、290、295、300、305、310、315、320、325、330、335、340、345、350、355、360、365、370、375、380、385、390、395、400、405、410、415、420、425、430、435、440、445、450、455、460、465、470、475、480、485、490和495mm3和/或至多约500、495、490、485、480、475、470、465、460、455、450、445、440、435、430、425、420、415、410、405、400、395、390、385、380、375、370、365、360、355、350、345、340、335、330、325、320、315、310、305、300、295、290、285、280、275、270、265、260、255、250、245、240、235、230、225、220、215、210、205、200、195、190、185、180、175、170、165、160、155、150、145、140、135、130、125、120、115、110、105、100、95、90、85、80、75、70、65、60、55、50、45、40、35、30、25、20、15和10mm3(例如，约20mm3至420mm3、约10mm3至500mm3等)。上述范围假设最大可插入部分涂层厚度为约5mm。In an example, the insertable volume is about 5 mm3 to about 500 mm3 , including all ranges and subranges therebetween. In another example, the insertable volume is about 10 mm3 to about 250 mm3 . In yet another example, the insertable volume is about 25 mm3 to about 150 mm3 . For example, the insertable volume is from at least about any of the following: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, 400, 405, 410, 415, 420, 425, 430, 435, 440, 445, 450, 455, 460, 465, 470, 475, 480, 485, 490 and 495 mm3 and/or up to about 500, 495, 490, 485, 480, 475, 470, 465, 460, 455, 450, 445, 440, 435, 430, 425, 420, 415, 410, 405, 400, 395, 390, 385, 380, 375, 370, 365, 360, 355, 350, 345, 340, 335, 330, 325, 320, 315, 310, 305, 300, 295, 290, 285, 280, 275, 2853 to 420 mm3 , about 10 mm3 to 500 mm3, etc. The above ranges assume a maximum insertable portion coating thickness of about 5 mm.
在示例中，聚合物层表面积与可插入表面积的比率为约0.1至约1，包括其间的所有范围和子范围。在另一示例中，聚合物层表面积与可插入表面积的比率为约0.2至约0.8。在另外的示例中，聚合物层表面积与可插入表面积的比率为约0.3至约0.7。例如，聚合物层表面积与可插入表面积的比率为从至少约以下各项中的任一者开始：0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8和0.9和/或至多约1、0.9、0.8、0.7、0.6、0.5、0.4、0.3和0.2(例如，约0.2至0.9、约0.5至0.8等)。上述范围假设传感器的有效面积为可插入部分的至少10％。In an example, the ratio of the polymer layer surface area to the insertable surface area is about 0.1 to about 1, including all ranges and sub-ranges therebetween. In another example, the ratio of the polymer layer surface area to the insertable surface area is about 0.2 to about 0.8. In another example, the ratio of the polymer layer surface area to the insertable surface area is about 0.3 to about 0.7. For example, the ratio of the polymer layer surface area to the insertable surface area is from at least about any one of the following: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 and 0.9 and/or at most about 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 and 0.2 (e.g., about 0.2 to 0.9, about 0.5 to 0.8, etc.). The above ranges assume that the effective area of the sensor is at least 10% of the insertable portion.
在示例中，生物活性物质释放膜70的聚合物层体积与可插入体积的比率为约1:100至约20:100(即1:5)，包括其间的所有范围和子范围。在另一示例中，生物活性物质释放膜70的聚合物层体积与可插入体积的比率为约1:50至约15:75(即1:5)。在另外的示例中，聚合物层体积与可插入体积的比率为约5:50(即1:10)至约10:80(即1:8)。例如，聚合物层体积与可插入体积的比率为从至少约以下各项中的任一者开始：1:100、2:100(即1:50)、3:100、4:100(即1:25)、5:100(即1:20)、6:100(即3:50)、7:100、8:100(即2:25)、9:100、10:100(即1:10)、11:100、12:100(即3:25)、13:100、14:100(即7:50)、15:100(即3:20)、16:100(即4:25)、17:100、18:100(即9:50)和19:100和/或至多约20:100(即1:5)、19:100、18:100(即9:50)、17:100、16:100(即4:25)、15:100(即3:20)、14:100(即7:50)、13:100、12:100(即3:25)、11:100、10:100(即1:10)、9:100、8:100(即2:25)、7:100、6:100(即3:50)、5:100(即1:20)、4:100(即1:25)、3:100和2:100(即1:50)(例如，约7:100至19:100、约3:100至17:100等)。In an example, the ratio of the polymer layer volume to the insertable volume of the bioactive substance release membrane 70 is about 1:100 to about 20:100 (i.e., 1:5), including all ranges and sub-ranges therebetween. In another example, the ratio of the polymer layer volume to the insertable volume of the bioactive substance release membrane 70 is about 1:50 to about 15:75 (i.e., 1:5). In another example, the ratio of the polymer layer volume to the insertable volume is about 5:50 (i.e., 1:10) to about 10:80 (i.e., 1:8). For example, the ratio of the polymer layer volume to the insertable volume is from at least about any of 1:100, 2:100 (i.e., 1:50), 3:100, 4:100 (i.e., 1:25), 5:100 (i.e., 1:20), 6:100 (i.e., 3:50), 7:100, 8:100 (i.e., 2:25), 9:100, 10:100 (i.e., 1:10), 11:100, 12:100 (i.e., 3:25), 13:100, 14:100 (i.e., 7:50), 15:100 (i.e., 3:20), 16:100 (i.e., 4:25), 17:100, 18:100 (i.e., 9:50), and 19:100 and/or at most about 1:50) (e.g., about 7:100 to 19:100, about 3:100 to 17:100, etc.).
提供连续分析物感测设备，并将包括至少一种聚合物和至少一种生物活性剂的可插入部分涂层组合物应用于可插入部分以提供本文所述的可插入部分涂层，从而形成上述连续分析物感测设备。在示例中，应用于可插入部分的可插入部分涂层组合物具有约10cP至约350cP的粘度，具有或不具有生物活性负载。在另一示例中，应用于可插入部分的可插入部分涂层组合物具有约20cP至约200cP的粘度，具有或不具有生物活性负载。在再一示例中，应用于可插入部分的可插入部分涂层组合物具有约30cP至约300cP的粘度，具有或不具有生物活性负载。A continuous analyte sensing device is provided, and an insertable portion coating composition including at least one polymer and at least one bioactive agent is applied to the insertable portion to provide the insertable portion coating as described herein, thereby forming the above-mentioned continuous analyte sensing device. In an example, the insertable portion coating composition applied to the insertable portion has a viscosity of about 10cP to about 350cP, with or without a bioactive load. In another example, the insertable portion coating composition applied to the insertable portion has a viscosity of about 20cP to about 200cP, with or without a bioactive load. In yet another example, the insertable portion coating composition applied to the insertable portion has a viscosity of about 30cP to about 300cP, with or without a bioactive load.
如本文先前所讨论的，在示例中，动态接触角，即在生物界面/生物活性物质释放膜70的表面的润湿(前进角)或去润湿(后退角)过程中出现的接触角具有约105°至约130°或110°至约120°的前进接触角。在又一示例中，动态接触角，即在生物界面/生物活性物质释放膜的表面的润湿(前进角)或去润湿(后退角)过程中出现的接触角具有约40°至约80°的后退接触角。在另一示例中，动态接触角，即在生物界面/生物活性物质释放膜70的表面的润湿(前进角)或去润湿(后退角)过程中出现的接触角具有约45°至约75°的后退接触角。在又一示例中，动态接触角，即在生物界面/生物活性物质释放膜70的表面的润湿(前进角)或去润湿(后退角)过程中出现的接触角具有约50°至约70°的后退接触角。在一些示例中，放置在分析物传感器上之后和灭菌之后在生物活性物质释放膜70上的动态接触角测量和表面粗糙度可使用Sigma 701力张力计并且执行前进接触角测量、后退接触角测量、滞后测量以及它们的组合中的一者或多者来进行。As previously discussed herein, in an example, the dynamic contact angle, i.e., the contact angle occurring during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface/bioactive substance release film 70, has an advancing contact angle of about 105° to about 130° or 110° to about 120°. In another example, the dynamic contact angle, i.e., the contact angle occurring during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface/bioactive substance release film, has a receding contact angle of about 40° to about 80°. In another example, the dynamic contact angle, i.e., the contact angle occurring during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface/bioactive substance release film 70, has a receding contact angle of about 45° to about 75°. In yet another example, the dynamic contact angle, i.e., the contact angle occurring during wetting (advancing angle) or dewetting (receding angle) of the surface of the biological interface/bioactive substance release film 70, has a receding contact angle of about 50° to about 70°. In some examples, dynamic contact angle measurements and surface roughness on the bioactive release membrane 70 after placement on the analyte sensor and after sterilization can be performed using a Sigma 701 force tensiometer and performing one or more of advancing contact angle measurements, receding contact angle measurements, hysteresis measurements, and combinations thereof.
此外，在示例中，所得生物活性物质释放膜70具有约20μm至约40μm的膜厚，包括其间的所有范围和子范围。在某些示例中，生物活性物质释放膜70的可插入部分涂层的厚度可为约0.1μm、约0.5μm、约1μm、约2μm、约4μm、约6μm、约8μm或更小至约10μm、约15μm、约20μm、约30μm、约40μm、约50μm、约75μm、约100μm、约125μm、约150μm、约175μm、约200μm或约250μm或更大。在这些示例中的一些示例中，可插入部分涂层的厚度有时可为约1μm至约5μm，并且有时可为约2μm至约7μm。在其他示例中，该可插入部分涂层可为约20μm或约25μm至约50μm、约55μm或约60μm厚。In addition, in the example, the resulting bioactive substance release film 70 has a film thickness of about 20 μm to about 40 μm, including all ranges and sub-ranges therebetween. In some examples, the thickness of the insertable portion coating of the bioactive substance release film 70 may be about 0.1 μm, about 0.5 μm, about 1 μm, about 2 μm, about 4 μm, about 6 μm, about 8 μm or less to about 10 μm, about 15 μm, about 20 μm, about 30 μm, about 40 μm, about 50 μm, about 75 μm, about 100 μm, about 125 μm, about 150 μm, about 175 μm, about 200 μm or about 250 μm or more. In some of these examples, the thickness of the insertable portion coating may sometimes be about 1 μm to about 5 μm, and sometimes may be about 2 μm to about 7 μm. In other examples, the insertable portion coating may be about 20 μm or about 25 μm to about 50 μm, about 55 μm, or about 60 μm thick.
在另一示例中，所得生物活性物质释放膜70的可插入部分涂层具有约1mm至约20mm的长度，包括其间的所有范围和子范围。在另一示例中，可插入部分涂层具有约2mm至约14mm的长度。在另外的示例中，可插入部分涂层具有约4mm至约12mm的长度。例如，可插入部分涂层具有至少约以下各项中的任一者的长度：1mm、2mm、3mm、4mm、5mm、6mm、7mm、8mm、9mm、10mm、11mm、12mm、13mm、14mm、15mm、16mm、17mm、18mm和19mm和/或至多约20mm、19mm、18mm、17mm、16mm、15mm、4mm、13mm、12mm、11mm、10mm、9mm、8mm、7mm、6mm、5mm、4mm、3mm和2mm(例如，约1mm至15mm、约5mm至18mm等)。In another example, the insertable part coating of gained bioactive substance release film 70 has a length of about 1mm to about 20mm, including all ranges and sub-ranges therebetween. In another example, the insertable part coating has a length of about 2mm to about 14mm. In other examples, the insertable part coating has a length of about 4mm to about 12mm. For example, the insertable part coating has a length of at least about any one of the following: 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm, 18mm and 19mm and/or at most about 20mm, 19mm, 18mm, 17mm, 16mm, 15mm, 4mm, 13mm, 12mm, 11mm, 10mm, 9mm, 8mm, 7mm, 6mm, 5mm, 4mm, 3mm and 2mm (for example, about 1mm to 15mm, about 5mm to 18mm etc.).
使用喷涂、移印、喷注涂覆、泡膜涂覆、液滴涂覆、浸洗、倒置浸洗或它们的任何组合中的至少一者来应用生物活性物质释放膜70。例如，当与洗涤组合使用浸涂时，所得可插入部分和可插入部分涂层的横截面包括具有限定的边缘或边界的多个同心圆，如图2C、图3I和图3J所展示的。相比之下，当所得器件未被浸渍时，横截面不包括明显的、限定的边缘或边界，而是在各层之间显示出逐渐的过渡。The bioactive material release membrane 70 is applied using at least one of spraying, pad printing, jet coating, bubble film coating, drop coating, dipping, inverted dipping, or any combination thereof. For example, when dipping is used in combination with washing, the cross-section of the resulting insertable portion and insertable portion coating includes multiple concentric circles with defined edges or boundaries, as shown in Figures 2C, 3I, and 3J. In contrast, when the resulting device is not dipped, the cross-section does not include a clear, defined edge or boundary, but rather shows a gradual transition between the layers.
生物活性物质释放膜70提供治疗益处，包括降低或延迟受试者在可插入部分所插入的组织中的免疫应答(例如，局部组织反应)。The bioactive substance releasing membrane 70 provides therapeutic benefits including reducing or delaying an immune response (eg, a local tissue reaction) in a subject's tissue into which the insertable portion is inserted.
类似地，降低或延迟免疫应答提高了本文所公开的连续分析物感测设备的灵敏度。例如，如图6B至图6E所示，与负载生物活性物质的传感器相比，对照传感器表现出显著更大的灵敏度下降，并且本文所述的在可插入部分的远侧端部上包括可插入部分涂层的连续分析物感测设备的传感器表现出灵敏度下降的最晚发生。实际上，在图6D所展示的测试结果中，在插入后15天，对照传感器具有53％的灵敏度存活率，负载生物活性物质的传感器具有78％的灵敏度存活率，并且仅在可插入部分的远侧端部上包括可插入部分涂层的负载生物活性物质的传感器具有94％的灵敏度存活率。Similarly, reducing or delaying the immune response improves the sensitivity of the continuous analyte sensing device disclosed herein. For example, as shown in Figures 6B to 6E, the control sensor exhibits a significantly greater sensitivity drop compared to the sensor loaded with the bioactive substance, and the sensor of the continuous analyte sensing device described herein including the insertable portion coating on the distal end of the insertable portion exhibits the latest occurrence of sensitivity drop. In fact, in the test results shown in Figure 6D, 15 days after insertion, the control sensor had a sensitivity survival rate of 53%, the sensor loaded with the bioactive substance had a sensitivity survival rate of 78%, and the sensor loaded with the bioactive substance including the insertable portion coating only on the distal end of the insertable portion had a sensitivity survival rate of 94%.
用于降低或延迟免疫应答的方法包括：(i)提供上述连续分析物感测设备100，该设备被配置为部署可插入部分102；(ii)在部署可插入部分102时，在受试者体内引起组织插入体积的形成(例如，发展或产生)；(iii)将至少一种生物活性剂110从生物活性物质释放膜70释放到组织插入体积中；以及(iv)响应于(iii)释放至少一种生物活性剂，降低或延迟关于组织插入体积的免疫应答。如本文先前所讨论的，组织插入体积包括皮下或皮内脂肪或肌肉组织，并且组织插入体积的组成基于插入部位而变化。在示例中，组织插入体积大于或等于可插入体积。在另外的示例中，至少一种生物活性剂110以每天约0.1μg至约5μg的平均释放速率(包括其间的所有范围和子范围)从生物活性物质释放膜70释放。The method for reducing or delaying an immune response includes: (i) providing the above-mentioned continuous analyte sensing device 100, which is configured to deploy an insertable portion 102; (ii) when deploying the insertable portion 102, causing the formation of a tissue insertion volume in the subject (e.g., development or generation); (iii) releasing at least one bioactive agent 110 from the bioactive substance release membrane 70 into the tissue insertion volume; and (iv) in response to (iii) releasing at least one bioactive agent, reducing or delaying an immune response about the tissue insertion volume. As previously discussed herein, the tissue insertion volume includes subcutaneous or intracutaneous fat or muscle tissue, and the composition of the tissue insertion volume varies based on the insertion site. In an example, the tissue insertion volume is greater than or equal to the insertable volume. In another example, at least one bioactive agent 110 is released from the bioactive substance release membrane 70 at an average release rate of about 0.1 μg to about 5 μg per day (including all ranges and subranges therebetween).
作为本文所述的方法的结果，在示例中，免疫应答被降低或延迟至少7天。在另一示例中，免疫应答被降低或延迟至少10天。在另外的示例中，免疫应答被降低或延迟至少14天。在又一示例中，免疫应答被降低或延迟至少21天。因此，本文所述的方法降低免疫应答至少7天、8天、9天、10天、11天、12天、13天、14天、15天或21天(甚至更长时间)。因此，本文所公开的连续分析物感测设备能够在插入后释放生物活性物质至少15天。As a result of the methods described herein, in an example, the immune response is reduced or delayed for at least 7 days. In another example, the immune response is reduced or delayed for at least 10 days. In another example, the immune response is reduced or delayed for at least 14 days. In yet another example, the immune response is reduced or delayed for at least 21 days. Thus, the methods described herein reduce the immune response for at least 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, or 21 days (or even longer). Thus, the continuous analyte sensing device disclosed herein is capable of releasing bioactive substances for at least 15 days after insertion.
本文中引用的所有参考文献(包括但不限于已公布和未公布的申请、专利和文献引用)全文以引用方式并入本文，并据此作为本说明书的一部分。就以引用方式并入的出版物和专利或专利申请与说明书中包含的公开内容相矛盾而言，说明书旨在取代和/或优先于任何此类矛盾的材料。All references cited herein (including but not limited to published and unpublished applications, patents, and literature citations) are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent that publications and patents or patent applications incorporated by reference conflict with the disclosure contained in the specification, the specification is intended to supersede and/or take precedence over any such conflicting material.
本说明书中使用的表示成分、反应条件等的量的所有数字应被理解为在所有情况下均由术语“约”修饰。因此，除非有相反的指示，否则本文所述的数值参数是近似值，其可根据寻求获得的所需性质而变化。在要求本申请优先权的任何申请中，每个数值参数都应当根据有效数字的数量和普通的四舍五入方法来解释，而不是试图将等同原则的应用限制于任何权利要求的范围。All numerals used in this specification that represent the amount of ingredients, reaction conditions, etc. should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise indicated, the numerical parameters described herein are approximate values that can vary depending on the desired properties sought to be obtained. In any application claiming priority to this application, each numerical parameter should be interpreted based on the number of significant digits and ordinary rounding methods, rather than attempting to limit the application of the doctrine of equivalents to the scope of any claim.
以上描述公开了本公开的若干方法和材料。本公开容易进行方法和材料的修改以及制造方法和装备的改变。通过考虑本公开或本文所公开的本公开内容的实践，此类修改对于本领域技术人员而言将变得显而易见。因此，本公开并非旨在限于本文所公开的具体示例，而是覆盖落入本公开的真实范围和精神内的所有修改和替代方案。The above description discloses several methods and materials of the present disclosure. The present disclosure is susceptible to modification of methods and materials and changes in manufacturing methods and equipment. Such modifications will become apparent to those skilled in the art by considering the practice of the present disclosure or the disclosure disclosed herein. Therefore, the present disclosure is not intended to be limited to the specific examples disclosed herein, but to cover all modifications and alternatives falling within the true scope and spirit of the present disclosure.
虽然已参考元件的特定组合说明了本公开的某些示例，但也可以提供各种其他组合而不脱离本公开的教导。因此，本公开不应被解释为限于本文所描述和附图中所展示的特定示例性示例，而是还可涵盖各种所展示的示例及其方面的元件的组合。Although certain examples of the present disclosure have been described with reference to specific combinations of elements, various other combinations may also be provided without departing from the teachings of the present disclosure. Therefore, the present disclosure should not be interpreted as being limited to the specific illustrative examples described herein and shown in the drawings, but may also cover combinations of elements of the various shown examples and aspects thereof.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US63/244,644 | 2021-09-15 | ||
| US202263318901P | 2022-03-11 | 2022-03-11 | |
| US63/318,901 | 2022-03-11 | ||
| PCT/US2022/043641WO2023043908A1 (en) | 2021-09-15 | 2022-09-15 | Bioactive releasing membrane for analyte sensor |
| Publication Number | Publication Date |
|---|---|
| CN118019491Atrue CN118019491A (en) | 2024-05-10 |
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202280061687.2APendingCN118019491A (en) | 2021-09-15 | 2022-09-15 | Bioactive substance releasing membrane for analyte sensor |
| Country | Link |
|---|---|
| CN (1) | CN118019491A (en) |
| Publication | Publication Date | Title |
|---|---|---|
| AU2023206215B2 (en) | Zwitterion surface modifications for continuous sensors | |
| US12360074B2 (en) | Enzyme immobilized adhesive layer for analyte sensors | |
| US20200359949A1 (en) | Analyte sensor | |
| US20220296867A1 (en) | Drug releasing membrane for analyte sensor | |
| WO2007120381A2 (en) | Analyte sensor | |
| US20230073214A1 (en) | Bioactive releasing membrane for analyte sensor | |
| JP2024534447A (en) | Bioactive releasing membranes for analyte sensors. | |
| CN118019491A (en) | Bioactive substance releasing membrane for analyte sensor | |
| CN117597066A (en) | Drug release film for analyte sensor | |
| US20240108258A1 (en) | Analyte sensor | |
| US20250221642A1 (en) | Polymers with dual functionality |
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |