技术领域Technical Field
本发明属于医疗器械技术领域。更具体地，涉及一种基于微针阵列的负压式快速提取储存组织液的装置。The present invention belongs to the technical field of medical devices, and more specifically, relates to a negative pressure device for quickly extracting and storing tissue fluid based on a microneedle array.
背景技术Background technique
皮肤作为人体中面积最大的器官，由表皮、真皮和皮下组织构成。其中，表皮层从内到外又可以细分为基底层、棘层、颗粒层、透明层和角质层。在角质层下方含有大量的组织液(ISF)。ISF由血液经过毛细血管过滤而来，成分和血浆类似，含有多种源自皮肤细胞和皮下毛细血管的生物标志物，如葡萄糖、乳酸、盐类和蛋白质等。ISF的组成成分以及其生化特性会因不同器官或细胞功能周期、炎症的产生、疾病发展进程等因素变化，可作为人体健康检测的良好样本，可用于人体健康监测、疾病诊断及预后判断。另外，目前采集血液样本惯用的静脉采血法或指尖采血法均会对患者带来疼痛感、创口以及感染风险。ISF位于皮肤下方数百微米的深度，仅有少量毛细血管末梢和真皮神经末梢，因此，在这种深度下对ISF进行采集的过程中承受的痛感较低，甚至可以做到无痛采样。因此，提取组织液可以作为传统采血的替代方法，具有重要医学应用价值。为了满足ISF的高效提取以进行其在生物医学领域的应用，需要一种对于ISF的高效提取方法。As the largest organ in the human body, the skin consists of the epidermis, dermis and subcutaneous tissue. Among them, the epidermis can be subdivided into the basal layer, spinous layer, granular layer, clear layer and stratum corneum from the inside to the outside. There is a large amount of interstitial fluid (ISF) below the stratum corneum. ISF is filtered from blood through capillaries. Its composition is similar to that of plasma and contains a variety of biomarkers derived from skin cells and subcutaneous capillaries, such as glucose, lactic acid, salts and proteins. The composition and biochemical properties of ISF will change due to factors such as different organ or cell function cycles, the occurrence of inflammation, and the progression of disease. It can be used as a good sample for human health testing and can be used for human health monitoring, disease diagnosis and prognosis. In addition, the current venous blood collection method or fingertip blood collection method used for collecting blood samples will cause pain, wounds and infection risks to patients. ISF is located at a depth of hundreds of microns below the skin, with only a small number of capillary endings and dermal nerve endings. Therefore, the pain in the process of collecting ISF at this depth is low, and even painless sampling can be achieved. Therefore, extracting tissue fluid can be used as an alternative to traditional blood collection and has important medical application value. In order to meet the requirements of efficient extraction of ISF for its application in the biomedical field, an efficient extraction method for ISF is needed.
微针阵列是数十至数百根针尖直径在1-300μm，针基底宽度在50-1500μm的针组成的阵列，利用微针向皮肤穿刺可以避免刺激真皮神经末梢，实现安全、无痛取样和药物递送。目前的ISF微针提取装置一般是借助空心微针孔道的毛细作用，通过毛细管引流来进行采样；或利用水凝胶微针的溶胀吸附作用来实现ISF采样。如现有技术《组织液提取装置》提供了一种组织液提取装置，该装置依靠微针的毛细作用来采取组织液，这种方式存在着采样速度慢、提取量低、力学性能较差、样品易污染等缺点，难以实现对ISF的快速、大量的采集和洁净的储存。The microneedle array is an array of dozens to hundreds of needles with a tip diameter of 1-300μm and a needle base width of 50-1500μm. Using microneedles to puncture the skin can avoid stimulating the dermal nerve endings, achieving safe and painless sampling and drug delivery. The current ISF microneedle extraction device generally uses the capillary action of the hollow microneedle channel to sample through capillary drainage; or uses the swelling and adsorption effect of hydrogel microneedles to achieve ISF sampling. For example, the prior art "Tissue Fluid Extraction Device" provides a tissue fluid extraction device that relies on the capillary action of microneedles to collect tissue fluid. This method has the disadvantages of slow sampling speed, low extraction volume, poor mechanical properties, and easy contamination of samples, making it difficult to achieve rapid, large-scale collection and clean storage of ISF.
因此，有必要提供一种能快速、大量采集组织液的组织液微针提取装置。Therefore, it is necessary to provide a tissue fluid microneedle extraction device that can quickly and massively collect tissue fluid.
发明内容Summary of the invention
本发明针的目的是提供一种基于微针阵列的负压式快速提取储存组织液的装置，用来解决传统组织液提取速度慢、提取量低、转移储存复杂的问题。The purpose of the needle of the present invention is to provide a negative pressure device for quickly extracting and storing tissue fluid based on a microneedle array, so as to solve the problems of slow tissue fluid extraction speed, low extraction volume and complex transfer and storage.
本发明的另一目的是提供上述基于微针阵列的负压式快速提取储存组织液的装置在组织液提取中的应用。Another object of the present invention is to provide the application of the above-mentioned negative pressure rapid extraction and storage tissue fluid device based on microneedle array in tissue fluid extraction.
本发明的又一目的是提供一种组织液提取方法。Another object of the present invention is to provide a method for extracting tissue fluid.
本发明上述目的通过以下技术方案实现：The above-mentioned purpose of the present invention is achieved through the following technical solutions:
本发明提供了一种基于微针阵列的负压式快速提取储存组织液的装置，由空腔台、微针阵列、连接管、负压发生及储存器构成；所述空腔台内部形成空腔结构；所述微针阵列由若干微针构成，设置在空腔台底部，并与空腔结构连通；微针上设置有若干个自微针表面贯穿空腔台底面的孔道；所述空腔台侧面设置有贯通的连接部，所述连接部通过连接管与负压发生及储存器连接。The present invention provides a negative pressure type rapid extraction and storage tissue fluid device based on a microneedle array, which is composed of a cavity platform, a microneedle array, a connecting tube, a negative pressure generator and a storage device; a cavity structure is formed inside the cavity platform; the microneedle array is composed of a plurality of microneedles, which are arranged at the bottom of the cavity platform and are connected to the cavity structure; the microneedles are provided with a plurality of channels which penetrate from the surface of the microneedles to the bottom of the cavity platform; a through connecting portion is provided on the side of the cavity platform, and the connecting portion is connected to the negative pressure generator and the storage device through the connecting tube.
该基于微针阵列的负压式快速提取储存组织液的装置具有从微针孔道到空腔台空腔，再到连接管管腔，最后到负压发生及储存器的连续通道。空腔台内部的空腔结构是由微针阵列提取的组织液的汇聚场所，同时也是将组织液输往外部的缓存空间，该场所通过空腔台的连接部与外部的连接管连通。在使用时将微针阵列刺入皮肤，组织液在毛细作用和负压驱动下，能够自动进入并储存在微针、空腔台、连接管和负压发生及储存器内；使用该装置提取组织液时，按压空腔台使微针阵列刺入皮肤，再将连接管带针头一端插入负压发生及储存器，形成从“微针孔道-空腔台空腔-连接管管腔-负压发生及储存器”的连续通道之后，不需要再有任何手动操作来进行采取组织液，只需等待组织液经微针自动进入空腔台、连接管和负压发生及储存器中。微针上设置若干个自微针表面贯穿空腔台底面的孔道，微针上的多个孔洞可以在提高组织液的提取速度的同时，避免单个孔洞堵塞造成组织液提取效率降低、甚至失败的情况发生。The negative pressure type device for quickly extracting and storing tissue fluid based on microneedle array has a continuous channel from the microneedle channel to the cavity of the cavity platform, then to the connecting tube cavity, and finally to the negative pressure generator and reservoir. The cavity structure inside the cavity platform is a gathering place for the tissue fluid extracted by the microneedle array, and is also a buffer space for transporting the tissue fluid to the outside. The place is connected to the external connecting tube through the connecting part of the cavity platform. When in use, the microneedle array is inserted into the skin, and the tissue fluid can automatically enter and be stored in the microneedles, the cavity platform, the connecting tube, the negative pressure generator and the reservoir under the capillary action and negative pressure drive; when using the device to extract tissue fluid, the cavity platform is pressed to make the microneedle array penetrate the skin, and then the connecting tube with a needle end is inserted into the negative pressure generator and reservoir, forming a continuous channel from "microneedle channel-cavity platform cavity-connecting tube cavity-negative pressure generator and reservoir", and no manual operation is required to take tissue fluid, and only the tissue fluid needs to be automatically entered into the cavity platform, the connecting tube, the negative pressure generator and the reservoir through the microneedle. The microneedle is provided with a plurality of holes which penetrate from the surface of the microneedle through the bottom surface of the cavity platform. The multiple holes on the microneedle can improve the extraction speed of tissue fluid while avoiding the situation that a single hole is blocked, causing the efficiency of tissue fluid extraction to be reduced or even fail.
在一个优选的实施方式中，所述微针的尖端周长小于微针底部周长。In a preferred embodiment, the circumference of the tip of the microneedle is smaller than the circumference of the base of the microneedle.
优选地，所述微针的形态包括但不限于圆锥形、方锥形、金字塔形、多重圆锥形、多重方锥形、多重金字塔形，或上述形态的组合。Preferably, the shape of the microneedle includes but is not limited to a cone, a square cone, a pyramid, multiple cones, multiple square cones, multiple pyramids, or a combination of the above shapes.
在一个优选的实施方式中，所述微针阵列由5×5～20×20个微针构成，面积为0.28～46.24cm2。该规模下的微针阵列考虑到微针的提取能力和贴片的大小，提取能力达到检测的提取要求。In a preferred embodiment, the microneedle array is composed of 5×5 to 20×20 microneedles with an area of 0.28 to 46.24 cm2 . The microneedle array at this scale takes into account the extraction capacity of the microneedles and the size of the patch, and the extraction capacity meets the extraction requirements of the test.
在一个优选的实施方式中，所述孔道的数量为1～4个。In a preferred embodiment, the number of the channels is 1 to 4.
在一个优选的实施方式中，所述孔道的内径为10～1000μm。In a preferred embodiment, the inner diameter of the pore is 10 to 1000 μm.
在一个优选的实施方式中，所述微针的长度为300～1500μm。该长度下的微针不足以与真皮层内神经末梢的接触，对人类皮肤创伤小，减小疼痛感。In a preferred embodiment, the length of the microneedle is 300-1500 μm. The microneedle of this length is not long enough to contact the nerve endings in the dermis, causing little trauma to human skin and reducing pain.
在一个优选的实施方式中，所述微针与相邻微针的中心间距为300～3000μm。该中心距可以适应不同场景下对器件大小的需求。In a preferred embodiment, the center distance between the microneedles and adjacent microneedles is 300-3000 μm, which can meet the requirements of device size in different scenarios.
在一个优选的实施方式中，所述空腔中设置有垂直的支撑体。该支撑体的作用在于支撑空腔结构，避免制作过程中、储存过程中和使用过程中，空腔台结构变形引起空腔闭合，造成下方微针的开口被封堵，或汇聚到该空腔结构中的组织液被封堵，而影响组织液的提取。同时支撑体还可以减少空腔台中空腔的死体积，减少通过微针提取的组织液在空腔台空腔内的残留。In a preferred embodiment, a vertical support is provided in the cavity. The function of the support is to support the cavity structure, to prevent the cavity from being closed due to deformation of the cavity platform structure during the manufacturing process, storage process and use process, resulting in the opening of the microneedle below being blocked, or the tissue fluid gathered in the cavity structure being blocked, thereby affecting the extraction of tissue fluid. At the same time, the support can also reduce the dead volume of the cavity in the cavity platform, and reduce the residual tissue fluid extracted by the microneedle in the cavity of the cavity platform.
在一个优选的实施方式中，所述支撑体的设置方式为在空腔台底面，避开微针贯通孔道在空腔台内的开口进行设置。避开微针贯通孔道在空腔台内的开口以避免堵塞微针的孔道，使组织液可以顺利的通往连接管。In a preferred embodiment, the support body is arranged on the bottom surface of the cavity platform, avoiding the opening of the microneedle through-hole in the cavity platform to avoid blocking the microneedle through-hole, so that the tissue fluid can smoothly pass to the connecting tube.
更优选地，所述支撑体相互平行设置。More preferably, the supports are arranged parallel to each other.
更优选地，所述支撑体围绕空腔中心设置，并且互不相连。More preferably, the supports are arranged around the center of the cavity and are not connected to each other.
更优选地，所述支撑体的数量为2-4个。More preferably, the number of the supports is 2-4.
在一个优选的实施方式中，所述支撑体上设置有孔洞。在支撑体上设置的孔洞即能让支撑体起到支撑空腔台顶面与底面的作用，又不封堵通过微针提取出来的组织液。In a preferred embodiment, the support body is provided with holes. The holes provided on the support body can enable the support body to play the role of supporting the top and bottom surfaces of the cavity platform without blocking the tissue fluid extracted by the microneedle.
在一个优选的实施方式中，所述支撑体互不相连。In a preferred embodiment, the supports are not connected to each other.
更优选地，所述支撑体与空腔台侧壁不相连。More preferably, the support body is not connected to the side wall of the cavity platform.
在一个优选的实施方式中，所述空腔台顶面为方形、或椭圆形、或圆形，或方形、椭圆形、圆形的组合形态。In a preferred embodiment, the top surface of the cavity platform is square, oval, circular, or a combination of square, oval and circular.
在一个优选的实施方式中，所述空腔台顶面具有或平面、或凸起、或凹陷的结构形态。空腔台的顶面从侧面观察可以是平面、或凸起、或凹陷的结构。In a preferred embodiment, the top surface of the cavity platform has a flat surface, a convex surface, or a concave surface. The top surface of the cavity platform can be a flat surface, a convex surface, or a concave surface when viewed from the side.
在一个优选的实施方式中，所述空腔结构的高度为0.5-2.5mm。优选为1mm。In a preferred embodiment, the height of the cavity structure is 0.5-2.5 mm, preferably 1 mm.
在一个优选的实施方式中，所述空腔台底面为平面结构。所述空腔台虽然为平面结构，但是当按压空腔台使微针阵列刺入皮肤以及在组织液提取过程中，空腔台依然可以紧密贴合皮肤。In a preferred embodiment, the bottom surface of the cavity platform is a planar structure. Although the cavity platform is a planar structure, when the cavity platform is pressed to make the microneedle array penetrate the skin and during the tissue fluid extraction process, the cavity platform can still fit the skin closely.
更优选地，所述空腔台底面具有柔性或者为可变形性结构。底面为柔性或者为可变形结构，当按压空腔台使微针阵列刺入皮肤以及在组织液提取过程中，空腔台可以更紧密贴合皮肤。More preferably, the bottom surface of the cavity platform is flexible or has a deformable structure. The bottom surface is flexible or has a deformable structure, and when the cavity platform is pressed to make the microneedle array penetrate the skin and during the tissue fluid extraction process, the cavity platform can fit the skin more closely.
在一个优选的实施方式中，所述空腔台底面为曲面结构，具有柔性或者为可变形性结构。当按压空腔台使微针阵列刺入皮肤以及在组织液提取过程中，底面为曲面的空腔台依然可以紧密贴合皮肤。In a preferred embodiment, the bottom surface of the cavity platform is a curved surface structure, which is flexible or deformable. When the cavity platform is pressed to allow the microneedle array to penetrate the skin and during the tissue fluid extraction process, the cavity platform with a curved bottom surface can still fit the skin closely.
在一个优选的实施方式中，所述连接部的数量为若干个。空腔台侧面可以设置有若干个贯通的连接部，用于各自接通不同的连接管和负压发生及储存器，使得一个空腔台装置可以配置若干套负压发生及储存器，提升本发明基于微针阵列的负压式快速提取储存组织液的装置组织液提取与储存能力。In a preferred embodiment, the number of the connecting parts is several. The side of the cavity platform can be provided with several through connecting parts, which are used to connect different connecting tubes and negative pressure generators and storage devices, so that one cavity platform device can be equipped with several sets of negative pressure generators and storage devices, thereby improving the tissue fluid extraction and storage capacity of the negative pressure type rapid extraction and storage device for tissue fluid based on the microneedle array of the present invention.
更优选地，所述连接部的数量为1-4个。More preferably, the number of the connecting parts is 1-4.
在一个优选的实施方式中，所述连接部为圆筒状结构。所述连接管与连接部嵌套连接，连接管为软管，嵌套在连接部的外侧。In a preferred embodiment, the connecting part is a cylindrical structure. The connecting pipe is nested and connected with the connecting part, and the connecting pipe is a hose nested on the outside of the connecting part.
在一个优选的实施方式中，所述连接管为两端开口的贯通管，两端开口之间为中空的连接管管腔。In a preferred embodiment, the connecting tube is a through tube with openings at both ends, and a hollow connecting tube lumen is formed between the openings at both ends.
在一个优选的实施方式中，所述负压发生及储存器为：In a preferred embodiment, the negative pressure generator and storage device is:
(a)负压发生与储存一体式装置；或(b)负压发生与储存分离式装置。(a) a negative pressure generating and storing device integrated with one body; or (b) a negative pressure generating and storing device separated with one body.
更优选地，所述负压发生与储存一体式装置包括但不限于预先抽成不同的真空度，利用其负压采集并同时储存样品的一体化装置。更优选为真空采样管、真空采血管、减压采样管、减压采血管。使用时，先按压空腔台，使微针阵列刺入皮肤；再将连接管带针头一端插入真空采样管、或真空采血管、或减压采样管、或减压采血管，利用真空采样管提供的负压，将组织液快速从皮肤下方提取转移至连接管和真空采样管、或真空采血管、或减压采样管、或减压采血管。More preferably, the negative pressure generating and storing integrated device includes but is not limited to an integrated device that is pre-drawn to different vacuum degrees and uses its negative pressure to collect and store samples at the same time. More preferably, it is a vacuum sampling tube, a vacuum blood collection tube, a decompression sampling tube, and a decompression blood collection tube. When in use, first press the cavity stage to allow the microneedle array to penetrate the skin; then insert one end of the connecting tube with the needle into the vacuum sampling tube, or the vacuum blood collection tube, or the decompression sampling tube, or the decompression blood collection tube, and use the negative pressure provided by the vacuum sampling tube to quickly extract the tissue fluid from under the skin and transfer it to the connecting tube and the vacuum sampling tube, or the vacuum blood collection tube, or the decompression sampling tube, or the decompression blood collection tube.
更优选地，所述负压发生与储存分离式装置包括但不限于在负压发生装置前添加一个储存器的装置。所述负压发生与储存分离式装置指的是通过负压空间驱动样品流动、抽取样品，而在负压驱动样品流动的通道上储存样品的装置，此储存空间与负压发生器的空间分离而不为同一空间。More preferably, the negative pressure generating and storing separated device includes but is not limited to a device with a storage device added in front of the negative pressure generating device. The negative pressure generating and storing separated device refers to a device that drives the sample flow and extracts the sample through the negative pressure space, and stores the sample in the channel where the negative pressure drives the sample flow, and the storage space is separated from the negative pressure generator space and is not the same space.
更优选地，所述在负压发生装置前添加的储存器为负压发生与储存一体式装置。此时形成多级的负压提供，使得一个空腔台可以配置多级负压提供装置，提升本发明涉及装置的组织液提取与储存能力。More preferably, the storage device added before the negative pressure generating device is a negative pressure generating and storing integrated device. At this time, multiple levels of negative pressure are provided, so that a cavity platform can be equipped with multiple levels of negative pressure providing devices, thereby improving the tissue fluid extraction and storage capabilities of the device of the present invention.
在一个优选的实施方式中，所述空腔台、微针阵列的材质包括但不限于有机高分子聚合物、无机材料。In a preferred embodiment, the materials of the cavity platform and the microneedle array include but are not limited to organic polymers and inorganic materials.
更优选地，所述无机材料包括金属、无机非金属材料。More preferably, the inorganic material includes metal and inorganic non-metallic material.
更优选地，所述有机高分子聚合物包括但不限于甲基丙烯酰化明胶、甲基丙烯酰化透明质酸、甲基丙烯酰化聚乙二醇等甲基丙烯酰化类末端高分子、聚二甲基硅氧烷、聚乙烯醇、聚氨酯、聚乙二醇、光固化树脂。More preferably, the organic high molecular polymer includes but is not limited to methacrylated gelatin, methacrylated hyaluronic acid, methacrylated polyethylene glycol and other methacrylated terminal polymers, polydimethylsiloxane, polyvinyl alcohol, polyurethane, polyethylene glycol, and light-curable resin.
更优选地，所述光固化树脂为生物相容性光固化树脂。More preferably, the photocurable resin is a biocompatible photocurable resin.
更优选地，所述生物相容性光固化树脂由甲基丙烯酸酯低聚物、甲基丙烯酸酯单体、丙烯酸单体和光引发剂反应制备得到。More preferably, the biocompatible photocurable resin is prepared by reacting methacrylate oligomers, methacrylate monomers, acrylic acid monomers and photoinitiators.
在一个优选的实施方式中，所述空腔台、微针阵列为一体成型结构。In a preferred embodiment, the cavity platform and the microneedle array are an integrally formed structure.
本发明还提供了上述空腔台、微针阵列的制备方法，采用一体成型工艺制备得到所述空腔台、微针阵列。The present invention also provides a method for preparing the above-mentioned cavity platform and microneedle array, and the cavity platform and microneedle array are prepared by an integrated molding process.
在一个优选的实施方式中，所述一体成型工艺包括但不限于3D打印、微浇铸、模板法、激光刻蚀法。In a preferred embodiment, the one-piece molding process includes but is not limited to 3D printing, micro casting, template method, and laser etching method.
本发明提供的基于微针阵列的负压式快速提取储存组织液的装置可以实现快速、大量的提取组织液，因此，本发明提供的基于微针阵列的负压式快速提取储存组织液的装置在组织液提取中的应用也应在本发明的保护范围内。The negative pressure device for quickly extracting and storing tissue fluid based on a microneedle array provided by the present invention can achieve rapid and large-scale extraction of tissue fluid. Therefore, the application of the negative pressure device for quickly extracting and storing tissue fluid based on a microneedle array provided by the present invention in tissue fluid extraction should also be within the protection scope of the present invention.
本发明还提供了一种组织液提取方法，将本发明提供的快速提取储存组织液的装置的微针阵列刺入皮肤，将连接管与负压发生及储存器连接，利用负压发生及储存器提供的负压进行组织液采集。The present invention also provides a method for extracting tissue fluid, wherein the microneedle array of the device for rapidly extracting and storing tissue fluid provided by the present invention is inserted into the skin, a connecting tube is connected to a negative pressure generator and storage device, and tissue fluid is collected using the negative pressure provided by the negative pressure generator and storage device.
在一个优选的实施方式中，所述负压发生及储存器包括但不限于真空采样管、或真空采血管、或减压采样管、或减压采血管。In a preferred embodiment, the negative pressure generator and storage device includes but is not limited to a vacuum sampling tube, a vacuum blood collection tube, a decompression sampling tube, or a decompression blood collection tube.
在一个优选的实施方式中，所述刺入皮肤的方法包括但不限于按压法、注射头辅助法。In a preferred embodiment, the method of piercing the skin includes but is not limited to a pressing method and an injection head-assisted method.
在一个优选的实施方式中，所述刺入皮肤后需保持微针阵列的按压状态，待组织液提取完成后，才可以松开。In a preferred embodiment, the microneedle array needs to be kept in a pressed state after piercing the skin, and can be released only after the tissue fluid extraction is completed.
在一个优选的实施方式中，所述组织液提取方法，在组织液提取完成后，先将微针阵列从皮肤表面取下，再将采液软管与负压发生及储存器分离。In a preferred embodiment, in the tissue fluid extraction method, after the tissue fluid extraction is completed, the microneedle array is first removed from the skin surface, and then the liquid collection hose is separated from the negative pressure generator and storage device.
在一个优选的实施方式中，提取的组织液可储存在空腔台空腔、连接管腔和/或真空采样管中。更优选为储存在真空采样管中。In a preferred embodiment, the extracted tissue fluid can be stored in the cavity of the cavity platform, the connecting tube cavity and/or the vacuum sampling tube. More preferably, it is stored in the vacuum sampling tube.
本发明具有以下有益效果：The present invention has the following beneficial effects:
本发明在通过负压发生及储存器提供的负压，从皮肤表面实现组织液的快速提取、大量提取；提取的组织液可储存在装置的主体空腔、连接管腔和真空采样管内，储存方便并且洁净；该装置的微针上设置有多个孔道，提高组织液提取效率的同时，还可以避免单个孔道堵塞后导致组织液样本提取失败的问题；该装置具有操作简便、无需大型设备、高效、低成本的优点，可以广泛应用于组织液的采集，通过该装置提取的组织液，可进行医学化验，以进行健康监测和疾病诊断。The present invention realizes rapid and large-scale extraction of tissue fluid from the skin surface through the negative pressure generated and provided by the storage device; the extracted tissue fluid can be stored in the main body cavity, the connecting tube cavity and the vacuum sampling tube of the device, and the storage is convenient and clean; a plurality of channels are arranged on the microneedle of the device, which improves the efficiency of tissue fluid extraction and can also avoid the problem of failure of tissue fluid sample extraction due to blockage of a single channel; the device has the advantages of simple operation, no need for large equipment, high efficiency and low cost, and can be widely used in the collection of tissue fluid. The tissue fluid extracted by the device can be subjected to medical tests for health monitoring and disease diagnosis.
附图说明BRIEF DESCRIPTION OF THE DRAWINGS
图1为实施例1基于微针阵列的负压式快速提取储存组织液的装置的结构示意图。FIG. 1 is a schematic structural diagram of a device for rapidly extracting and storing tissue fluid using negative pressure based on a microneedle array in Example 1.
图2为图1所示的基于微针阵列的负压式快速提取储存组织液的装置的空腔台、微针阵列的结构示意图。FIG. 2 is a schematic structural diagram of a cavity platform and a microneedle array of the device for negative pressure rapid extraction and storage of tissue fluid based on a microneedle array shown in FIG. 1 .
图3为实施例2基于微针阵列的负压式快速提取储存组织液的装置的空腔台、微针阵列及连接部示意图。3 is a schematic diagram of the cavity platform, microneedle array and connecting part of the device for negative pressure rapid extraction and storage of tissue fluid based on microneedle array in Example 2.
图4为图3所示的基于微针阵列的负压式快速提取储存组织液的装置的空腔台、微针阵列的结构示意图。FIG. 4 is a schematic structural diagram of a cavity platform and a microneedle array of the device for negative pressure rapid extraction and storage of tissue fluid based on a microneedle array shown in FIG. 3 .
图5为实施例3所述的基于微针阵列的负压式快速提取储存组织液的装置的空腔结构示意图。FIG5 is a schematic diagram of the cavity structure of the device for negative pressure rapid extraction and storage of tissue fluid based on a microneedle array as described in Example 3.
图6为实施例4的基于微针阵列的负压式快速提取储存组织液的装置的空腔结构示意图。FIG6 is a schematic diagram of the cavity structure of the device for negative pressure rapid extraction and storage of tissue fluid based on a microneedle array in Example 4.
图7为图6所示的基于微针阵列的负压式快速提取储存组织液的装置的空腔结构示意图。FIG. 7 is a schematic diagram of the cavity structure of the device for rapidly extracting and storing tissue fluid using negative pressure based on a microneedle array as shown in FIG. 6 .
图8为实施例5 3D打印制备得到的基于微针阵列的负压式快速提取储存组织液的装置空腔台和微针实例图。FIG8 is an example diagram of a cavity platform and microneedles of a negative pressure device for rapid extraction and storage of tissue fluid based on a microneedle array prepared by 3D printing in Example 5.
图9为实施例5制备得到的基于微针阵列的负压式快速提取储存组织液的装置的微针的扫描电子显微镜表征图。FIG9 is a scanning electron microscope characterization image of the microneedles of the negative pressure rapid extraction and storage tissue fluid device based on the microneedle array prepared in Example 5.
图10为基于微针阵列的负压式快速提取储存组织液的装置的一种实物装置图。FIG. 10 is a diagram of a physical device of a negative pressure device for rapidly extracting and storing tissue fluid based on a microneedle array.
图11为在1％琼脂糖凝胶皮肤模型下进行提取测试的结果。FIG. 11 shows the results of extraction test in 1% agarose gel skin model.
图12为活体小鼠皮肤下穿刺及恢复测试中不同时间点小鼠皮肤的实拍图。FIG12 is a real picture of the mouse skin at different time points during the subcutaneous puncture and recovery test of live mice.
图13为在活体小鼠皮肤下穿刺后皮肤组织切片后苏木精-伊红染色结果。FIG. 13 shows the results of hematoxylin-eosin staining of skin tissue sections after puncture under the skin of living mice.
图14为采用不同规模的微针阵列提取新西兰兔组织液的提取量。FIG. 14 shows the amount of New Zealand rabbit tissue fluid extracted using microneedle arrays of different sizes.
图注：1-空腔台；2-微针阵列；3-连接管；4-负压发生及储存器；5-空腔；6-连接部；7-连接管管腔；8-支撑体；9-储存器；10-负压发生装置。Figure captions: 1-cavity platform; 2-microneedle array; 3-connecting tube; 4-negative pressure generator and reservoir; 5-cavity; 6-connecting part; 7-connecting tube lumen; 8-support body; 9-reservoir; 10-negative pressure generating device.
具体实施方式Detailed ways
下面详细描述本发明的实施例，所述实施例的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。Embodiments of the present invention are described in detail below, examples of which are shown in the accompanying drawings, wherein the same or similar reference numerals throughout represent the same or similar elements or elements having the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary and are intended to be used to explain the present invention, and should not be construed as limiting the present invention.
实施例1一种基于微针阵列的负压式快速提取储存组织液的装置Example 1 A negative pressure device for rapid extraction and storage of tissue fluid based on a microneedle array
如图1，一种基于微针阵列的负压式快速提取储存组织液的装置，由空腔台1、微针阵列2、连接管3、负压发生及储存器4构成；所述空腔台1内部形成空腔结构5；所述微针阵列2设置在空腔台1底部与空腔5结构连通，微针阵列2由5×5个微针构成，微针上设置有两个自微针表面贯穿空腔台底面的孔道；所述空腔台1侧面设置有贯通的连接部6(图2)，接通连接管3与负压发生及储存器4；所述空腔台1顶面为方形；所述空腔台1底面为平面结构，且具有柔性；所述连接管3为两端开口的贯通管，两端开口之间为中空的连接管管腔7；所述负压发生及储存器4为真空采样管；所述微针的形态为圆锥形；所述空腔结构的高度为1mm；所述孔道的内径为300μm；所述微针的长度为800μm；所述微针与相邻微针的中心间距为2000μm；所述微针阵列的面积为1.21cm2；所述连接部为圆筒状结构，连接管与连接部嵌套连接，连接管为软管，嵌套在连接件的外侧。所述空腔、微针的材质为生物相容性光固化树脂。As shown in FIG1 , a negative pressure type rapid extraction and storage device for tissue fluid based on a microneedle array is composed of a cavity platform 1, a microneedle array 2, a connecting tube 3, and a negative pressure generator and reservoir 4; a cavity structure 5 is formed inside the cavity platform 1; the microneedle array 2 is arranged at the bottom of the cavity platform 1 and is connected to the cavity 5 structure, and the microneedle array 2 is composed of 5×5 microneedles, and the microneedles are provided with two channels that penetrate the bottom surface of the cavity platform from the surface of the microneedles; a through connection portion 6 ( FIG2 ) is provided on the side of the cavity platform 1, which connects the connecting tube 3 with the negative pressure generator and reservoir 4; the top surface of the cavity platform 1 is square; the bottom surface of the cavity platform 1 is a flat structure and is flexible; the connecting tube 3 is a through tube with openings at both ends, and the hollow connecting tube lumen 7 is between the openings at both ends; the negative pressure generation and storage 4 is a vacuum sampling tube; the microneedle is conical; the height of the cavity structure is 1mm; the inner diameter of the channel is 300μm; the length of the microneedle is 800μm; the center distance between the microneedle and the adjacent microneedle is 2000μm; the area of the microneedle array is1.21cm2 ; the connecting part is a cylindrical structure, the connecting tube is nested with the connecting part, and the connecting tube is a hose, which is nested on the outside of the connecting part. The material of the cavity and microneedle is biocompatible light-curing resin.
在使用时通过按压空腔台将微针阵列刺入皮肤，连接真空采样管，在真空采样管提供的负压的作用下，皮肤组织中的组织液通过微针阵列的孔道流入空腔台中，被提取出来的组织液进一步通过连接管进入真空采样管中储存转运；将微针阵列按入皮肤后需要保持按压状态，待组织液提取完成后才可以松开；在组织液提取完成后，先将微针阵列从皮肤表面取下，再将采液软管与负压发生及储存器分离。When in use, the microneedle array is inserted into the skin by pressing the cavity table, and the vacuum sampling tube is connected. Under the action of the negative pressure provided by the vacuum sampling tube, the tissue fluid in the skin tissue flows into the cavity table through the holes of the microneedle array, and the extracted tissue fluid further enters the vacuum sampling tube through the connecting tube for storage and transportation; after the microneedle array is pressed into the skin, the pressing state needs to be maintained and the pressure can be released only after the tissue fluid extraction is completed; after the tissue fluid extraction is completed, the microneedle array is first removed from the skin surface, and then the liquid sampling hose is separated from the negative pressure generator and storage device.
实施例2一种基于微针阵列的负压式快速提取储存组织液的装置Example 2 A negative pressure device for rapid extraction and storage of tissue fluid based on a microneedle array
如图3，一种基于微针阵列的负压式快速提取储存组织液的装置，由空腔台1、微针阵列2、连接管3、负压发生及储存器4构成；所述空腔台1内部形成空腔结构5；所述微针阵列2设置在空腔台1底部与空腔5结构连通，微针阵列2由10×10个微针构成，微针上设置有三个自微针表面贯穿空腔台底面的孔道；所述空腔台1两侧设置有贯通的连接部6(图4)，所述连接部6通过连接管3与负压发生及储存器4连接；所述空腔台1顶面为方形；所述空腔台1底面为平面结构，且具有柔性；所述连接管3为两端开口的贯通管，两端开口之间为中空的连接管管腔7；所述负压发生及储存器4为负压发生与储存分离式装置，提取的组织液储存在储存器9中，由负压发生装置10提供负压；所述微针的形态为圆锥形；所述空腔结构的高度为0.5mm；所述孔道的内径为1000μm；所述微针的长度为300μm；所述微针与相邻微针的中心间距为3000μm；所述微针阵列的面积为9.36cm2；所述连接部为圆筒状结构，连接管与连接部嵌套连接，连接管为软管，嵌套在连接件的外侧；所述空腔、微针的材质为甲基丙烯酰化明胶；所述空腔、微针阵列为一体成型结构。As shown in FIG3 , a negative pressure type device for quickly extracting and storing tissue fluid based on a microneedle array is composed of a cavity platform 1, a microneedle array 2, a connecting tube 3, and a negative pressure generator and reservoir 4; a cavity structure 5 is formed inside the cavity platform 1; the microneedle array 2 is arranged at the bottom of the cavity platform 1 and is connected to the cavity 5 structure, and the microneedle array 2 is composed of 10×10 microneedles, and the microneedles are provided with three channels that penetrate the bottom surface of the cavity platform from the surface of the microneedles; through-connecting parts 6 ( FIG4 ) are provided on both sides of the cavity platform 1, and the connecting parts 6 are connected to the negative pressure generator and reservoir 4 through the connecting tube 3; the top surface of the cavity platform 1 is square; The bottom surface of the cavity platform 1 is a flat structure and is flexible; the connecting tube 3 is a through tube with openings at both ends, and a hollow connecting tube lumen 7 is formed between the openings at both ends; the negative pressure generating and storing device 4 is a negative pressure generating and storing separate device, the extracted tissue fluid is stored in the storing device 9, and the negative pressure is provided by the negative pressure generating device 10; the microneedle is conical in shape; the height of the cavity structure is 0.5 mm; the inner diameter of the channel is 1000 μm; the length of the microneedle is 300 μm; the center distance between the microneedle and the adjacent microneedle is 3000 μm; the area of the microneedle array is 9.36 cm2 ; the connecting part is a cylindrical structure, the connecting tube is nested and connected with the connecting part, and the connecting tube is a hose nested on the outside of the connecting part; the material of the cavity and the microneedle is methacrylated gelatin; the cavity and the microneedle array are an integrated structure.
在使用时通过按压空腔台将微针阵列刺入皮肤，连接真空采样管，在真空采样管提供的负压的驱动作用下，皮肤组织中的组织液通过微针阵列的孔道流入空腔台中汇聚，再进一步通过连接管进入真空采样管中储存转运；将微针阵列按入皮肤后需要保持按压状态，待组织液提取完成后才可以松开；在组织液提取完成后，先将微针阵列从皮肤表面取下，再将采液软管与负压发生及储存器分离。When in use, the microneedle array is inserted into the skin by pressing the cavity table, and the vacuum sampling tube is connected. Driven by the negative pressure provided by the vacuum sampling tube, the tissue fluid in the skin tissue flows into the cavity table through the holes of the microneedle array and gathers, and then further enters the vacuum sampling tube through the connecting tube for storage and transportation; after the microneedle array is pressed into the skin, the pressing state needs to be maintained and can only be released after the tissue fluid extraction is completed; after the tissue fluid extraction is completed, the microneedle array is first removed from the skin surface, and then the liquid sampling hose is separated from the negative pressure generator and storage device.
实施例3一种基于微针阵列的负压式快速提取储存组织液的装置Example 3 A negative pressure device for rapid extraction and storage of tissue fluid based on a microneedle array
一种基于微针阵列的负压式快速提取储存组织液的装置，由空腔台1、微针阵列2、连接管3、负压发生及储存器4构成；所述空腔台1内部形成空腔结构5；所述微针阵列2设置在空腔台1底部与空腔5结构连通，微针阵列2由20×20个微针构成，微针上设置有四个自微针表面贯穿空腔台底面的孔道；所述空腔台1侧面设置有贯通的连接部6，所述连接部6通过连接管3与负压发生及储存器4连接；所述空腔5中设置有垂直的支撑体，支撑体的数量为4个，围绕空腔中心设置，并且互不相连(图5)；所述空腔台1顶面为圆形；所述空腔台1底面为平面结构，且具有柔性；所述连接管3为两端开口的贯通管，两端开口之间为中空的连接管管腔7；所述负压发生及储存器4为真空采样管；所述微针的形态为方锥形；所述空腔结构的高度为2.5mm；所述孔道的内径为10μm；所述微针的长度为1500μm；所述微针与相邻微针的中心间距为300μm；所述微针阵列的面积为0.37cm2；所述连接部为圆筒状结构，连接管与连接部嵌套连接，连接管为软管，嵌套在连接件的外侧；所述空腔、微针的材质为金属；所述空腔、微针阵列为一体成型结构。A negative pressure type device for quickly extracting and storing tissue fluid based on a microneedle array, comprising a cavity platform 1, a microneedle array 2, a connecting tube 3, and a negative pressure generator and storage device 4; a cavity structure 5 is formed inside the cavity platform 1; the microneedle array 2 is arranged at the bottom of the cavity platform 1 and is connected to the cavity 5 structure, the microneedle array 2 is composed of 20×20 microneedles, and the microneedles are provided with four channels that penetrate the bottom surface of the cavity platform from the surface of the microneedles; a through connection part 6 is provided on the side of the cavity platform 1, and the connection part 6 is connected to the negative pressure generator and storage device 4 through the connecting tube 3; a vertical support body is provided in the cavity 5, and the number of the support bodies is There are 4 microneedles, which are arranged around the center of the cavity and are not connected to each other (Figure 5); the top surface of the cavity platform 1 is circular; the bottom surface of the cavity platform 1 is a flat structure and is flexible; the connecting tube 3 is a through tube with openings at both ends, and a hollow connecting tube lumen 7 is between the openings at both ends; the negative pressure generation and storage device 4 is a vacuum sampling tube; the shape of the microneedle is a square cone; the height of the cavity structure is 2.5mm; the inner diameter of the channel is 10μm; the length of the microneedle is 1500μm; the center distance between the microneedle and the adjacent microneedle is 300μm; the area of the microneedle array is0.37cm2 ; the connecting part is a cylindrical structure, the connecting tube is nested and connected to the connecting part, and the connecting tube is a hose, which is nested on the outside of the connecting part; the material of the cavity and the microneedle is metal; the cavity and the microneedle array are an integrated structure.
在使用时通过按压空腔台将微针阵列刺入皮肤，连接真空采样管，在真空采样管提供的负压的作用下，皮肤组织中的组织液通过微针阵列的孔道流入空腔台中，被提取出来的组织液进一步通过连接管进入真空采样管中储存转运；将微针阵列按入皮肤后需要保持按压状态，待组织液提取完成后才可以松开；在组织液提取完成后，先将微针阵列从皮肤表面取下，再将采液软管与负压发生及储存器分离。When in use, the microneedle array is inserted into the skin by pressing the cavity table, and the vacuum sampling tube is connected. Under the action of the negative pressure provided by the vacuum sampling tube, the tissue fluid in the skin tissue flows into the cavity table through the holes of the microneedle array, and the extracted tissue fluid further enters the vacuum sampling tube through the connecting tube for storage and transportation; after the microneedle array is pressed into the skin, the pressing state needs to be maintained and the pressure can be released only after the tissue fluid extraction is completed; after the tissue fluid extraction is completed, the microneedle array is first removed from the skin surface, and then the liquid sampling hose is separated from the negative pressure generator and storage device.
实施例4一种基于微针阵列的负压式快速提取储存组织液的装置Example 4 A negative pressure device for rapid extraction and storage of tissue fluid based on a microneedle array
如图6，一种基于微针阵列的负压式快速提取储存组织液的装置，由空腔台1、微针阵列2、连接管3、负压发生及储存器构成；所述空腔台1内部形成空腔结构5；所述微针阵列2设置在空腔台1底部与空腔5结构连通，微针阵列2由10×10个微针构成，微针上设置有三个自微针表面贯穿空腔台底面的孔道；所述空腔台1侧面设置有贯通的连接部6，所述连接部6通过连接管3与负压发生及储存器连接；所述空腔5中设置有垂直的支撑体，支撑体的数量为4个，在空腔台底面，避开微针贯通孔道在空腔台内的开口平行设置(图7)；所述空腔台1顶面为方形；所述空腔台1底面为平面结构，且具有柔性；所述连接管3为两端开口的贯通管，两端开口之间为中空的连接管管腔7；所述负压发生及储存器为负压发生与储存分离式装置，提取的组织液储存在储存器9中，由负压发生装置10提供负压；所述微针的形态为圆锥形；所述空腔结构的高度为0.5mm；所述孔道的内径为1000μm；所述微针的长度为300μm；所述微针与相邻微针的中心间距为3000μm；所述微针阵列的面积为36.72cm2；所述连接部为圆筒状结构，连接管与连接部嵌套连接，连接管为软管，嵌套在连接件的外侧；所述空腔、微针的材质为甲基丙烯酰化明胶；所述空腔、微针阵列为一体成型结构。As shown in Figure 6, a negative pressure-type rapid extraction and storage device for tissue fluid based on a microneedle array is composed of a cavity platform 1, a microneedle array 2, a connecting tube 3, a negative pressure generator and a reservoir; a cavity structure 5 is formed inside the cavity platform 1; the microneedle array 2 is arranged at the bottom of the cavity platform 1 and is connected to the cavity 5 structure, and the microneedle array 2 is composed of 10×10 microneedles, and the microneedles are provided with three channels that penetrate the bottom surface of the cavity platform from the surface of the microneedles; a through connection part 6 is provided on the side of the cavity platform 1, and the connection part 6 is connected to the negative pressure generator and the reservoir through the connecting tube 3; a vertical support body is provided in the cavity 5, and the number of the support bodies is 4, on the bottom surface of the cavity platform, avoiding the through-holes of the microneedles on the cavity platform The openings inside are arranged in parallel (Figure 7); the top surface of the cavity platform 1 is square; the bottom surface of the cavity platform 1 is a flat structure and is flexible; the connecting tube 3 is a through tube with openings at both ends, and the hollow connecting tube lumen 7 is between the openings at both ends; the negative pressure generation and storage device is a negative pressure generation and storage separate device, the extracted tissue fluid is stored in the storage device 9, and the negative pressure is provided by the negative pressure generating device 10; the shape of the microneedle is conical; the height of the cavity structure is 0.5mm; the inner diameter of the channel is 1000μm; the length of the microneedle is 300μm; the center distance between the microneedle and the adjacent microneedle is 3000μm; the area of the microneedle array is36.72cm2 ; the connecting part is a cylindrical structure, the connecting tube is nested and connected with the connecting part, and the connecting tube is a hose, which is nested on the outside of the connecting part; the material of the cavity and the microneedle is methacrylated gelatin; the cavity and the microneedle array are an integrated molding structure.
在使用时通过按压空腔台将微针阵列刺入皮肤，连接真空采样管，在真空采样管提供的负压的作用下，皮肤组织中的组织液通过微针阵列的孔道流入空腔台中，被提取出来的组织液进一步通过连接管进入真空采样管中储存转运；将微针阵列按入皮肤后需要保持按压状态，待组织液提取完成后才可以松开；在组织液提取完成后，先将微针阵列从皮肤表面取下，再将采液软管与负压发生及储存器分离。When in use, the microneedle array is inserted into the skin by pressing the cavity table, and the vacuum sampling tube is connected. Under the action of the negative pressure provided by the vacuum sampling tube, the tissue fluid in the skin tissue flows into the cavity table through the holes of the microneedle array, and the extracted tissue fluid further enters the vacuum sampling tube through the connecting tube for storage and transportation; after the microneedle array is pressed into the skin, the pressing state needs to be maintained and the pressure can be released only after the tissue fluid extraction is completed; after the tissue fluid extraction is completed, the microneedle array is first removed from the skin surface, and then the liquid sampling hose is separated from the negative pressure generator and storage device.
实施例5一种基于微针阵列的负压式快速提取储存组织液的装置的制备方法Example 5 Preparation method of a negative pressure device for rapid extraction and storage of tissue fluid based on microneedle array
采用3D打印方法进行基于微针阵列的负压式快速提取储存组织液的装置的空腔台和微针阵列的制备。The 3D printing method is used to prepare the cavity platform and microneedle array of the device for negative pressure rapid extraction and storage of tissue fluid based on microneedle array.
使用建模软件Cinema 4D设计微针原型，以.STL格式输入到高精度3D打印系统所连接的电脑，将模型以所设定层厚切片成打印时所需的扫描横截面预备打印。高精度3D打印系统的打印技术是光固化成型技术，借由紫外光的照射到光敏树脂的液面上，使树脂液面固化成扫描的模型横截面层膜，完成固化后在刚形成的层膜上继续扫描逐层固化树脂直至完成模型。本实施例中使用的高精度3D打印机具有较高的分辨率(x轴和y轴分辨率可为10μm，层厚为10μm)，使用的材料为生物相容性光固化树脂。高精度3D打印系统对模型打印完成度有影响的两个主要参数是UV曝光强度和UV曝光时间。针对本案例中打印微针的微细结构所使用的打印层数为500，单层厚度厚为10μm，按照自空腔台面至微针阵列针尖的顺序，第一层UV曝光强度为50，UV曝光时间为5秒；第二层第一层UV曝光强度为45，UV曝光时间为4秒；第三层UV曝光强度为40，UV曝光时间为4秒；第四层UV曝光强度为40，UV曝光时间为3秒；第五层UV曝光强度为40，UV曝光时间为3秒(3D打印一体成型制备得到的空腔台和微针阵列如图8所示，本申请的基于微针阵列的负压式快速提取储存组织液的装置的微针阵列可以制备成不同的规格，在本实施例中制备了两种规格的微针阵列，微针数量分别为5×5、11×11)。The microneedle prototype was designed using the modeling software Cinema 4D, and was input into the computer connected to the high-precision 3D printing system in .STL format. The model was sliced into the scanned cross-section required for printing with the set layer thickness for preparation of printing. The printing technology of the high-precision 3D printing system is photocuring molding technology. By irradiating the liquid surface of the photosensitive resin with ultraviolet light, the resin liquid surface is solidified into a scanned model cross-section layer film. After the curing is completed, the resin is continued to be scanned layer by layer on the newly formed layer film until the model is completed. The high-precision 3D printer used in this embodiment has a high resolution (the x-axis and y-axis resolution can be 10μm, and the layer thickness is 10μm), and the material used is a biocompatible photocurable resin. The two main parameters of the high-precision 3D printing system that affect the printing completion of the model are UV exposure intensity and UV exposure time. For the microstructure of printed microneedles in this case, the number of printing layers used is 500, and the thickness of a single layer is 10 μm. In order from the cavity table to the tip of the microneedle array, the UV exposure intensity of the first layer is 50, and the UV exposure time is 5 seconds; the UV exposure intensity of the first layer of the second layer is 45, and the UV exposure time is 4 seconds; the UV exposure intensity of the third layer is 40, and the UV exposure time is 4 seconds; the UV exposure intensity of the fourth layer is 40, and the UV exposure time is 3 seconds; the UV exposure intensity of the fifth layer is 40, and the UV exposure time is 3 seconds (the cavity table and microneedle array prepared by one-piece 3D printing are shown in Figure 8. The microneedle array of the device for negative pressure rapid extraction and storage of tissue fluid based on the microneedle array of the present application can be prepared into different specifications. In this embodiment, two specifications of microneedle arrays are prepared, and the number of microneedles is 5×5 and 11×11, respectively).
使用扫描电子显微镜观察微针阵列的结构，观察结果如图9所示，本申请的基于微针阵列的负压式快速提取储存组织液的装置的微针阵列上的微针的孔道可以有若干个，图9中展示的分别是单个孔道和两个孔道的微针扫描电子显微镜的观察结果。The structure of the microneedle array was observed using a scanning electron microscope, and the observation results are shown in FIG9 . The microneedle array of the device for negative pressure rapid extraction and storage of tissue fluid based on a microneedle array of the present application may have several channels, and FIG9 shows the scanning electron microscope observation results of the microneedles with a single channel and two channels, respectively.
应用例Application Examples
一、皮肤模型提取测试1. Skin model extraction test
使用1％琼脂糖水凝胶模拟人体皮肤，并将罗丹明B染料掺入水凝胶中以便肉眼观察真空采样管内提取情况。1% agarose hydrogel was used to simulate human skin, and rhodamine B dye was incorporated into the hydrogel to facilitate visual observation of the extraction in the vacuum sampling tube.
将连有连接管的空腔台(微针数量分别为5×5、11×11)压入水凝胶皮肤模型表面，保持按压状态，将连接管另一端接入真空采样管(基于微针阵列的负压式快速提取储存组织液的装置的实物如图10所示)。开始计时，保持按压状态并观察真空采样管内提取情况，待提取基本完成，无液体流入采样管后，将组织液提取装置从皮肤模型中移除，连接管与真空采样管断开连接。提取量为真空采样管提取前后质量差。Press the cavity stage (the number of microneedles is 5×5 and 11×11 respectively) with a connecting tube into the surface of the hydrogel skin model, keep pressing, and connect the other end of the connecting tube to the vacuum sampling tube (the actual negative pressure rapid extraction and storage device of tissue fluid based on microneedle array is shown in Figure 10). Start timing, keep pressing and observe the extraction in the vacuum sampling tube. When the extraction is basically completed and no liquid flows into the sampling tube, remove the tissue fluid extraction device from the skin model and disconnect the connecting tube from the vacuum sampling tube. The extraction amount is the mass difference before and after the vacuum sampling tube extraction.
采样结果表明，在2分钟采样时间内，本发明提供的基于微针阵列的负压式快速提取储存组织液的装置采样量可达到490μL以上(图11)。The sampling results show that within a sampling time of 2 minutes, the sampling volume of the negative pressure device for rapid extraction and storage of tissue fluid based on a microneedle array provided by the present invention can reach more than 490 μL ( FIG. 11 ).
二、小鼠活体穿刺实验2. In vivo puncture experiment in mice
实验小鼠(20g的雌性BALB/c裸鼠)背部用碘伏进行消毒后使用脱毛膏脱毛，然后用生理盐水擦拭干净。将连有连接管的空腔台微针(微针数量为11×11)压入脱毛小鼠的背部后，保持按压状态，将连接管另一端接入真空采样管。保持按压状态3分钟后，移除提取装置，在移除提取装置后的0、5、15和30分钟拍摄小鼠背部插入位置的皮肤，观察小鼠皮肤的愈合情况。The back of the experimental mouse (20g female BALB/c nude mouse) was disinfected with iodine tincture, depilated with depilatory cream, and then wiped clean with saline. After the cavity microneedle (microneedle number 11×11) with a connecting tube was pressed into the back of the depilated mouse, the pressing state was maintained, and the other end of the connecting tube was connected to the vacuum sampling tube. After maintaining the pressing state for 3 minutes, the extraction device was removed, and the skin at the insertion position on the back of the mouse was photographed at 0, 5, 15 and 30 minutes after the extraction device was removed to observe the healing of the mouse skin.
另外，对移除提取装置后5、15、30分钟的小鼠皮肤进行切片，并用苏木精-伊红(H&E)染色以展示微针在小鼠皮肤中的插入深度。In addition, the mouse skin was sectioned 5, 15, and 30 minutes after the removal of the extraction device and stained with hematoxylin-eosin (H&E) to demonstrate the insertion depth of the microneedles in the mouse skin.
小鼠皮肤背部观察结果如图12所示，小鼠皮肤组织切片苏木精-伊红染色结果如图13所示。可见，可见微针阵列到小鼠皮肤表层下，微针阵列插入小鼠皮肤5分钟后取下时皮肤上可以看到明显的孔状阵列，微针阵列取下15分钟时，孔状深度逐渐变浅，随着时间推移到30分钟，小鼠皮肤的针孔逐渐恢复。The observation results of the back of the mouse skin are shown in Figure 12, and the results of hematoxylin-eosin staining of the mouse skin tissue section are shown in Figure 13. It can be seen that the microneedle array is visible under the surface of the mouse skin. When the microneedle array is removed after being inserted into the mouse skin for 5 minutes, an obvious hole array can be seen on the skin. When the microneedle array is removed for 15 minutes, the depth of the hole gradually becomes shallower. As time goes by to 30 minutes, the pinholes in the mouse skin gradually recover.
结果表明，利用微针阵列提取小鼠皮肤组织液后，对于小鼠皮肤并未形成创面或损伤。经微针按压后小鼠皮肤形成的针孔很快就能自行恢复，表明该基于空心微针的组织液提取储存装置对于小鼠皮肤的影响较低，是一种皮肤友好的组织液提取方式。The results showed that after extracting mouse skin tissue fluid using the microneedle array, no wounds or damage were formed on the mouse skin. The pinholes formed on the mouse skin after microneedle pressing could quickly recover on their own, indicating that the tissue fluid extraction and storage device based on hollow microneedles had little impact on the mouse skin and was a skin-friendly tissue fluid extraction method.
三、新西兰兔活体组织液提取及提取的组织液的成分化验3. Extraction of tissue fluid from New Zealand rabbits and analysis of the components of the extracted tissue fluid
将新西兰兔(2.5kg，雌性)称重并固定于兔固定台上，按1mL/kg、3％的剂量配制戊巴比妥钠生理盐水溶液，沿耳缘静脉注射缓慢注射戊巴比妥钠麻醉剂。确认麻醉成功后，用碘伏进行消毒。使用脱毛剂在兔耳背侧脱毛，并用生理盐水擦拭干净。将连有连接管的空腔台微针(微针数量分别为5×5、11×11)压入兔耳后，保持按压状态，将连接管另一端接入真空采样管。保持按压状态5分钟后，统计提取到组织液的量，结果如图14所示。可见，本发明的基于微针阵列的负压式快速提取储存组织液的装置在5分钟内可采集到大于80μL的组织液。New Zealand rabbits (2.5 kg, female) were weighed and fixed on a rabbit fixing table, and sodium pentobarbital saline solution was prepared at a dose of 1 mL/kg and 3%, and sodium pentobarbital anesthetic was slowly injected along the ear vein. After confirming that anesthesia was successful, disinfection was performed with iodine tincture. Depilatory agents were used to remove hair on the dorsal side of the rabbit ears, and wiped clean with saline. After the cavity stage microneedles (the number of microneedles was 5×5 and 11×11, respectively) connected to the connecting tube were pressed into the rabbit ears, the pressing state was maintained, and the other end of the connecting tube was connected to the vacuum sampling tube. After maintaining the pressing state for 5 minutes, the amount of tissue fluid extracted was counted, and the results are shown in Figure 14. It can be seen that the negative pressure type device for quickly extracting and storing tissue fluid based on the microneedle array of the present invention can collect more than 80 μL of tissue fluid within 5 minutes.
利用本发明涉及到的装置，提取新西兰兔活体组织液后，采用市售血糖和尿酸仪可直接测定其组织液中葡萄糖和尿酸的浓度。测量结果发现，其组织液中葡萄糖浓度为13.43mmol/L，尿酸浓度为225.67μmol/L。The device involved in the present invention is used to extract tissue fluid from New Zealand rabbits, and then the concentrations of glucose and uric acid in the tissue fluid can be directly measured using a commercially available blood glucose and uric acid meter. The measurement results show that the glucose concentration in the tissue fluid is 13.43mmol/L and the uric acid concentration is 225.67μmol/L.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。此外，本领域的技术人员可以将本说明书中描述的不同实施例或示例进行接合和组合。In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine different embodiments or examples described in this specification.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary the above embodiments within the scope of the present invention.
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| CN202310301758.8ACN116509458B (en) | 2023-03-13 | 2023-03-13 | Device for rapidly extracting and storing tissue fluid under negative pressure based on microneedle array |
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| CN202310301758.8ACN116509458B (en) | 2023-03-13 | 2023-03-13 | Device for rapidly extracting and storing tissue fluid under negative pressure based on microneedle array |
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