CN102068719A - Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereof - Google Patents
Adhesion prevention material formed by physical crosslinking hydrogel composition and preparation method and application thereofDownload PDFInfo
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Abstract
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Description
Translated fromChinese技术领域technical field
本发明属于高分子材料和医疗技术领域，具体涉及一种物理交联水凝胶组合物材料，其水体系能够随着温度升高发生热敏凝胶化，即温度低于凝胶转变温度时，组合物为液体，当温度升高至溶胶－凝胶转变温度或以上时，组合物自发形成凝胶。该材料可以注射及涂覆在术后创面，作为医用术后防粘连阻隔材料使用。The invention belongs to the field of polymer materials and medical technology, and specifically relates to a physically cross-linked hydrogel composition material, the water system of which can undergo heat-sensitive gelation as the temperature rises, that is, when the temperature is lower than the gel transition temperature , the composition is liquid, and when the temperature rises to the sol-gel transition temperature or above, the composition spontaneously forms a gel. The material can be injected and coated on postoperative wounds, and used as a medical postoperative anti-adhesion barrier material.
背景技术Background technique
术后粘连是长期困扰外科手术领域的一个重要问题。腹腔术后产生的粘连会导致盆腔疼痛，肠梗阻以及不孕不育等一系列并发症，在肌腱修复手术中，粘连会导致患者运动功能障碍的问题。目前预防术后粘连的方法很多，包括手术方法的改进、术后局部药物的应用、术后局部阻隔材料的应用，以及术后早期适当的活动和后期的锻炼等等。其中可降解吸收的阻隔材料由于其优良的组织隔离效果，以及无需二次手术取出材料的便利，在术后预防粘连领域已受到越来越多的关注。Postoperative adhesion is an important problem that has plagued the surgical field for a long time. Adhesions after abdominal surgery can lead to a series of complications such as pelvic pain, intestinal obstruction, and infertility. In tendon repair surgery, adhesions can cause motor dysfunction in patients. At present, there are many ways to prevent postoperative adhesions, including the improvement of surgical methods, the application of postoperative local drugs, the application of postoperative local barrier materials, and appropriate early postoperative activities and postoperative exercises. Among them, degradable and absorbable barrier materials have received more and more attention in the field of postoperative adhesion prevention due to their excellent tissue isolation effect and the convenience of removing materials without secondary surgery.
目前常用的可降解的阻隔材料分为两大类：The commonly used degradable barrier materials are divided into two categories:
一类是可降解的固态薄膜，包括聚乳酸膜、多聚纤维素膜等，其中部分材料已经产业化。但是这类材料由于其固体形态的特点，导致了其在微创手术中的应用存在一定困难。更重要的是，薄膜容易粘在带液体的表面，导致了在放置器械的过程中容易粘在操作者的手套以及其它非创面部位，因此实际操作并不方便。One is degradable solid film, including polylactic acid film, polycellulose film, etc., some of which have been industrialized. However, due to the characteristics of solid form, this kind of material has certain difficulties in its application in minimally invasive surgery. More importantly, the film is easy to stick to the surface with liquid, which makes it easy to stick to the operator's gloves and other non-wound parts during the placement of the device, so the actual operation is not convenient.
而另一类材料属于水溶液和凝胶，因为它具有一定的流动能力，可以注射和涂覆在手术创面，提高了体内复杂几何形态创面的覆盖率，也增加了材料应用的方便性，因此其作为医疗植入材料的应用越来越受关注。比如：美国麻省理工大学的Kohane等人曾报导化学交联的葡聚糖、海藻酸钠及纤维素衍生物水凝胶应用于术后防粘连，此类化学凝胶需要使用具有一定生物毒性的化学交联引发剂，其生物安全隐患是制约它们实际应用的一个大问题。某些具有温度响应的物理凝胶，由于它们具备在体温下自发成胶的特点，被认为有希望取得临床应用。泊洛沙姆（Poloxamer）便是其中之一，但这种由PEG和PPG组成的嵌段聚合物不能被生物降解，而且凝胶在体内只能维持数天即被体液稀释，因此作为预防粘连的阻隔材料的效果并不是十分理想。申请号200910304210.9和201010138739.0的中国专利，提出了由PEG和PCL组成的三嵌段共聚物作为温敏的凝胶材料用于术后防粘连；申请号201010133541.3的中国专利报道了由MPEG和PLA组成的两嵌段聚合物温敏凝胶用于术后防粘连。上述专利所用的材料均为单一组分的该类嵌段共聚物。该类聚合物具有单一组成和分子量分布，一定浓度下具有热敏凝胶化的性能。The other type of material belongs to aqueous solution and gel, because it has a certain flow ability, it can be injected and coated on the surgical wound, which improves the coverage of complex geometric wounds in the body, and also increases the convenience of material application, so its Applications as medical implant materials are gaining more and more attention. For example: Kohane et al. from the Massachusetts Institute of Technology have reported that chemically cross-linked dextran, sodium alginate and cellulose derivative hydrogels are used for postoperative anti-adhesion. This type of chemical gel needs to be used with certain biological toxicity. The chemical cross-linking initiators, their biological safety hazard is a big problem restricting their practical application. Certain temperature-responsive physical gels are considered promising for clinical applications due to their spontaneous gelation at body temperature. Poloxamer (Poloxamer) is one of them, but this block polymer composed of PEG and PPG cannot be biodegraded, and the gel can only last for a few days in the body before being diluted by body fluids, so as to prevent adhesions The effect of the barrier material is not very ideal. Chinese patents with application numbers 200910304210.9 and 201010138739.0 propose a triblock copolymer composed of PEG and PCL as a temperature-sensitive gel material for postoperative anti-adhesion; Diblock polymer thermosensitive gel for postoperative anti-adhesion. The materials used in the above-mentioned patents are all single-component block copolymers. This type of polymer has a single composition and molecular weight distribution, and has heat-sensitive gelling performance at a certain concentration.
但是，单一组分的该类嵌段共聚物存在如下问题：But, there is following problem in this type of block copolymer of single component:
（1）超出一定组成和/或分子量的大小，就只能够完全溶于水或者部分或完全变为沉淀，从而丧失了溶胶－凝胶转变、不再具有相关的热敏凝胶化的性能；(1) Exceeding a certain composition and/or molecular weight, it can only be completely dissolved in water or partially or completely become precipitated, thus losing the sol-gel transition and no longer having the relevant heat-sensitive gelling performance;
（2）此外，部分聚合物即使可以出现热敏特性，其凝胶化温度也不合适人体应用；(2) In addition, even if some polymers can have heat-sensitive properties, their gelation temperature is not suitable for human application;
（3）其降解速率的调节范围和动力学过程有一定局限性，限制了其医学用途。(3) The adjustment range and kinetic process of its degradation rate have certain limitations, which limits its medical use.
发明内容Contents of the invention
本发明的目的是提供一种具有热敏凝胶化性能的医用高分子材料，作为术后预防组织粘连的阻隔材料。该材料基本组成是具有良好生物相容性的可降解材料，降解速率在一定范围内可以通过改变共聚物组成调节，与不同场合的应用需求相匹配，材料具有良好的生物相容性，没有明显的细胞毒性和溶血行为。The purpose of the present invention is to provide a medical polymer material with heat-sensitive gelling performance as a barrier material for preventing tissue adhesion after operation. The basic composition of the material is a degradable material with good biocompatibility. The degradation rate can be adjusted within a certain range by changing the composition of the copolymer to match the application requirements of different occasions. The material has good biocompatibility without obvious cytotoxicity and hemolytic behavior.
本发明的热敏凝胶化的水凝胶组合物构成的防粘连材料，是两种或两种以上聚合物的混合物，其水体系能够随着温度升高发生热敏凝胶化，当温度低于溶胶－凝胶转变温度时，聚合物混合物可溶解于水，在温度高于溶胶－凝胶转变温度时，聚合物混合物的水溶液自发形成凝胶，并且这一过程是可逆的；其中的聚合物中包括由聚乙二醇（PEG）为亲水嵌段、可降解的聚酯为疏水嵌段所构成的嵌段共聚物。The anti-adhesion material formed by the heat-sensitive gelling hydrogel composition of the present invention is a mixture of two or more polymers, and its water system can undergo heat-sensitive gelation as the temperature rises. When the temperature When the temperature is lower than the sol-gel transition temperature, the polymer mixture can be dissolved in water. When the temperature is higher than the sol-gel transition temperature, the aqueous solution of the polymer mixture spontaneously forms a gel, and this process is reversible; The polymer includes a block copolymer composed of polyethylene glycol (PEG) as a hydrophilic block and degradable polyester as a hydrophobic block.
本发明的聚合物混合物溶液中含调节剂，其在水体系中的重量百分含量介于0-15%，优选0.5-15%，更优选1-10%，因具体需要而定；调节剂可选自糖、盐、羧甲基纤维素钠、（碘）甘油、二甲硅油、丙二醇、卡波姆、甘露醇、山犁醇、表面活性剂、吐温20、吐温40、吐温80、木糖醇、低聚糖、软骨素、甲壳素、壳聚糖、胶原蛋白、明胶、蛋白胶、透明质酸、聚乙二醇中的一种或其组合。调节剂可为其它医用敷料，如但不限于，填充剂、增溶剂、吸收促进剂、成膜剂、凝胶剂、致孔剂、赋型剂或阻滞剂等。Contain regulator in the polymer mixture solution of the present invention, its weight percentage in water system is between 0-15%, preferably 0.5-15%, more preferably 1-10%, depends on specific needs; Regulator Can be selected from sugar, salt, sodium carboxymethylcellulose, (iodo)glycerin, simethicone, propylene glycol, carbomer, mannitol, behenitol, surfactant, Tween 20, Tween 40, Tween 80. One or a combination of xylitol, oligosaccharides, chondroitin, chitin, chitosan, collagen, gelatin, protein glue, hyaluronic acid, polyethylene glycol. Conditioning agents can be other medical dressings, such as, but not limited to, fillers, solubilizers, absorption enhancers, film formers, gelling agents, porogens, excipients, or blocking agents.
本发明的聚合物混合物中，有一种或一种以上嵌段共聚物的水体系单独不具有热敏凝胶化的性质，这一种或一种以上嵌段共聚物本身在1－50°C范围内均只能溶解于水中，因而单独不能出现热敏凝胶化；或者，一种或一种以上嵌段共聚物在1－50°C范围内不能溶于水或不能完全溶解于水中，因而单独也不能出现热敏凝胶化。In the polymer mixture of the present invention, the water system with one or more block copolymers alone does not have the property of heat-sensitive gelation, and the one or more block copolymers themselves have a temperature of 1-50°C All within the range can only be dissolved in water, so heat-sensitive gelation cannot occur alone; or, one or more block copolymers cannot be dissolved in water or cannot be completely dissolved in water in the range of 1-50 ° C, Therefore, heat-sensitive gelation cannot occur alone.
本发明的聚合物混合物中，有一种或一种以上嵌段共聚物本身在1－50°C范围内均只能溶解于水中，同时，另外一种或一种以上嵌段共聚物在1－50°C范围内不能溶于水或不能完全溶解于水中。In the polymer mixture of the present invention, one or more block copolymers themselves can only be dissolved in water in the range of 1-50°C, and at the same time, another one or more block copolymers are soluble in 1-50°C. Insoluble or not completely soluble in water within 50°C.
本发明的聚合物混合物中，各个嵌段共聚物的水体系也可以均不具有热敏凝胶化的性质。In the polymer mixture of the present invention, the aqueous system of each block copolymer may not have the property of heat-sensitive gelation.
本发明的聚合物混合物中每种嵌段共聚物的重量百分比含量介于5-95%。The content of each block copolymer in the polymer mixture of the present invention is 5-95% by weight.
本发明的嵌段共聚物包括10-90 wt %的含有具有400至8000的平均分子量的聚乙二醇的亲水性A聚合物嵌段和90-10 wt %的疏水性B聚合物嵌段。The block copolymer of the present invention comprises 10-90 wt % of hydrophilic A polymer blocks containing polyethylene glycol having an average molecular weight of 400 to 8000 and 90-10 wt % of hydrophobic B polymer blocks .
本发明的疏水性B聚合物嵌段为具有500-40000的平均分子量的聚酯。The hydrophobic B polymer block of the present invention is a polyester having an average molecular weight of 500-40,000.
本发明的聚酯选自各种聚DL-丙交酯、聚D-丙交酯、聚L-丙交酯、聚乙交酯、聚原酸酯、聚ε-己内酯、聚ε-烷基取代己内酯、聚δ-戊内酯、聚1,4,8–三氧杂螺[4.6]–9–十一烷酮、聚对二氧六环酮、聚酰胺酯、聚碳酸酯、聚丙烯酸酯、聚醚酯中的任何一种，或者上述各类聚酯的任何形式的共聚物。The polyester of the present invention is selected from various polyDL-lactide, polyD-lactide, polyL-lactide, polyglycolide, polyorthoester, polyε-caprolactone, polyε- Alkyl-substituted caprolactone, polydelta-valerolactone, poly-1,4,8-trioxaspiro[4.6]-9-undecanone, polydioxanone, polyesteramide, polycarbonate Any one of esters, polyacrylates, polyether esters, or any form of copolymer of the above-mentioned types of polyesters.
本发明的嵌段共聚物为ABA、BAB嵌段构型的三嵌段共聚物、BA嵌段构型的二嵌段共聚物和A(BA)n或B(AB)n嵌段构型的多嵌段共聚物，其中n为2至10的整数。The block copolymer of the present invention is ABA, the triblock copolymer of BAB block configuration, the diblock copolymer of BA block configuration and A(BA)n or B(AB)n block configuration Multi-block copolymers, whereinn is an integer from 2 to 10.
本发明的聚合物混合物在水溶液中的重量百分比含量介于3-50%，但以10-30％为优选，15-28％为最优选。The weight percent content of the polymer mixture of the present invention in the aqueous solution ranges from 3-50%, but is preferably 10-30%, and most preferably 15-28%.
本发明的聚合物混合物溶液中的溶剂可以是纯水、注射用水、生理盐水、缓冲溶液、动植物或人体的体液、组织培养液、细胞培养液，或者为其它水溶液和不以有机溶剂为主体的介质。The solvent in the polymer mixture solution of the present invention can be pure water, water for injection, physiological saline, buffer solution, animal, plant or human body fluid, tissue culture fluid, cell culture fluid, or other aqueous solutions and not based on organic solvents medium.
本发明的聚合物混合物与溶剂的体系中，除了嵌段共聚物与溶剂以外，可以包含其它类型的聚合物或/和非聚合物成分。In addition to the block copolymer and solvent, the polymer mixture and solvent system of the present invention may contain other types of polymer and/or non-polymer components.
本发明的水凝胶组合物构成的防粘连材料，其应用场合包括预防手术后导致的肠粘连、腹腔粘连、肌腱粘连、输卵管粘连和输尿管粘连等。The application of the anti-adhesion material composed of the hydrogel composition of the present invention includes prevention of intestinal adhesion, abdominal cavity adhesion, tendon adhesion, fallopian tube adhesion and ureteral adhesion caused after operation.
本发明的水凝胶组合物构成的防粘连材料，还可负载消炎、镇痛或生长因子等药物，以进一步促进伤口愈合，防止创面之间粘连的发生。The anti-adhesion material composed of the hydrogel composition of the present invention can also be loaded with drugs such as anti-inflammatory, analgesic or growth factors to further promote wound healing and prevent the occurrence of adhesion between wound surfaces.
本发明的水凝胶组合物构成的防粘连材料的制备方法是：首先混合两种或两种以上聚合物，然后在低温溶解聚合物混合物于水中；或者首先在低温分别溶解两种或两种以上聚合物，然后混合各自的水溶液；或者首先在低温溶解具有水溶性的聚合物，然后再加入不具有或不完全具有水溶性的聚合物进行增溶，从而制备水凝胶组合物。以上所述低温指低于组合物的溶胶－凝胶转变温度。所制备的聚合物混合物的水溶液在温度高于溶胶－凝胶转变温度时能够热敏形成水凝胶。通常，所制备的聚合物混合物的水溶液在-10℃或以下存储备用，使用前升温复溶后使用。The preparation method of the anti-adhesion material composed of the hydrogel composition of the present invention is: first mix two or more polymers, then dissolve the polymer mixture in water at low temperature; or first dissolve two or two polymers respectively at low temperature The above polymers are then mixed with their respective aqueous solutions; or the water-soluble polymers are firstly dissolved at low temperature, and then non- or incompletely water-soluble polymers are added for solubilization, thereby preparing a hydrogel composition. The low temperature mentioned above means below the sol-gel transition temperature of the composition. The prepared aqueous solution of the polymer mixture can thermosensitively form a hydrogel when the temperature is higher than the sol-gel transition temperature. Usually, the prepared aqueous solution of the polymer mixture is stored at -10°C or below for future use, and is used after heating up and reconstituted before use.
上述方法中，聚合物混合物溶液中还含调节剂，其在水体系中的重量百分含量介于0-15%，优选0.5-15%，更优选1-10%，因具体需要而定；调节剂可选自糖、盐、羧甲基纤维素钠、（碘）甘油、二甲硅油、丙二醇、卡波姆、甘露醇、山犁醇、表面活性剂、吐温20、吐温40、吐温80、木糖醇、低聚糖、软骨素、甲壳素、壳聚糖、胶原蛋白、明胶、蛋白胶、透明质酸、聚乙二醇中的一种或其组合。调节剂可为其它医用敷料，如但不限于，填充剂、增溶剂、吸收促进剂、成膜剂、凝胶剂、致孔剂、赋型剂或阻滞剂等。In the above method, the polymer mixture solution also contains a regulator, and its weight percentage in the water system is between 0-15%, preferably 0.5-15%, more preferably 1-10%, depending on specific needs; Conditioning agents may be selected from sugar, salt, sodium carboxymethylcellulose, (iodo)glycerin, simethicone, propylene glycol, carbomer, mannitol, behenitol, surfactants, Tween 20, Tween 40, One or a combination of Tween 80, xylitol, oligosaccharides, chondroitin, chitin, chitosan, collagen, gelatin, protein glue, hyaluronic acid, polyethylene glycol. Conditioning agents can be other medical dressings, such as, but not limited to, fillers, solubilizers, absorption enhancers, film formers, gelling agents, porogens, excipients, or blocking agents.
上述方法中，低温指0℃到室温。In the above method, low temperature refers to 0°C to room temperature.
上述方法中，低温特别指冰箱冷藏温度（4℃）。In the above method, the low temperature especially refers to the refrigeration temperature of the refrigerator (4°C).
上述方法中，聚合物为由聚乙二醇（PEG）为亲水嵌段、可降解的聚酯为疏水嵌段所构成的嵌段共聚物。In the above method, the polymer is a block copolymer composed of polyethylene glycol (PEG) as a hydrophilic block and degradable polyester as a hydrophobic block.
上述方法中，嵌段共聚物通过热缩合或开环聚合得到。In the above method, the block copolymer is obtained by thermal condensation or ring-opening polymerization.
上述方法中，开环聚合采用的催化剂为异辛酸亚锡、氢化钙或锌粉。In the above method, the catalyst used in the ring-opening polymerization is stannous isooctanoate, calcium hydride or zinc powder.
上述方法中，混合物中有一种或一种以上嵌段共聚物的水体系单独不具有热敏凝胶化的性质，这一种或一种以上嵌段共聚物本身在1－50°C范围内均只能溶解于水中，因而单独不能出现热敏凝胶化；或者，一种或一种以上嵌段共聚物在1－50°C范围内不能溶于水或不能完全溶解于水中，因而单独也不能出现热敏凝胶化。In the above method, the water system with one or more block copolymers in the mixture does not have the property of thermosensitive gelation alone, and the one or more block copolymers themselves are in the range of 1-50°C Both can only be dissolved in water, so heat-sensitive gelation cannot occur alone; or, one or more block copolymers are insoluble in water or cannot be completely dissolved in water in the range of 1-50°C, so they cannot be dissolved in water alone. Heat-sensitive gelation cannot occur either.
上述方法中，混合物中的一种或一种以上嵌段共聚物本身在1－50°C范围内只能溶解于水中，同时，另外一种或一种以上嵌段共聚物在1－50°C范围内不能溶于水或不能完全溶解于水中。In the above method, one or more block copolymers in the mixture can only dissolve in water in the range of 1-50°C, and at the same time, another one or more block copolymers can only dissolve in water at 1-50°C. In the range of C, it cannot be dissolved in water or cannot be completely dissolved in water.
上述方法中，混合物中的各个嵌段共聚物的水体系单独都不具有热敏凝胶化的性质。In the above method, the aqueous system of each block copolymer in the mixture does not have the property of heat-sensitive gelation alone.
上述方法中，混合物中的每种嵌段共聚物的重量百分比含量介于5-95%。In the above method, the content of each block copolymer in the mixture is 5-95% by weight.
上述方法中，嵌段共聚物包括： In the above-mentioned method, block copolymer comprises:
a）10-90 wt %的含有具有400至8000的平均分子量的聚乙二醇的亲水性A聚合物嵌段；a) 10-90 wt % of a hydrophilic A polymer block containing polyethylene glycol having an average molecular weight of 400 to 8000;
b）90-10 wt %的疏水性B聚合物嵌段。b) 90–10 wt% hydrophobic B polymer block.
上述方法中，疏水性B聚合物嵌段为具有500-40000的平均分子量的聚酯。In the above method, the hydrophobic B polymer block is a polyester having an average molecular weight of 500-40,000.
上述方法中，聚酯选自各种聚DL-丙交酯、聚D-丙交酯、聚L-丙交酯、聚乙交酯、聚原酸酯、聚ε-己内酯、聚ε-烷基取代己内酯、聚δ-戊内酯、聚1,4,8–三氧杂螺[4.6]–9–十一烷酮、聚对二氧六环酮、聚酰胺酯、聚碳酸酯、聚丙烯酸酯、聚醚酯中的任何一种以及上述各类聚酯的任何形式的共聚物。In the above method, the polyester is selected from various polyDL-lactide, polyD-lactide, polyL-lactide, polyglycolide, polyorthoester, polyε-caprolactone, polyε -Alkyl-substituted caprolactone, polydelta-valerolactone, poly-1,4,8-trioxaspiro[4.6]-9-undecanone, polydioxanone, polyesteramide, poly Any one of carbonates, polyacrylates, polyether esters, and any form of copolymer of the above-mentioned types of polyesters.
上述方法中，嵌段共聚物为ABA、BAB嵌段构型的三嵌段共聚物、BA嵌段构型的二嵌段共聚物或A(BA)n或B(AB)n嵌段构型的多嵌段共聚物，其中n为2至10的整数。In the above method, the block copolymer is a triblock copolymer of ABA, BAB block configuration, a diblock copolymer of BA block configuration or A(BA)n or B(AB)n block configuration A multi-block copolymer, whereinn is an integer from 2 to 10.
上述方法中，聚合物混合物在水溶液中的重量百分含量介于3-50%，但以10-30％为优选，15-28％为最优选。In the above method, the weight percentage of the polymer mixture in the aqueous solution is between 3-50%, but preferably 10-30%, most preferably 15-28%.
上述方法中，聚合物混合物溶液中的溶剂可以是纯水、注射用水、生理盐水、缓冲溶液、动植物或人体的体液、组织培养液、细胞培养液，或者为其它水溶液和不以有机溶剂为主体的介质。In the above-mentioned method, the solvent in the polymer mixture solution can be pure water, water for injection, physiological saline, buffer solution, animal, plant or human body fluid, tissue culture fluid, cell culture fluid, or other aqueous solutions and not organic solvents. The medium of the subject.
上述方法中，可以在含有嵌段共聚物的混合物中进一步混合其他类型的聚合物、甚至非聚合物成分，以促进物理凝胶的出现或者调节在溶液中的溶胶－凝胶转变温度、材料的降解速率等参量。In the above method, other types of polymers and even non-polymer components can be further mixed in the mixture containing block copolymers to promote the appearance of physical gel or adjust the sol-gel transition temperature in solution, the material's Degradation rate and other parameters.
上述方法中，聚合物混合物溶液中还可同时负载消炎、镇痛、生长因子等药物，以进一步促进伤口愈合，防止创面之间粘连的发生。In the above method, the polymer mixture solution can also be loaded with anti-inflammatory, analgesic, growth factors and other drugs to further promote wound healing and prevent the occurrence of adhesion between wound surfaces.
上述方法中，嵌段共聚物的比例可以予以调节，从而得到所需要的溶胶－凝胶转变温度和降解速率等。In the above method, the ratio of the block copolymer can be adjusted to obtain the desired sol-gel transition temperature and degradation rate.
本发明优点在于：The present invention has the advantage that:
本发明提出的防粘连材料具有可逆的温敏性，其聚合物混合物能够在常温或低于常温时显示水溶性，并在热血动物生理条件下（即在pH值为7左右和37℃下）能够进行热可逆凝胶化，从而使得材料的制备过程简单，实际操作和应用非常方便。The anti-adhesion material proposed by the present invention has reversible temperature sensitivity, and its polymer mixture can show water solubility at room temperature or lower than room temperature, and can be used under the physiological conditions of warm-blooded animals (that is, at a pH value of about 7 and 37 ° C) It is capable of thermally reversible gelation, so that the preparation process of the material is simple, and the actual operation and application are very convenient.
本发明提出的防粘连材料具有良好的生物相容性、可降解性及凝胶的柔顺性，该材料会在给定时间内完全降解为无毒的α-醇酸和其它相应的单体。The anti-adhesion material proposed by the present invention has good biocompatibility, degradability and gel flexibility, and the material can be completely degraded into non-toxic α-alkyd and other corresponding monomers within a given time.
本发明提出的防粘连材料包含了PEG嵌段，由于PEG具有天然的阻抗细胞和蛋白黏附的性能，因此在阻止粘附生成和发展的效果上，包含PEG的聚酯-聚醚嵌段共聚物有更好的效果。The anti-adhesion material proposed by the present invention contains PEG blocks. Since PEG has natural resistance to cell and protein adhesion, the polyester-polyether block copolymer containing PEG is more effective in preventing the formation and development of adhesion. Have a better effect.
附图说明Description of drawings
图1. 为按照不同重量比例混合得到的嵌段共聚物混合物其PBS溶液随着温度变化时的相图。用小管倒置法测定。Figure 1. is the phase diagram of the PBS solution of the block copolymer mixture obtained by mixing according to different weight ratios as the temperature changes. Measured by tube inversion method.
图 2. 为按照不同重量比例混合得到的嵌段共聚物混合物水凝胶在体外降解实验中平均分子量随降解时间的变化曲线（隔4天更换缓冲液，保持pH稳定），说明材料具有可降解性。Figure 2. The curve of the average molecular weight versus degradation time in the in vitro degradation experiment of the block copolymer mixture hydrogel mixed according to different weight ratios (buffer solution is replaced every 4 days to keep the pH stable), indicating that the material is degradable sex.
图 3. 为MTT法表征添加了不同浓度且由不同重量比例混合得到的嵌段共聚物混合物材料的培养液对MC-3T3细胞活力的影响，证实材料具有良好的生物相容性。Figure 3. The MTT method was used to characterize the effect of the culture medium of block copolymer mixture materials with different concentrations and mixed in different weight ratios on the viability of MC-3T3 cells, confirming that the materials have good biocompatibility.
具体实施方式Detailed ways
下面通过实例进一步描述本发明，但不限于这些实施例。The present invention is further described by examples below, but not limited to these examples.
实施例1Example 1
在250 ml三口烧瓶中加入PEG（1500），油浴加热到150℃，搅拌下真空抽滤三个小时，以去除PEG中残留的水分，然后加入摩尔比为4:1的DL-丙交酯和乙交酯，真空下加热使其完全熔融之后，加入120 μl辛酸亚锡，油浴升温到160℃，在氩气气氛下继续反应24个小时。反应完毕，真空抽滤两个小时以除去没有反应的单体和低沸点的产物。把初产物溶于二氯甲烷溶液中，乙醚沉淀，产率约为80％。通过凝胶渗透色谱仪（GPC）（采用聚苯乙烯作为标样）测定所述BAB嵌段共聚物（PLGA-PEG-PLGA, Copolymer-1）的数均与重均分子量（Mn，Mw）分别为5510和6390，分子量分布系数（Mw/Mn）为1.16。此共聚物本身在水中不具有热敏凝胶化的性能。Add PEG (1500) into a 250 ml three-necked flask, heat the oil bath to 150°C, and vacuum filter for three hours while stirring to remove the residual moisture in the PEG, and then add DL-lactide with a molar ratio of 4:1 And glycolide, after heating under vacuum to make it melt completely, add 120 μl stannous octoate, the oil bath is heated up to 160 ℃, continue to react under argon atmosphere for 24 hours. After the reaction was completed, vacuum filtration was performed for two hours to remove unreacted monomers and low-boiling products. The initial product was dissolved in dichloromethane solution and precipitated with ether, the yield was about 80%. The number-average and weight-average molecular weight (Mn ,Mw ) of the BAB block copolymer (PLGA-PEG-PLGA, Copolymer-1) was measured by gel permeation chromatography (GPC) (using polystyrene as a standard sample) ) were 5510 and 6390, respectively, and the molecular weight distribution coefficient(Mw/Mn ) was1.16 . The copolymer itself does not have thermosensitive gelling properties in water.
实施例2Example 2
在250 ml三口烧瓶中加入单端甲氧基聚乙二醇MPEG（550），油浴加热到150℃，搅拌下真空抽滤三个小时，以去除MPEG中残留的水分，然后加入摩尔比为3:1的DL-丙交酯和乙交酯，真空下加热使其完全熔融之后，加入120 μl辛酸亚锡，油浴升温到160℃，在氩气气氛下继续反应24个小时。反应完毕，真空抽滤两个小时以除去没有反应的单体和低沸点的产物。把初产物溶于二氯甲烷溶液中，乙醚沉淀，产率约为85％。通过凝胶渗透色谱仪（GPC）（采用聚苯乙烯作为标样）测定所述AB嵌段共聚物（MPEG-PLGA, Copolymer-14）的数均与重均分子量（Mn，Mw）分别为3550和4620，分子量分布系数（Mw/Mn）为1.30。此共聚物本身在水中不具有热敏凝胶化的性能。Add single-ended methoxypolyethylene glycol MPEG (550) into a 250 ml three-necked flask, heat the oil bath to 150°C, and vacuum filter for three hours while stirring to remove residual moisture in MPEG, and then add the molar ratio of 3:1 DL-lactide and glycolide, heated under vacuum to melt completely, then added 120 μl stannous octoate, heated the oil bath to 160°C, and continued the reaction for 24 hours under an argon atmosphere. After the reaction was completed, vacuum filtration was performed for two hours to remove unreacted monomers and low-boiling products. The initial product was dissolved in dichloromethane solution and precipitated with ether, the yield was about 85%. The number average and weight average molecular weight (Mn ,Mw ) of the AB block copolymer (MPEG-PLGA, Copolymer-14) were measured by gel permeation chromatography (GPC) (using polystyrene as a standard sample), respectively are 3550 and 4620, and the molecular weight distribution coefficient (Mw /Mn ) is 1.30. The copolymer itself does not have thermosensitive gelling properties in water.
实施例3Example 3
在250 ml三口烧瓶中加入聚乙二醇（1000）和PLGA（Mn4750，Mw6020，LA/GA=1/1）的混合物，真空下加热使其完全熔融之后，油浴升温到160℃缩合反应18小时。反应完毕，把初产物溶于二氯甲烷溶液中，用大量乙醚沉淀，产率约为85％。通过凝胶渗透色谱仪（GPC）（采用聚苯乙烯作为标样）测定所述BAB嵌段共聚物的数均与重均分子量（Mn，Mw）分别为6520和8340（PLGA-PEG-PLGA, Copolymer-15），分子量分布系数（Mw/Mn）为1.28。此共聚物本身在水中不具有热敏凝胶化的性能。Add a mixture of polyethylene glycol (1000) and PLGA (Mn 4750,Mw 6020, LA/GA=1/1) into a 250 ml three-neck flask, heat it under vacuum to melt it completely, and heat the oil bath to 160 °C condensation reaction for 18 hours. After the reaction is complete, the initial product is dissolved in dichloromethane solution and precipitated with a large amount of ether, and the yield is about 85%. The number-average and weight-average molecular weights (Mn ,Mw ) of the BAB block copolymer measured by gel permeation chromatography (GPC) (using polystyrene as a standard sample) were 6520 and 8340 (PLGA-PEG- PLGA, Copolymer-15), the molecular weight distribution coefficient (Mw /Mn ) is 1.28. The copolymer itself does not have thermosensitive gelling properties in water.
实施例4Example 4
按照实施例1给出的基本步骤，用不同分子量的PEG和不同的单体合成其它嵌段共聚物。这些共聚物的性能列于下表1：Following the basic procedure given in Example 1, other block copolymers were synthesized using PEGs of different molecular weights and different monomers. The properties of these copolymers are listed in Table 1 below:
表2：Table 2:
表3：table 3:
表1和表2的嵌段共聚物均不具有热敏凝胶化的性能，其中表1的嵌段共聚物只是能够在水中溶解，表2的嵌段共聚物不能够溶解于水或不能够完全溶解于水；而表3的嵌段共聚物本身就具有热敏凝胶化的性能。可以从表3中选取一种或一种以上嵌段共聚物同从表1和/或表2中选取一种或一种以上嵌段共聚物以一定比例混合得到的混合物能够在温度低于凝胶转变温度时溶解于水，在温度高于凝胶转变温度时，聚合物混合物的水溶液形成凝胶，并且这一过程是可逆的；也可以从表1中选取一种或一种以上嵌段共聚物同从表2中选取一种或一种以上嵌段共聚物以一定比例混合得到的混合物也具有热敏凝胶化的性能。The block copolymers in Table 1 and Table 2 do not have the performance of thermosensitive gelation, wherein the block copolymers in Table 1 can only be dissolved in water, and the block copolymers in Table 2 cannot be dissolved in water or cannot It is completely soluble in water; and the block copolymers in Table 3 have thermosensitive gelling properties. One or more block copolymers can be selected from Table 3 and one or more block copolymers selected from Table 1 and/or Table 2 can be selected from Table 1 and/or Table 2. The mixture obtained by mixing in a certain proportion can be obtained at a temperature lower than the condensation temperature. Soluble in water at the gel transition temperature, when the temperature is higher than the gel transition temperature, the aqueous solution of the polymer mixture forms a gel, and this process is reversible; one or more blocks can also be selected from Table 1 The mixture obtained by mixing the copolymer with one or more block copolymers selected from Table 2 in a certain ratio also has the property of thermosensitive gelation.
实施例5Example 5
首先以1/1的比例混合表1中的嵌段共聚物Copolymer-1和表2中的嵌段共聚物Copolymer-9得到相应的混合物，然后加入一定量的PBS溶液，配制成重量百分比浓度为25％的样品，最后在冰箱冷藏温度（4℃）通过磁力搅拌，使得聚合物混合物在PBS中溶解制备相应的水溶液。制备的聚合物混合物的PBS溶液在温度高于溶胶－凝胶转变温度时能够自发形成凝胶。具体使用时将溶液通过0.22 mm微孔滤膜灭菌，然后用注射器慢慢滴到创面上，由于体温作用，在创面上会立刻形成一层凝胶。First mix the block copolymer Copolymer-1 in the table 1 and the block copolymer Copolymer-9 in the table 2 to obtain the corresponding mixture with the ratio of 1/1, then add a certain amount of PBS solution, be mixed with the weight percent concentration of 25% of the sample was finally stirred by magnetic force at refrigerator temperature (4°C), so that the polymer mixture was dissolved in PBS to prepare the corresponding aqueous solution. The PBS solution of the prepared polymer mixture can spontaneously form a gel when the temperature is higher than the sol-gel transition temperature. When in use, the solution is sterilized through a 0.22 mm microporous membrane, and then slowly dripped onto the wound with a syringe. Due to body temperature, a layer of gel will immediately form on the wound.
实施例6Example 6
首先在室温配制重量百分比浓度为12.5％的嵌段共聚物Copolymer-1的PBS溶液，然后再在上述水溶液中加入同样重量百分比的嵌段共聚物Copolymer-9，最后在室温通过磁力搅拌，使得嵌段共聚物Copolymer-9增溶进入溶液，制备相应的重量百分比浓度为25％的PBS溶液。制备的聚合物混合物的水溶液在温度高于溶胶－凝胶转变温度时能够自发形成凝胶；并且凝胶性能与实施例5中配制的样品相同。First prepare a PBS solution of block copolymer Copolymer-1 with a weight percent concentration of 12.5% at room temperature, then add the same weight percent block copolymer Copolymer-9 to the above aqueous solution, and finally stir it magnetically at room temperature to make the block copolymer The segment copolymer Copolymer-9 was solubilized into the solution, and a corresponding PBS solution with a concentration of 25% by weight was prepared. The prepared aqueous solution of the polymer mixture can spontaneously form a gel when the temperature is higher than the sol-gel transition temperature; and the performance of the gel is the same as that of the sample prepared in Example 5.
实施例7Example 7
首先在冰箱冷藏温度（4℃）配制重量百分比浓度为25％的嵌段共聚物Copolymer-1的PBS溶液和同样重量百分比浓度的嵌段共聚物Copolymer-16的PBS溶液，然后以1/1的比例均匀混合上述溶液制备相应的聚合物混合物的PBS溶液。在温度高于溶胶－凝胶转变温度时，制备的聚合物混合物的水溶液能够自发形成凝胶。First prepare the PBS solution of the block copolymer Copolymer-1 with the concentration of 25% by weight and the PBS solution of the block copolymer Copolymer-16 with the same concentration of the weight percent at the refrigerator temperature (4°C), and then add 1/1 Proportionally mix the above solutions uniformly to prepare the PBS solution of the corresponding polymer mixture. The aqueous solution of the prepared polymer mixture can spontaneously form a gel at a temperature higher than the sol-gel transition temperature.
实施例8Example 8
研究了嵌段共聚物Copolymer-1和Copolymer-9按照不同重量比例混合得到的三嵌段共聚物混合物在PBS溶液中的凝胶化行为。制备了从5％到25％的不同重量百分比浓度的混合物PBS溶液，测定了其在0℃到60℃之间的粘度变化。观察试管倒置时在20秒内不发生流动来定义是否凝胶化。图1即为Copolymer-1和Copolymer-9不同重量比例混合得到样品其不同浓度的PBS溶液随着温度变化时的相图。The gelation behavior of the triblock copolymer mixture obtained by mixing the block copolymers Copolymer-1 and Copolymer-9 in different weight ratios in PBS solution was studied. The mixture PBS solutions with different weight percent concentrations from 5% to 25% were prepared, and the viscosity changes between 0°C and 60°C were measured. Gelation was defined by observing that no flow occurred within 20 seconds when the tube was inverted. Figure 1 is the phase diagram of PBS solutions with different concentrations of samples obtained by mixing Copolymer-1 and Copolymer-9 in different weight ratios as the temperature changes.
实施例9Example 9
在Copolymer-1和Copolymer-9以1/1重量比例混合得到浓度为25%PBS溶液中加入重量百分比为2％的PEG（2000）聚合物时，其凝胶强度没有发生显著变化，其溶胶－凝胶转变温度从32℃降低为30℃。When Copolymer-1 and Copolymer-9 were mixed in a 1/1 weight ratio to obtain a concentration of 25% PBS solution, when 2% by weight PEG (2000) polymer was added, the gel strength did not change significantly, and the sol- The gel transition temperature decreased from 32°C to 30°C.
实施例10Example 10
在Copolymer-1和Copolymer-9以1/1重量比例混合得到浓度为25%PBS溶液中加入重量百分比为0.5％的透明质酸时，其溶胶－凝胶转变温度从32℃降低为31℃, 其最大凝胶强度下降了大约25％。When Copolymer-1 and Copolymer-9 were mixed in a 1/1 weight ratio to obtain a concentration of 25% in PBS solution, when 0.5% by weight of hyaluronic acid was added, the sol-gel transition temperature decreased from 32°C to 31°C, Its maximum gel strength decreased by about 25%.
实施例11Example 11
表3中的嵌段共聚物Copolymer-16的浓度为25%PBS溶液在9℃时发生溶胶－凝胶转变，形成水凝胶；Copolymer-1的25%PBS溶液不具有热敏凝胶化的性能；以不同的重量比例混合上述两种溶液得到的样品，其溶胶－凝胶转变温度可以在9～37℃之间调节。The concentration of the block copolymer Copolymer-16 in Table 3 is that the 25% PBS solution undergoes a sol-gel transition at 9°C to form a hydrogel; the 25% PBS solution of Copolymer-1 does not have the effect of heat-sensitive gelation Properties: The sol-gel transition temperature of the samples obtained by mixing the above two solutions in different weight ratios can be adjusted between 9 and 37°C.
实施例12Example 12
在pH为7.4的PBS中测定了Copolymer-1和Copolymer-9以1/1或1/2重量比例混合得到浓度为25%PBS溶液或凝胶（0.5 ml）在37℃时体外降解情况。图2即为Copolymer-1和Copolymer-9不同重量比例混合得到的嵌段共聚物混合物水凝胶在体外降解实验中平均分子量随降解时间的变化曲线。The in vitro degradation of Copolymer-1 and Copolymer-9 mixed in 1/1 or 1/2 weight ratio to obtain a 25% PBS solution or gel (0.5 ml) at a pH of 7.4 was measured at 37°C. Figure 2 is the variation curve of the average molecular weight with the degradation time in the in vitro degradation experiment of the block copolymer mixture hydrogel obtained by mixing Copolymer-1 and Copolymer-9 in different weight ratios.
实施例13Example 13
采用体外培养的MC-3T3细胞，在无菌条件下将细胞接种于96孔细胞培养板内，密度104个/well，在细胞至对数生长期时，将Copolymer-1和Copolymer-9以1/1或1/2重量比例混合得到不同浓度的样品加入细胞培养板内，一组不加样品的为空白对照，一组加同样浓度的F-127的作为阴性对照，另外一组加同样浓度的SDS的作为阳性对照，每组4个平行样品。放入培养箱内（37℃）静置培养，细胞与材料共培养24小时后四甲基偶氮唑盐微量酶反应比色法（MTT法）检测细胞活力。图3即为MTT法表征添加了不同浓度且由不同重量比例混合得到的嵌段共聚物混合物材料的培养液对MC-3T3细胞活力的影响，证实材料具有良好的生物相容性。Using MC-3T3 cells cultured in vitro, the cells were seeded in 96-well cell culture plates under sterile conditions at a density of10 cells/well. When the cells reached the logarithmic growth phase, Copolymer-1 and Copolymer-9 were
实施例14Example 14
首先按照实施例5的方法得到了Copolymer-1和Copolymer-9以1/2重量比例混合得到浓度为25%PBS溶液，然后往其中添加消炎药布洛芬，浓度为0.1-5 %（优选浓度为1-2 %），溶液在室温下搅拌2小时以上使药物得到充分溶解和混和，然后采用0.22 mm微孔滤膜灭菌。使用时直接将溶液滴到创面上形成凝胶。First according to the method of
实施例15、医用防粘连效果的检验（1）Example 15. Inspection of medical anti-adhesion effect (1)
本实施例中使用了Copolymer-1和Copolymer-9以1/2重量比例混合得到浓度为25%PBS溶液，首先按照实施例5的方法，制备了已灭菌的水凝胶材料。实验动物模型采用新西兰兔的腹壁-盲肠损伤模型，新西兰兔麻醉后，沿中心线切开腹腔，在右侧腹腔内壁距离切口1厘米位置外，切去一块3×4厘米见方腹壁肌肉，创面深度约1毫米，然后将对应位置的盲肠用手术刷摩擦，粘膜破坏至渗血。对于凝胶材料组，我们将水凝胶慢慢滴在腹腔壁和盲肠的创面上，而对照组动物的创面不加处理，手术完成后缝合腹壁肌肉和皮肤。动物正常饲养一个月后处死，打开腹腔检查粘连情况，实验结果表明，对照组的动物，腹壁和盲肠存在严重粘连；而使用水凝胶材料的动物，腹壁和盲肠间没有发生粘连，创面愈合良好。说明这种可降解温敏水凝胶能够有效抑制术后粘连的发生，且生物相容性良好，不影响创面的愈合。In this example, Copolymer-1 and Copolymer-9 were mixed in a 1/2 weight ratio to obtain a 25% PBS solution. First, a sterilized hydrogel material was prepared according to the method in Example 5. The experimental animal model adopts the abdominal wall-cecum injury model of New Zealand rabbits. After the New Zealand rabbits are anesthetized, the abdominal cavity is cut along the center line, and a piece of abdominal wall muscle of 3 × 4 cm square is cut off from the inner wall of the right
实施例16、 医用防粘连效果的检验（2）Example 16. Inspection of medical anti-adhesion effect (2)
本实施例中使用了实施例10中制备的样品，即Copolymer-1和Copolymer-9以1/1重量比例混合得到浓度为25%PBS溶液，并且样品中添加了0.5％的透明质酸。同样按照实施例5的方法，对水凝胶材料进行灭菌。实验动物模型采用新西兰兔的腹壁-盲肠损伤模型，新西兰兔麻醉后，沿中心线切开腹腔，在右侧腹腔内壁距离切口1厘米位置外，切去一块3×4厘米见方腹壁肌肉，创面深度约1毫米，然后将对应位置的盲肠用手术刷摩擦，粘膜破坏至渗血。对于凝胶材料组，我们将水凝胶慢慢滴在腹腔壁和盲肠的创面上，而对照组动物的创面不加处理，手术完成后缝合腹壁肌肉和皮肤。动物正常饲养一个月后处死，打开腹腔检查粘连情况，实验结果表明，对照组的动物，腹壁和盲肠存在严重粘连；而使用水凝胶材料的动物，腹壁和盲肠间没有发生粘连，创面愈合良好。说明这种可降解温敏水凝胶能够有效抑制术后粘连的发生，且生物相容性良好，不影响创面的愈合。In this example, the sample prepared in Example 10 was used, that is, Copolymer-1 and Copolymer-9 were mixed in a 1/1 weight ratio to obtain a 25% PBS solution, and 0.5% hyaluronic acid was added to the sample. Also according to the method of Example 5, the hydrogel material was sterilized. The experimental animal model adopts the abdominal wall-cecum injury model of New Zealand rabbits. After the New Zealand rabbits are anesthetized, the abdominal cavity is cut along the center line, and a piece of abdominal wall muscle of 3 × 4 cm square is cut off from the inner wall of the right
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Cited By (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103251986A (en)* | 2013-05-17 | 2013-08-21 | 四川大学 | Use of PDLLLA (Poly Dl Lactic Acid)-PEG (Polyethylene Glycol)-PDLLA triblock copolymer in preparing medical anti-adhesion material |
| CN103405773A (en)* | 2013-07-12 | 2013-11-27 | 南京泛太化工医药研究所 | Preparation and application of biodegradable thermosensitive in-situ hydrogel |
| CN104689381A (en)* | 2013-12-10 | 2015-06-10 | 复旦大学 | Hydrogel composition for gastrointestinal submucosal injection and application of hydrogel composition |
| CN104800895A (en)* | 2014-12-25 | 2015-07-29 | 上海景峰制药有限公司 | Preparation method of PDLLA-PEG-PDLLA triblock copolymer anti-adhesion gel |
| CN104845382A (en)* | 2015-05-08 | 2015-08-19 | 复旦大学 | Silk protein/cellulose derivative blending hydrogel and preparation method thereof |
| CN105477689A (en)* | 2015-12-22 | 2016-04-13 | 上海景峰制药有限公司 | Preparing method of PDLLA-PEG-PDLLA triblock copolymer anti-adhesion gel |
| CN106279722A (en)* | 2015-08-21 | 2017-01-04 | 北京师范大学 | high intensity physical cross-linking hydrogel and elastomer and preparation method thereof |
| CN106730023A (en)* | 2016-12-20 | 2017-05-31 | 上海纳米技术及应用国家工程研究中心有限公司 | A kind of polyphosphoric acids calcium is modified IPDI PCLLA PEG PCLLA porous supports and preparation and application |
| CN107875444A (en)* | 2017-11-03 | 2018-04-06 | 西安工业大学 | Preparation method for the hydrogel scaffold material of the biological degradability of cardiac repair |
| CN109195642A (en)* | 2016-06-07 | 2019-01-11 | 医药研究产品有限公司 | Tissue enhancing filled compositions comprising nucleic acid, chitosan and hyaluronic acid and preparation method thereof |
| CN109675122A (en)* | 2018-12-18 | 2019-04-26 | 复旦大学 | A kind of thermotropic hydrogel composites of Instant and the preparation method and application thereof |
| CN109762567A (en)* | 2019-02-22 | 2019-05-17 | 山东省农业科学院农业资源与环境研究所 | A temperature-sensitive gel type heavy metal solidifying agent, a method for solidifying and restoring heavy metal polluted soil, and a method for recovering the solidifying agent |
| CN111187607A (en)* | 2019-07-15 | 2020-05-22 | 浙江工业大学 | Temperature response type hydrogel temporary plugging diversion fracturing fluid and preparation method and application thereof |
| CN111286204A (en)* | 2020-03-12 | 2020-06-16 | 复旦大学 | Polymer compound capable of being rapidly dissolved or dispersed in aqueous solvent and preparation method and application thereof |
| CN111346047A (en)* | 2020-03-12 | 2020-06-30 | 复旦大学 | Thermotropic hydrogel metformin sustained-release preparation and preparation method and application thereof |
| CN111617314A (en)* | 2019-02-28 | 2020-09-04 | 新加坡科技研究局 | Materials and associated methods suitable for use as vitreous substitutes |
| CN112023114A (en)* | 2019-06-03 | 2020-12-04 | 上海禾思凯尔医疗科技有限公司 | Lacrimal canaliculus obstruction core material for lacrimal canaliculus embolism operation and preparation method thereof |
| CN112512602A (en)* | 2018-09-05 | 2021-03-16 | 国立研究开发法人物质·材料研究机构 | Adhesion-preventing material |
| CN113444232A (en)* | 2021-07-12 | 2021-09-28 | 东北师范大学 | Degradable polymer for wound dressing, preparation method thereof and wound dressing |
| CN114306725A (en)* | 2021-11-30 | 2022-04-12 | 南方科技大学 | Single-sided adhesive hydrogel adhesive and preparation method and application thereof |
| CN114404650A (en)* | 2022-02-09 | 2022-04-29 | 山东畜牧兽医职业学院 | Preparation method and product of temperature-sensitive hydrogel dressing |
| CN114514043A (en)* | 2019-07-08 | 2022-05-17 | 株式会社再生生物链 | Temperature-sensitive hydrogel composition for preventing tissue adhesion and preparation method thereof |
| CN114681683A (en)* | 2016-09-30 | 2022-07-01 | 东丽株式会社 | Adhesion-preventing material |
| CN116271265A (en)* | 2021-12-21 | 2023-06-23 | 四川大学 | A thermosensitive hydrogel for preventing postoperative tissue adhesion and preparation method thereof |
| CN117018287A (en)* | 2023-06-30 | 2023-11-10 | 北京诺康达医药科技股份有限公司 | Temperature-sensitive physical hydrogel freeze-dried preparation and preparation method and application thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2416126A1 (en)* | 2000-07-28 | 2002-02-07 | Anika Therapeutics, Inc. | Bioabsorbable composites of derivatized hyaluronic acid |
| CN1436801A (en)* | 2002-02-05 | 2003-08-20 | 成都贝德曼生物医用材料研究所 | Synthesis and application of post-operative adhesion-preventing material |
| CN101347410A (en)* | 2008-06-19 | 2009-01-21 | 济南基福医药科技有限公司 | Anticancer sustained-release injection containing octadecyl dimethyl-4-piperidine phosphate |
| CA2748907A1 (en)* | 2009-01-03 | 2010-07-08 | Russell Anderson | Enhanced carriers for the delivery of microparticles to bodily tissues and fluids |
| CN101804066A (en)* | 2010-03-26 | 2010-08-18 | 四川大学 | Application of MPEG-PLA (Methoxypolyethylene Glycols-Polylactic Acid) diblock copolymers in preparation of medical anti-blocking material |
| CN101837006A (en)* | 2010-04-06 | 2010-09-22 | 四川大学 | Application of PCL-PEG-PCL tri-block copolymer in preparation of medical anti-blocking material |
| CN101862454A (en)* | 2009-04-20 | 2010-10-20 | 复旦大学 | A kind of physically cross-linked hydrogel composition and its preparation method and application |
- 2011
- 2011-01-18CNCN2011100201967Apatent/CN102068719A/enactivePending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2416126A1 (en)* | 2000-07-28 | 2002-02-07 | Anika Therapeutics, Inc. | Bioabsorbable composites of derivatized hyaluronic acid |
| CN1436801A (en)* | 2002-02-05 | 2003-08-20 | 成都贝德曼生物医用材料研究所 | Synthesis and application of post-operative adhesion-preventing material |
| CN101347410A (en)* | 2008-06-19 | 2009-01-21 | 济南基福医药科技有限公司 | Anticancer sustained-release injection containing octadecyl dimethyl-4-piperidine phosphate |
| CA2748907A1 (en)* | 2009-01-03 | 2010-07-08 | Russell Anderson | Enhanced carriers for the delivery of microparticles to bodily tissues and fluids |
| CN101862454A (en)* | 2009-04-20 | 2010-10-20 | 复旦大学 | A kind of physically cross-linked hydrogel composition and its preparation method and application |
| CN101804066A (en)* | 2010-03-26 | 2010-08-18 | 四川大学 | Application of MPEG-PLA (Methoxypolyethylene Glycols-Polylactic Acid) diblock copolymers in preparation of medical anti-blocking material |
| CN101837006A (en)* | 2010-04-06 | 2010-09-22 | 四川大学 | Application of PCL-PEG-PCL tri-block copolymer in preparation of medical anti-blocking material |
Non-Patent Citations (1)
| Title |
|---|
| LIN YU: "Biodegradability and Biocompatibility of Thermoreversible Hydrogels Formed from Mixing a Sol and a Precipitate of Block Copolymers in Water", 《BIOMACROMOLECULES》, vol. 11, no. 8, 15 July 2010 (2010-07-15), pages 2169 - 2178* |
Cited By (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103251986A (en)* | 2013-05-17 | 2013-08-21 | 四川大学 | Use of PDLLLA (Poly Dl Lactic Acid)-PEG (Polyethylene Glycol)-PDLLA triblock copolymer in preparing medical anti-adhesion material |
| CN103251986B (en)* | 2013-05-17 | 2015-03-04 | 四川大学 | Use of PDLLLA (Poly Dl Lactic Acid)-PEG (Polyethylene Glycol)-PDLLA triblock copolymer in preparing medical anti-adhesion material |
| CN103405773A (en)* | 2013-07-12 | 2013-11-27 | 南京泛太化工医药研究所 | Preparation and application of biodegradable thermosensitive in-situ hydrogel |
| CN103405773B (en)* | 2013-07-12 | 2016-02-24 | 南京泛太化工医药研究所 | A kind of preparation and application of biodegradable Thermo-sensitive in-situ hydrogel |
| CN104689381A (en)* | 2013-12-10 | 2015-06-10 | 复旦大学 | Hydrogel composition for gastrointestinal submucosal injection and application of hydrogel composition |
| CN104800895A (en)* | 2014-12-25 | 2015-07-29 | 上海景峰制药有限公司 | Preparation method of PDLLA-PEG-PDLLA triblock copolymer anti-adhesion gel |
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| CN106279722A (en)* | 2015-08-21 | 2017-01-04 | 北京师范大学 | high intensity physical cross-linking hydrogel and elastomer and preparation method thereof |
| CN106279722B (en)* | 2015-08-21 | 2018-11-06 | 北京师范大学 | High-strength physically-crosslinked hydrogel and elastomer and preparation method thereof |
| CN105477689A (en)* | 2015-12-22 | 2016-04-13 | 上海景峰制药有限公司 | Preparing method of PDLLA-PEG-PDLLA triblock copolymer anti-adhesion gel |
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| CN109195642B (en)* | 2016-06-07 | 2021-12-10 | 医药研究有限公司 | Filling composition for tissue enhancement comprising nucleic acid, chitosan and hyaluronic acid and preparation method thereof |
| CN114681683A (en)* | 2016-09-30 | 2022-07-01 | 东丽株式会社 | Adhesion-preventing material |
| CN106730023A (en)* | 2016-12-20 | 2017-05-31 | 上海纳米技术及应用国家工程研究中心有限公司 | A kind of polyphosphoric acids calcium is modified IPDI PCLLA PEG PCLLA porous supports and preparation and application |
| CN107875444B (en)* | 2017-11-03 | 2021-01-05 | 西安工业大学 | Preparation method of biodegradable hydrogel scaffold material for cardiac repair |
| CN107875444A (en)* | 2017-11-03 | 2018-04-06 | 西安工业大学 | Preparation method for the hydrogel scaffold material of the biological degradability of cardiac repair |
| CN112512602A (en)* | 2018-09-05 | 2021-03-16 | 国立研究开发法人物质·材料研究机构 | Adhesion-preventing material |
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| CN109762567A (en)* | 2019-02-22 | 2019-05-17 | 山东省农业科学院农业资源与环境研究所 | A temperature-sensitive gel type heavy metal solidifying agent, a method for solidifying and restoring heavy metal polluted soil, and a method for recovering the solidifying agent |
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| CN111617314B (en)* | 2019-02-28 | 2023-09-19 | 新加坡科技研究局 | Materials suitable for use as vitreous substitutes and related methods |
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| CN116271265A (en)* | 2021-12-21 | 2023-06-23 | 四川大学 | A thermosensitive hydrogel for preventing postoperative tissue adhesion and preparation method thereof |
| CN114404650A (en)* | 2022-02-09 | 2022-04-29 | 山东畜牧兽医职业学院 | Preparation method and product of temperature-sensitive hydrogel dressing |
| CN114404650B (en)* | 2022-02-09 | 2022-09-23 | 山东畜牧兽医职业学院 | Preparation method and product of temperature-sensitive hydrogel dressing |
| CN117018287A (en)* | 2023-06-30 | 2023-11-10 | 北京诺康达医药科技股份有限公司 | Temperature-sensitive physical hydrogel freeze-dried preparation and preparation method and application thereof |
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