WO2018121630A1

WO2018121630A1 - Composite tissue repair sheet and preparation method and application thereof

Info

Publication number: WO2018121630A1
Application number: PCT/CN2017/119133
Authority: WO
Inventors: 李林静; 邓坤学; 袁玉宇
Original assignee: 广州迈普再生医学科技有限公司
Priority date: 2016-12-28
Filing date: 2017-12-27
Publication date: 2018-07-05
Also published as: CN106693059A; CN106693059B; CN111840649B; CN111840648B; CN111803711A; CN111803710A; CN111840649A; CN111803711B; CN111803710B; CN111840648A

Abstract

A composite tissue repair sheet and a preparation method and application thereof. The composite tissue repair sheet comprises: a nanofiber membrane, a woven mesh, and an adhesive. The adhesive is located between the nanofiber membrane and the woven mesh. The adhesive comprises a hydrophilic material. The nanofiber membrane and the woven mesh are connected through the adhesive, and the adhesive enters into pores of the nanofiber membrane and the woven mesh. The peel strength between the nanofiber membrane and the woven mesh is 20-75 cN/mm. The strength at break of the composite tissue repair sheet is 8-12.5 MPa. The elongation at break of the composite tissue repair sheet is 20-250%. The porosity is 50-90%. The composite tissue repair sheet is not easily delaminated and has good mechanical properties and softness.

Description

复合组织修复补片及其制备方法和应用Composite tissue repair patch and preparation method and application thereof

交叉引用cross reference

本公开主张2016年12月28日提交的中国专利申请号为201611238612.X的优先权，其全部内容通过引用包含于此。The present disclosure claims priority to Chinese Patent Application No. 201611238612.X filed on Dec. 28, 2016, the entire disclosure of which is hereby incorporated by reference.

技术领域Technical field

本公开涉及一种复合组织修复补片及其制备方法和应用，属于植入医疗材料领域。The present disclosure relates to a composite tissue repair patch and a preparation method and application thereof, and belongs to the field of implanted medical materials.

背景技术Background technique

目前，常用的组织修复补片包括有编织网片和静电纺丝纳米纤维膜。编织网片具有良好的力学性能，可以提供足够的力学支撑。但是，由于编织网片存在硬度大、表面粗糙、容易与组织粘连等问题，因此，难以取得理想的修复效果。Currently, commonly used tissue repair patches include woven mesh and electrospun nanofiber membranes. The woven mesh has good mechanical properties and can provide sufficient mechanical support. However, since the woven mesh sheet has problems such as high hardness, rough surface, and adhesion to tissues, it is difficult to obtain an ideal repairing effect.

静电纺丝纳米纤维膜具有极大的比表面积、高孔隙率与高表面能等特点，能够作为细胞生长的多孔支架，促进细胞的迁移；还具有三维多孔结构，易于输送营养和氧气以利于细胞的增殖和分化。因此，静电纺丝纳米纤维膜具有良好的组织修复性能。但是静电纺丝纳米纤维膜的力学强度较弱，不能直接应用于力学强度要求较高部位的组织修复(例如疝气修复)。Electrospun nanofiber membrane has the characteristics of large specific surface area, high porosity and high surface energy. It can be used as a porous scaffold for cell growth and promote cell migration. It also has a three-dimensional porous structure, which is easy to transport nutrients and oxygen to facilitate cells. Proliferation and differentiation. Therefore, the electrospun nanofiber membrane has good tissue repair properties. However, the mechanical strength of the electrospun nanofiber membrane is weak and cannot be directly applied to tissue repair (such as helium repair) where the mechanical strength is required to be high.

现有技术中，编织网片和静电纺丝纳米纤维膜的结合方式主要有热压、焊接、粘合或者将纳米纤维丝接收在编织网片上等。其中，热压和焊接均要求有较高的温度，加工工艺难以控制，容易破坏编织网片或静电纺丝纳米纤维膜的结构。粘合对所采用的粘合剂的材料与组织的相容性较差，容易与组织粘连，并且粘合的强度较低。而直接将纳米纤维丝接收在编织网片上的处理方式并不牢固(陈艳春等，PP/PLA盆底复合补片的制备与性能[J]，东华大学学报(自然科学版)，2014,40(6):687-691)，在临床使用时容易分层，无法实现修复的效果。In the prior art, the combination of the woven mesh sheet and the electrospun nanofiber membrane mainly includes hot pressing, welding, bonding or receiving the nanofiber filament on the woven mesh sheet. Among them, hot pressing and welding require higher temperature, the processing process is difficult to control, and it is easy to destroy the structure of the woven mesh or the electrospun nanofiber membrane. The adhesion of the adhesive to the material of the adhesive is poorly compatible with the tissue, easily adheres to the tissue, and the strength of the bond is low. However, the treatment method of directly receiving nanofibers on woven mesh sheets is not strong (Chen Yanchun et al. Preparation and performance of PP/PLA pelvic composite patch [J], Journal of Donghua University (Natural Science Edition), 2014, 40 (6): 687-691), it is easy to stratify in clinical use, and the effect of repair cannot be achieved.

专利申请文件CN105435309A公开了一种静电纺丝膜与编织网片的复合补片，所述复合补片采用熔点较低的粘合层，通过热压的方式复合得到。但是其采用的粘合层材料的熔点必须远低于静电纺丝膜层材料的熔点，以防止后续热压过程中破坏静电纺丝膜层的结构，复合的工艺较复杂，且复合补片的孔隙率较小。The patent application document CN105435309A discloses a composite patch of an electrospun film and a woven mesh sheet which is obtained by heat-compression bonding using an adhesive layer having a lower melting point. However, the melting point of the adhesive layer material used must be much lower than the melting point of the electrospinning film layer material to prevent the structure of the electrospinning film layer from being destroyed during the subsequent hot pressing process, and the composite process is complicated, and the composite patch is The porosity is small.

发明内容Summary of the invention

发明要解决的问题Problems to be solved by the invention

本公开提供一种复合组织修复补片及其制备方法和应用。本公开的复合组织修复补片通过采用合适的黏附材料，将纳米纤维膜和编织网片进行有效复合，使得所述复合组织修复补片不仅具有良好的力学性能，可以提供足够的力学支撑，还具有良好的生物相容性。The present disclosure provides a composite tissue repair patch and a preparation method and application thereof. The composite tissue repair patch of the present disclosure effectively combines the nanofiber membrane and the woven mesh sheet by using a suitable adhesive material, so that the composite tissue repair patch not only has good mechanical properties, but also provides sufficient mechanical support, and Has good biocompatibility.

进一步地，本公开还提供一种制备复合组织修复补片的方法，不仅保留了纳米纤维膜原有结构的特性，还能够改善编织网片的生物相容性。Further, the present disclosure also provides a method for preparing a composite tissue repair patch, which not only retains the characteristics of the original structure of the nanofiber membrane, but also improves the biocompatibility of the woven mesh sheet.

用于解决问题的方案Solution to solve the problem

本公开提供一种复合组织修复补片，所述复合组织修复补片包括：The present disclosure provides a composite tissue repair patch comprising:

纳米纤维膜、编织网片和黏附材料，其中，所述黏附材料位于所述纳米纤维膜与所述编织网片之间；a nanofiber film, a woven mesh sheet, and an adhesive material, wherein the adhesive material is located between the nanofiber film and the woven mesh sheet;

所述黏附材料包括亲水性物质，所述纳米纤维膜和所述编织网片通过所述黏附材料相结合，且所述黏附材料嵌入到所述纳米纤维膜和所述编织网片的孔隙中；The adhesion material includes a hydrophilic substance, the nanofiber membrane and the woven mesh sheet are combined by the adhesion material, and the adhesion material is embedded in the pores of the nanofiber membrane and the woven mesh sheet ;

所述纳米纤维膜与所述编织网片之间的剥离强度为20～75cN/mm；所述复合组织修复补片的断裂强度为8～12.5Mpa；优选地，所述复合组织修复补片的断裂伸长量为20～250％；更优选地，所述复合组织修复补片的孔隙率为50～90％。The peeling strength between the nanofiber membrane and the woven mesh sheet is 20 to 75 cN/mm; the breaking strength of the composite tissue repair patch is 8 to 12.5 MPa; preferably, the composite tissue repairing patch The elongation at break is 20 to 250%; more preferably, the composite tissue repair patch has a porosity of 50 to 90%.

根据本公开的复合组织修复补片，其中，所述复合组织修复补片还包括防粘连层，所述防粘连层黏附于所述编织网片的与纳米纤维膜所在侧相反的面上。A composite tissue repair patch according to the present disclosure, wherein the composite tissue repair patch further comprises an anti-adhesion layer adhered to a face of the woven mesh opposite the side on which the nanofiber membrane is located.

根据本公开的复合组织修复补片，所述亲水性物质的重均分子量为50000～2000000Da。According to the composite tissue repair patch of the present disclosure, the hydrophilic substance has a weight average molecular weight of 50,000 to 2,000,000 Da.

根据本公开的复合组织修复补片，所述亲水性物质包括：含氮类化合物及其衍生物、纤维素类化合物及其衍生物、醇类化合物及其衍生物、壳聚糖类化合物及其衍生物、糖类化合物及其衍生物中的一种或多种。According to the composite tissue repairing patch of the present disclosure, the hydrophilic substance includes: a nitrogen-containing compound and a derivative thereof, a cellulose compound and a derivative thereof, an alcohol compound and a derivative thereof, a chitosan compound, and One or more of its derivatives, saccharide compounds and derivatives thereof.

根据本公开的复合组织修复补片，所述含氮类化合物包括蛋白质类化合物，优选包括胶原蛋白、明胶中的一种或两种；所述壳聚糖类化合物包括：羧甲基壳聚糖、羟丙基壳聚糖中的一种或两种；所述纤维素类化合物包括：羧甲基纤维素、羧甲基纤维素钠中的一种或两种。According to the composite tissue repair patch of the present disclosure, the nitrogen-containing compound includes a proteinaceous compound, preferably one or both of collagen and gelatin; and the chitosan compound comprises: carboxymethyl chitosan One or two of hydroxypropyl chitosan; the cellulose compound includes one or both of carboxymethyl cellulose and sodium carboxymethyl cellulose.

根据本公开的复合组织修复补片，所述亲水性物质包括改性的亲水性物质，优选包括经过交联剂改性得到的亲水性物质。According to the composite tissue repair patch of the present disclosure, the hydrophilic substance comprises a modified hydrophilic substance, preferably comprising a hydrophilic substance modified by a crosslinking agent.

根据本公开的复合组织修复补片，所述纳米纤维膜与编织网片之间的距离为0.1～3mm；优选为0.2～2mm。According to the composite tissue repair patch of the present disclosure, the distance between the nanofiber membrane and the woven mesh sheet is 0.1 to 3 mm; preferably 0.2 to 2 mm.

根据本公开的复合组织修复补片，所述纳米纤维膜采用包括静电纺丝步骤的方法制得。According to the composite tissue repair patch of the present disclosure, the nanofiber membrane is produced by a method including an electrospinning step.

根据本公开的复合组织修复补片，所述纳米纤维膜由直径为10nm～100μm的纤维丝交织而成，优选地，所述纤维丝由可降解材料制成，更优选地，所述可降解材料包括聚乳酸、聚DL-乳酸、聚己内酯、聚羟基脂肪酸酯、聚乙交酯、聚已交-丙交酯；胶原蛋白、明胶、壳聚糖、透明质酸、纤维素中的一种或多种。According to the composite tissue repair patch of the present disclosure, the nanofiber membrane is interwoven from filaments having a diameter of 10 nm to 100 μm, preferably the filament is made of a degradable material, and more preferably, the degradable Materials include polylactic acid, poly-DL-lactic acid, polycaprolactone, polyhydroxyalkanoate, polyglycolide, poly-lactide; collagen, gelatin, chitosan, hyaluronic acid, cellulose One or more.

根据本公开的复合组织修复补片，所述纳米纤维膜中加载有药物，所述药物优选包括生长因子；更优选包括表皮生长因子、成纤维细胞生长因子中的一种或两种。According to the composite tissue repair patch of the present disclosure, the nanofiber membrane is loaded with a drug, preferably comprising a growth factor; more preferably comprising one or both of an epidermal growth factor, a fibroblast growth factor.

根据本公开的复合组织修复补片，所述编织网片由不可降解材料制成，优选地，所述不可降解材料包括聚丙烯、聚偏二氟乙烯、聚对苯二四酸乙二醇酯、膨化聚四氟乙烯中的一种或多种。A composite tissue repair patch according to the present disclosure, the woven mesh sheet being made of a non-degradable material, preferably, the non-degradable material comprises polypropylene, polyvinylidene fluoride, polyethylene terephthalate And one or more of expanded polytetrafluoroethylene.

本公开还提供一种根据本公开的复合组织修复补片的制备方法，包括：The present disclosure also provides a method of preparing a composite tissue repair patch according to the present disclosure, comprising:

复合步骤：制备黏附材料溶液，将所述纳米纤维膜和所述编织网片用所述黏附材料溶液复合得到所述复合组织修复补片；a composite step: preparing an adhesive material solution, and compounding the nanofiber membrane and the woven mesh sheet with the adhesive material solution to obtain the composite tissue repair patch;

优选地，利用所述黏附材料溶液，通过冷冻干燥工艺、涂覆工艺或流延工艺将所述纳米纤维膜与所述编织网片复合。Preferably, the nanofiber membrane is compounded with the woven mesh sheet by a freeze drying process, a coating process or a casting process using the adhesion material solution.

根据本公开的方法，调整所述黏附材料的分子量和/或所述黏附材料溶液的浓度，使得所述黏附材料溶液从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层。Adjusting the molecular weight of the adhesion material and/or the concentration of the adhesion material solution according to the method of the present disclosure such that the adhesion material solution overflows from the pores of the woven mesh sheet and is nano-sized in the woven mesh sheet An anti-blocking solution layer is formed on the opposite side of the side on which the fiber membrane is located.

根据本公开的方法，所述冷冻干燥工艺包括以下步骤：According to the method of the present disclosure, the freeze drying process comprises the following steps:

将所述亲水性物质溶解，得到黏附材料溶液；Dissolving the hydrophilic substance to obtain a solution of an adhesive material;

将所述黏附材料溶液平铺于所述纳米纤维膜上，并静置；Laminating the adhesion material solution on the nanofiber membrane and standing still;

将所述编织网片平铺于所述黏附材料溶液上，通过冷冻干燥得到所述复合组织修复补片。The woven mesh sheet is laid flat on the adhesive material solution, and the composite tissue repair patch is obtained by freeze drying.

根据本公开的方法，所述冷冻干燥工艺中，所述黏附材料溶液的厚度为0.1～3mm，优选0.2～2mm；所述静置的时间为1～24h，优选3～6h；所述黏附材料溶液中，黏附材料的质量浓度为0.1～20％，优选为5～15％；优选地，所述冷冻干燥工艺的预冻温度为-80～-10℃，优选为-80～-50℃；干燥温度为-20～30℃，优选为-10～25℃。According to the method of the present disclosure, in the freeze-drying process, the thickness of the solution of the adhesive material is 0.1 to 3 mm, preferably 0.2 to 2 mm; the time of the standing is 1 to 24 hours, preferably 3 to 6 hours; the adhesion material The concentration of the adhesive material in the solution is 0.1-20%, preferably 5-15%; preferably, the freeze-drying process has a pre-freezing temperature of -80 to -10 ° C, preferably -80 to -50 ° C; The drying temperature is -20 to 30 ° C, preferably -10 to 25 ° C.

根据本公开的方法，所述冷冻干燥工艺中，所述亲水性物质包括纤维素类化合物和/或其衍生物，优选包括羟乙基纤维素、羧甲基纤维素、羟丙基甲基纤维素的一种或几种；优选地，所述亲水性物质包括经改性处理的纤维素类化合物和/或其衍生物，优选包括经改性处理的羟乙基纤维素、羧甲基纤维素、羟丙基甲基纤维素的一种或几种。According to the method of the present disclosure, in the freeze-drying process, the hydrophilic substance includes a cellulose compound and/or a derivative thereof, preferably including hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl group. One or more kinds of cellulose; preferably, the hydrophilic substance comprises a modified cellulose compound and/or a derivative thereof, preferably comprising modified hydroxyethyl cellulose, carboxymethyl One or more of cellulose, hydroxypropyl methylcellulose.

根据本公开的方法，所述冷冻干燥工艺中，所述改性处理包括：采用交联剂进行交联反应的步骤；优选地，所述交联剂包括醛类化合物，优选包括甲醛、乙醛、戊二醛中的一种或多种，更优选包括戊二醛。According to the method of the present disclosure, in the freeze-drying process, the modifying treatment includes a step of performing a crosslinking reaction using a crosslinking agent; preferably, the crosslinking agent includes an aldehyde compound, preferably including formaldehyde, acetaldehyde One or more of glutaraldehyde, more preferably glutaraldehyde.

根据本公开的方法，所述冷冻干燥工艺中，所述改性处理还包括：在盐溶液中进行交联反应；优选地，所述盐包括中性盐，更优选地，所述中性盐为水溶性铝盐、钠盐、钙盐和铁盐中的一种或多种。According to the method of the present disclosure, in the freeze-drying process, the modifying treatment further comprises: performing a crosslinking reaction in a salt solution; preferably, the salt includes a neutral salt, and more preferably, the neutral salt It is one or more of water-soluble aluminum salts, sodium salts, calcium salts and iron salts.

根据本公开的方法，所述冷冻干燥工艺中，所述改性处理是在溶液中进行的，优选地，所述溶液的pH值呈酸性。According to the method of the present disclosure, in the freeze-drying process, the modification treatment is carried out in a solution, and preferably, the pH of the solution is acidic.

根据本公开的方法，所述冷冻干燥工艺中，所述改性处理的温度为50～130℃，优选为60～80℃；所述改性处理的时间为20～240min，优选40～80min；所述黏附材料溶液中，所述亲水性物质的质量浓度的0.1～20％，优选5～15％。The temperature of the modification treatment is 50-130 ° C, preferably 60-80 ° C; the modification treatment time is 20-240 min, preferably 40-80 min; In the solution of the adhering material, the hydrophilic substance has a mass concentration of 0.1 to 20%, preferably 5 to 15%.

根据本公开的方法，所述涂覆工艺包括以下步骤：According to the method of the present disclosure, the coating process includes the following steps:

将所述黏附材料溶液涂覆在所述纳米纤维膜上，并静置；Coating the adhesion material solution on the nanofiber membrane and standing;

将所述编织网片平铺于所述黏附材料溶液上挥发干燥，得到所述复合组织修复补片。The woven mesh sheet is tiled on the adhesive material solution and evaporated to dryness to obtain the composite tissue repair patch.

根据本公开的方法，所述涂覆工艺中，所述黏附材料溶液的厚度为0.1～3mm，优选1～2mm；所述静置的时间为1～72h，优选为24～48h；所述黏附材料溶液中，所述黏附材料的质量浓度为1～50％，优选为10～20％。According to the method of the present disclosure, in the coating process, the thickness of the solution of the adhesive material is 0.1 to 3 mm, preferably 1 to 2 mm; the time of the standing is 1 to 72 hours, preferably 24 to 48 hours; the adhesion In the material solution, the mass concentration of the adhesion material is from 1 to 50%, preferably from 10 to 20%.

根据本公开的方法，所述涂覆工艺中，所述亲水性物质包括蛋白质类化合物和/或其衍生物，优选包括胶原蛋白、明胶中的一种或两种；According to the method of the present disclosure, in the coating process, the hydrophilic substance includes a proteinaceous compound and/or a derivative thereof, preferably one or both of collagen and gelatin;

优选地，所述亲水性物质包括经改性处理的蛋白质类化合物，优选包括经改性处理的胶原蛋白、明胶中的一种或两种。Preferably, the hydrophilic substance comprises a modified protein compound, preferably one or both of modified modified collagen and gelatin.

根据本公开的方法，所述涂覆工艺中，所述改性处理包括：采用交联剂进行交联反应的步骤；优选地，所述交联剂包括碳化二亚胺/N-羟基琥珀酰亚胺、京尼平、醛类化合物中的一种或多种，优选包括碳化二亚胺、碳化二亚胺/N-羟基琥珀酰亚胺的一种或两种，更优选包括碳化二亚胺/N-羟基琥珀酰亚胺。According to the method of the present disclosure, in the coating process, the modifying treatment includes a step of performing a crosslinking reaction using a crosslinking agent; preferably, the crosslinking agent includes a carbodiimide/N-hydroxysuccinyl group One or more of the imine, genipin, and an aldehyde compound, preferably including one or both of carbodiimide, carbodiimide/N-hydroxysuccinimide, more preferably including carbonized secondary Amine/N-hydroxysuccinimide.

根据本公开的方法，所述涂覆工艺中，所述改性处理的温度为10～70℃，优选25～50℃；所述改性处理的时间为1～72h，优选12～72h；所述黏附材料溶液中，所述亲水性物质的质量为1～50％，优选为10～20％。In the coating process, the temperature of the modification treatment is 10 to 70 ° C, preferably 25 to 50 ° C; the modification treatment time is 1 to 72 h, preferably 12 to 72 h; In the solution of the adhesive material, the hydrophilic substance has a mass of 1 to 50%, preferably 10 to 20%.

根据本公开的方法，所述流延工艺包括以下步骤：According to the method of the present disclosure, the casting process includes the following steps:

将所述编织网片平铺于所述纳米纤维膜上；Spreading the woven mesh sheet on the nanofiber membrane;

将所述黏附材料溶液流延在所述编织网片上并静置，挥发干燥得到所述复合组织修复补片。The adhesive material solution is cast on the woven mesh sheet and allowed to stand, and evaporated to obtain the composite tissue repair patch.

根据本公开的方法，所述流延工艺中，所述黏附材料溶液的厚度为0.1～3mm，优选1～2mm；所述静置的处理时间为1～72h，优选24～48h；所述黏附材料溶液中，所述黏附材料的质量浓度为0.1～20％，优选5～15％。According to the method of the present disclosure, in the casting process, the thickness of the solution of the adhesive material is 0.1 to 3 mm, preferably 1 to 2 mm; the treatment time of the standing is 1 to 72 hours, preferably 24 to 48 hours; In the material solution, the mass concentration of the adhesion material is from 0.1 to 20%, preferably from 5 to 15%.

根据本公开的方法，所述流延工艺中，所述亲水性物质包括壳聚糖类化合物和/或其衍生物，优选包括羧甲基壳聚糖、羟丙基壳聚糖中的一种或两种；According to the method of the present disclosure, in the casting process, the hydrophilic substance includes a chitosan compound and/or a derivative thereof, preferably one of carboxymethyl chitosan and hydroxypropyl chitosan. Species or two;

优选地，所述亲水性物质包括改性处理的壳聚糖类化合物，优选包括经改性处理的羧甲基壳聚糖、羟丙基壳聚糖中的一种或两种。Preferably, the hydrophilic substance comprises a modified chitosan compound, preferably one or both of modified modified carboxymethyl chitosan, hydroxypropyl chitosan.

根据本公开的方法，所述流延工艺中，所述改性处理包括：采用交联剂进行交联反应的步骤；优选地，所述交联剂包括丙三醇和水；优选地，所述丙三醇和水的体积比为0.1～5:1，优选为0.5～2:1。According to the method of the present disclosure, in the casting process, the modifying treatment includes a step of performing a crosslinking reaction using a crosslinking agent; preferably, the crosslinking agent includes glycerin and water; preferably, the The volume ratio of glycerol to water is from 0.1 to 5:1, preferably from 0.5 to 2:1.

根据本公开的方法，所述流延工艺中，所述改性处理的温度为10～50℃，优选20～30℃；所述改性处理的时间为1～48h，优选12～24h；所述黏附材料溶液中，所述亲水性物质的质量浓度为0.1～20％，优选5～15％。According to the method of the present disclosure, in the casting process, the temperature of the modification treatment is 10 to 50 ° C, preferably 20 to 30 ° C; the modification treatment time is 1 to 48 h, preferably 12 to 24 h; In the solution of the adhesive material, the hydrophilic substance has a mass concentration of 0.1 to 20%, preferably 5 to 15%.

本公开还提供一种根据本公开的复合组织修复补片在制备疝气修复补片、盆底修复补片、尿失禁悬吊带、肩袖修复补片、***补片、创面修复补片、瘘修复补片中的应用。The present disclosure also provides a composite tissue repair patch according to the present disclosure in preparing a hernia repair patch, a pelvic floor repair patch, a urinary incontinence suspension strap, a rotator cuff repair patch, a breast patch, a wound repair patch, and a hernia repair. The application in the patch.

发明的效果Effect of the invention

本公开的复合组织修复补片不易分层，有良好的力学性能和柔软特性。The composite tissue repair patch of the present disclosure is not easy to be layered, and has good mechanical properties and soft properties.

进一步地，本公开的复合组织修复补片还能够从纳米尺度上模仿天然胞外基质，可作为细胞生长的多孔支架，促进新生组织和血管的再生。Further, the composite tissue repair patch of the present disclosure is also capable of mimicking the natural extracellular matrix from the nanometer scale, and can serve as a porous scaffold for cell growth, promoting regeneration of new tissues and blood vessels.

另外，本公开的制备复合组织修复补片的方法简单，不会影响和改变纳米纤维膜的原有结构，更好地保留了纳米纤维膜原有的多孔隙三维网状结构的特性。In addition, the method for preparing a composite tissue repair patch of the present disclosure is simple, does not affect and change the original structure of the nanofiber membrane, and better preserves the characteristics of the original porous three-dimensional network structure of the nanofiber membrane.

附图说明DRAWINGS

图1为本公开实施例1制备得到的复合组织修复补片的结构示意图；1 is a schematic structural view of a composite tissue repair patch prepared in Example 1 of the present disclosure;

图2为本公开实施例2制备得到的复合组织修复补片的结构示意图；2 is a schematic structural view of a composite tissue repair patch prepared in Example 2 of the present disclosure;

图3为采用本公开实施例2制备得到的复合组织修复补片进行疝气修复手术修补后的照片；3 is a photograph of a composite tissue repair patch prepared in Example 2 of the present disclosure after repairing a hernia repair operation;

图4为采用本公开实施例4制备得到的复合组织修复补片进行疝气修复手术修补后的照片；4 is a photograph of a composite tissue repair patch prepared in Example 4 of the present disclosure after repairing a hernia repair operation;

图5为采用编织网片进行疝气修复手术修补后的照片；Figure 5 is a photograph of a hernia repair after repair with a woven mesh;

图6为采用实施例2制备得到的复合组织修复补片进行疝气修复手术后两周的修复效果图；Figure 6 is a diagram showing the repair effect of the composite tissue repair patch prepared in Example 2 for two weeks after the hernia repair operation;

图7为采用实施例4制备得到的复合组织修复补片进行疝气修复手术后两周的修复效果图；7 is a view showing the repair effect of the composite tissue repair patch prepared in Example 4 for two weeks after the hernia repair operation;

图8为采用编织网片进行疝气修复手术后两周的修复效果图。Fig. 8 is a view showing the effect of repairing two weeks after the hernia repair operation using the woven mesh.

具体实施方式detailed description

本公开提供一种复合组织修复补片，包括：纳米纤维膜、编织网片和黏附材料，其中，所述黏附材料位于所述纳米纤维膜与所述编织网片之间。The present disclosure provides a composite tissue repair patch comprising: a nanofiber membrane, a woven mesh, and an adhesive material, wherein the adhesive material is between the nanofiber membrane and the woven mesh.

所述黏附材料包括亲水性物质，优选包括可降解的亲水性物质；所述纳米纤维膜和所述编织网片通过所述黏附材料相结合，且所述黏附材料嵌入所述纳米纤维膜层和所述编织网片层的孔隙中。The adhesion material comprises a hydrophilic substance, preferably comprising a degradable hydrophilic substance; the nanofiber membrane and the woven mesh sheet are combined by the adhesion material, and the adhesion material is embedded in the nanofiber membrane The layers and the pores of the woven mesh layer.

其中，所述亲水性物质可以是亲水性天然物质和/或其衍生物、经改性处理的亲水性天然物质和/或其衍生物以及一些亲水性的非天然物质等。通过黏附材料将纳米纤维膜和编织网片的有效复合，不仅不会影响纳米纤维膜和编织网片的原有结构，保留了纳米纤维膜和编织网片原有结构的特性，还能够促进组织、血管的修复与再生。The hydrophilic substance may be a hydrophilic natural substance and/or a derivative thereof, a modified hydrophilic natural substance and/or a derivative thereof, and some hydrophilic non-natural substances. The effective compounding of the nanofiber membrane and the woven mesh by the adhesive material not only does not affect the original structure of the nanofiber membrane and the woven mesh, retains the characteristics of the original structure of the nanofiber membrane and the woven mesh, and also promotes the tissue. , repair and regeneration of blood vessels.

所述黏附材料嵌入所述纳米纤维膜和所述编织网片的孔隙中，使纳米纤维膜和编织网片紧密的粘合为一体，从而使得制备得到的复合组织修复补片具备较高的剥离强度和断裂强度，能够实现在对力学强度要求较高的部位进行组织修复。The adhesive material is embedded in the pores of the nanofiber membrane and the woven mesh sheet, so that the nanofiber membrane and the woven mesh sheet are tightly bonded together, so that the prepared composite tissue repair patch has high peeling. Strength and breaking strength enable tissue repair in areas where high mechanical strength is required.

选用亲水性物质，特别是亲水性天然物质和/或其衍生物或经改性处理的亲水性天然物质和/或其衍生物作为黏附材料，可以快速降解，还能够使得纳米纤维膜和编织网片紧密的粘合为一体。The use of hydrophilic substances, in particular hydrophilic natural substances and / or their derivatives or modified hydrophilic natural substances and / or their derivatives as adhesion materials, can be rapidly degraded, and can also make nanofiber membranes It is tightly bonded to the woven mesh.

根据本公开的复合组织修复补片，还包括防粘连层，所述防粘连层黏附于所述编织网片的与纳米纤维膜所在侧相反的面上。所述编织网片的与纳米纤维膜所在侧相反的面上其意指编织网片的远离所述纳米纤维膜的一面。从而使得所述复合修复补片不仅能够促进组织生长与修复，还可以起到防粘连的作用，有利于防止复合组织修复补片与脏器粘连以及补片皱缩等情况，可以有效减少病人的持续疼痛或手术部位部分失去功能等并发症，是一种多功能的复合组织修复补片。The composite tissue repair patch according to the present disclosure further includes an anti-adhesion layer adhered to a face of the woven mesh opposite the side on which the nanofiber film is located. The face of the woven mesh opposite the side on which the nanofiber membrane is located means the side of the woven mesh that is remote from the nanofiber membrane. Therefore, the composite repair patch can not only promote tissue growth and repair, but also can play an anti-adhesion function, which is beneficial to prevent the composite tissue repair patch and the organ adhesion and the patch shrinkage, etc., and can effectively reduce the patient's Complications such as persistent pain or partial loss of function in the surgical site are a multifunctional composite tissue repair patch.

所述纳米纤维膜具有三维多孔结构、极大的比表面积、高孔隙率与高表面能等特点，可作为细胞生长的多孔支架，促进细胞的迁移和增殖，并且具有三维多孔结构的纳米纤维膜，更易于输送营养和氧气，从而更利于细胞的增殖和分化。The nanofiber membrane has a three-dimensional porous structure, a large specific surface area, a high porosity and a high surface energy, and can be used as a porous scaffold for cell growth, promotes cell migration and proliferation, and has a three-dimensional porous structure of a nanofiber membrane. It is easier to transport nutrients and oxygen, which is more conducive to cell proliferation and differentiation.

同时，利用黏附材料在编织网片表面成膜后能够进一步改善编织网片的生物相容性。At the same time, the biocompatibility of the woven mesh sheet can be further improved by using the adhesive material to form a film on the surface of the woven mesh sheet.

根据本公开的复合组织修复补片，其中，所述亲水性物质的重均分子量为50000～2000000Da。A composite tissue repair patch according to the present disclosure, wherein the hydrophilic substance has a weight average molecular weight of 50,000 to 2,000,000 Da.

根据本公开的复合组织修复补片，其中，所述亲水性物质包括：含氮类化合物及其衍生物、纤维素类化合物及其衍生物、醇类化合物及其衍生物、壳聚糖类化合物及其衍生物、糖类化合物及其衍生物中的一种或多种；优选地，经过改性处理后的一种或多种上述的亲水性物质。A composite tissue repairing patch according to the present disclosure, wherein the hydrophilic substance comprises: a nitrogen-containing compound and a derivative thereof, a cellulose compound and a derivative thereof, an alcohol compound and a derivative thereof, and a chitosan One or more of a compound and a derivative thereof, a saccharide compound, and a derivative thereof; preferably, one or more of the above-mentioned hydrophilic substances after the modification treatment.

根据本公开的复合组织修复补片，其中，所述含氮类化合物包括蛋白质类化合物，如：胶原蛋白、明胶中的一种或两种；所述壳聚糖类化合物包括：羧甲基壳聚糖、羟丙基壳聚糖中的一种或两种；所述纤维素类化合物包括：羧甲基纤维素、羧甲基纤维素钠中的一种或两种。A composite tissue repair patch according to the present disclosure, wherein the nitrogen-containing compound comprises a proteinaceous compound such as one or both of collagen and gelatin; and the chitosan compound comprises: a carboxymethyl shell One or two of a polysaccharide, hydroxypropyl chitosan; and the cellulose compound includes one or both of carboxymethylcellulose and sodium carboxymethylcellulose.

根据本公开的复合组织修复补片，其中，所述纳米纤维膜与编织网片之间的距离为0.1～3mm；优选为0.2～2mm，也就是说，夹在纳米纤维膜与编织网片之间的黏附材料的厚度(不包含嵌入纳米纤维膜与编织网片内部的黏附材料)为0.1～3mm；优选为0.2～2mm。可以通过采用测量仪(例如：刻度尺)随机取多个点(例如3个点)测定纳米纤维膜与编织网片之间的距离得到。A composite tissue repair patch according to the present disclosure, wherein a distance between the nanofiber membrane and the woven mesh sheet is 0.1 to 3 mm; preferably 0.2 to 2 mm, that is, sandwiched between the nanofiber membrane and the woven mesh sheet The thickness of the adhesive material (excluding the adhesion material embedded in the nanofiber film and the inside of the woven mesh sheet) is 0.1 to 3 mm; preferably 0.2 to 2 mm. The distance between the nanofiber membrane and the woven mesh can be determined by randomly taking a plurality of points (for example, 3 points) using a measuring instrument (for example, a scale).

一般而言，黏附材料的厚度与黏附材料的分子量、黏附材料溶液的厚度、黏附材料溶液中黏附材料的浓度等因素相关。举例而言，当黏附材料溶液的厚度较薄且黏附材料溶液中黏附材料的浓度较低时，黏附材料的厚度也变薄；当黏附材料溶液的厚度较厚且黏附材料溶液中黏附材料的浓度较高时，黏附材料的厚度也相应变厚。In general, the thickness of the adhesive material is related to factors such as the molecular weight of the adhesive material, the thickness of the adhesive material solution, and the concentration of the adhesive material in the adhesive material solution. For example, when the thickness of the adhesion material solution is thin and the concentration of the adhesion material in the adhesion material solution is low, the thickness of the adhesion material is also thin; when the thickness of the adhesion material solution is thick and the concentration of the adhesion material in the adhesion material solution is When higher, the thickness of the adhesive material also becomes thicker.

如果纳米纤维膜与编织网片之间的距离小于0.1mm，则黏附材料过薄，导致剥离强度稍差，影响材料的复合效果；如果纳米纤维膜与编织网片之间的距离大于3mm，则黏附材料过厚，从而会影响复合补片与组织的生物相容性。If the distance between the nanofiber membrane and the woven mesh sheet is less than 0.1 mm, the adhesion material is too thin, resulting in a slightly poor peel strength, affecting the composite effect of the material; if the distance between the nanofiber membrane and the woven mesh sheet is greater than 3 mm, then The adhesion material is too thick, which affects the biocompatibility of the composite patch to the tissue.

一般而言，本公开中所述的黏附材料溶液的厚度均指夹在纳米纤维膜与编织网片之间的黏附材料溶液的厚度。In general, the thickness of the solution of the adhesive material described in the present disclosure refers to the thickness of the solution of the adhesive material sandwiched between the nanofiber membrane and the woven mesh sheet.

根据本公开的复合组织修复补片，其中，所述复合组织修复补片的整体厚度为0.3～5mm；优选为0.5～3mm。The composite tissue repair patch according to the present disclosure, wherein the composite tissue repair patch has an overall thickness of 0.3 to 5 mm; preferably 0.5 to 3 mm.

根据本公开所述的复合组织修复补片，其中，所述纳米纤维膜采用包括静电纺丝的方法制得，当然，所述纳米纤维膜也可以购买获得。The composite tissue repair patch according to the present disclosure, wherein the nanofiber membrane is produced by a method including electrospinning, of course, the nanofiber membrane is also commercially available.

本公开提供一种静电纺丝的方法，具体包括以下步骤：The present disclosure provides a method of electrospinning, specifically comprising the following steps:

将制备纳米纤维膜的可降解材料溶于溶剂中，得到聚合物溶液；Dissolving the degradable material for preparing the nanofiber membrane in a solvent to obtain a polymer solution;

将聚合物溶液置于静电纺丝注射器中，进行静电纺丝，得到纤维丝，并将纤维丝接收为膜状结构，得到纳米纤维膜。The polymer solution was placed in an electrospinning syringe, electrospun, to obtain a fiber filament, and the fiber filament was received into a film-like structure to obtain a nanofiber membrane.

优选地，所述溶剂包括三氟乙醇、六氟异丙醇、三氟乙酸、环己酮、丙酮、丁酮、四氢呋喃、氯仿、冰乙酸、甲酸、丙酸、水中的一种或多种。Preferably, the solvent comprises one or more of trifluoroethanol, hexafluoroisopropanol, trifluoroacetic acid, cyclohexanone, acetone, methyl ethyl ketone, tetrahydrofuran, chloroform, glacial acetic acid, formic acid, propionic acid, and water.

优选地，在所述静电纺丝过程中，调节微量注射泵的速率为0.1～15mL/h，调节高压发生器的电压为10～35kV，调节接收装置的接收距离为5～30cm。Preferably, in the electrospinning process, the rate of adjusting the micro syringe pump is 0.1-15 mL/h, the voltage of the high voltage generator is adjusted to 10 to 35 kV, and the receiving distance of the receiving device is 5-30 cm.

根据本公开的组织修复补片，其中，所述纳米纤维膜由直径为10nm～100μm的纤维丝交织而成。A tissue repair patch according to the present disclosure, wherein the nanofiber membrane is interwoven by filaments having a diameter of 10 nm to 100 μm.

优选地，所述可降解材料包括聚乳酸(PLA)、聚L-乳酸(PLLA)、聚DL-乳酸(PDLLA)、聚己内酯(PCL)、聚羟基脂肪酸酯(PHA)、聚乙交酯(PGA)、聚已交-丙交酯(PLGA)、胶原(Collagen)及其衍生物、明胶(Gelatin)及其衍生物、壳聚糖(Chitosan)及其衍生物、透明质酸(HA)及其衍生物、纤维素及其衍生物中的一种或多种。Preferably, the degradable material comprises polylactic acid (PLA), poly-L-lactic acid (PLLA), poly-DL-lactic acid (PDLLA), polycaprolactone (PCL), polyhydroxyalkanoate (PHA), polyethyl b. Lactide (PGA), poly-lactide (PLGA), collagen (Collagen) and its derivatives, gelatin (Gelatin) and its derivatives, chitosan (Chitosan) and its derivatives, hyaluronic acid ( One or more of HA) and its derivatives, cellulose and its derivatives.

根据本公开的防粘连组织修复补片，其中，所述纳米纤维膜中加载有药物，所述药物优选包括生长因子；更优选包括表皮生长因子、成纤维细胞生长因子中的一种或两种。复合组织修复补片同时可以作为一种药物的载体，能够减少药物降解及损失，降低副作用，提高生物利用度。生长因子是指一类通过与细胞膜特异受体结合，发挥调节细胞生长作用的肽类分子，通过加载生长因子，能够使得修复补片通过缝合的方式，植入伤口组织时，能够加快细胞生长，促进伤口愈合。An anti-adhesion tissue repair patch according to the present disclosure, wherein the nanofiber membrane is loaded with a drug, preferably comprising a growth factor; more preferably comprising one or both of an epidermal growth factor, a fibroblast growth factor . The composite tissue repair patch can also serve as a carrier for drugs, which can reduce drug degradation and loss, reduce side effects, and improve bioavailability. Growth factor refers to a class of peptide molecules that regulate cell growth by binding to cell membrane-specific receptors. By loading growth factors, the repair patch can accelerate cell growth by suturing the wound tissue. Promote wound healing.

根据本公开的复合组织修复补片，其中，所述编织网片由不可降解材料制成，优选地，所述不可降解材料包括聚丙烯、聚偏二氟乙烯、聚对苯二四酸乙二醇酯、膨化聚四氟乙烯中的一种或多种。A composite tissue repair patch according to the present disclosure, wherein the woven mesh sheet is made of a non-degradable material, preferably, the non-degradable material comprises polypropylene, polyvinylidene fluoride, polyethylene terephthalate One or more of an alcohol ester and a expanded polytetrafluoroethylene.

复合步骤：制备黏附材料溶液，将所述纳米纤维膜和所述编织网片用所述黏附材料溶液复合得到所述复合组织修复补片；优选地，通过冷冻干燥工艺或涂覆工艺或流延工艺将所述纳米纤维膜与所述编织网片用所述黏附材料溶液进行复合。a compounding step of preparing an adhesion material solution, compounding the nanofiber membrane and the woven mesh sheet with the adhesion material solution to obtain the composite tissue repair patch; preferably, by a freeze drying process or a coating process or casting The process recombines the nanofiber membrane with the woven mesh sheet with the solution of the adherent material.

根据本公开的方法，其中，调整所述黏附材料的分子量和/或所述黏附材料溶液的浓度，使得所述黏附材料溶液从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层。优选地，可以通过控制所述黏附材料的分子量和/或所述黏附材料溶液的浓度，使得编织网片浸没在黏附材料溶液中，即在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层，从而干燥后在编织网片的与纳米纤维膜所在侧相反的表面上形成一层防粘连膜。a method according to the present disclosure, wherein a molecular weight of the adhesion material and/or a concentration of the adhesion material solution is adjusted such that the adhesion material solution overflows from the pores of the woven mesh sheet and is in the woven mesh sheet An anti-blocking solution layer is formed on the surface opposite to the side on which the nanofiber membrane is located. Preferably, the woven mesh sheet may be immersed in the adhesive material solution by controlling the molecular weight of the adhesive material and/or the concentration of the adhesive material solution, that is, on the side of the woven mesh sheet opposite to the side of the nanofiber membrane. An anti-blocking solution layer is formed on the surface to form an anti-blocking film on the surface of the woven mesh sheet opposite to the side on which the nanofiber film is located after drying.

在一种具体的实施方式中，所述冷冻干燥工艺包括以下步骤：In a specific embodiment, the freeze-drying process comprises the following steps:

将所述编织网片平铺于所述黏附材料溶液上，冷冻干燥后得到复合组织修复补片。The woven mesh sheet is laid on the adhesive material solution, and freeze-dried to obtain a composite tissue repair patch.

优选地，所述黏附材料溶液从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层，冷冻干燥后得到复合组织修复补片；使得该复合组织修复补片在所述编织网片的与纳米纤维膜所在侧相反的面上具有防粘连层。Preferably, the adhesive material solution overflows from the pores of the woven mesh sheet and forms an anti-blocking solution layer on a surface of the woven mesh sheet opposite to the side where the nanofiber membrane is located, and freeze-dried to obtain a composite tissue repairing patch. a sheet; the composite tissue repair patch having an anti-adhesion layer on a side of the woven mesh opposite the side on which the nanofiber membrane is located.

优选的，所述亲水性物质包括纤维素类化合物和/或基衍生物，优选包括羟乙基纤维素、羧甲基纤维素、羟丙基甲基纤维素的一种或几种；更优选地，所述亲水性物质包括经改性处理的纤维素类化合物/或其衍生物；进一步优选地，所述亲水性物质包括经改性处理的羟乙基纤维素、羧甲基纤维素、羟丙基甲基纤维素的一种或几种。Preferably, the hydrophilic substance comprises a cellulose compound and/or a base derivative, preferably one or more of hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose; Preferably, the hydrophilic substance comprises a modified cellulose compound/or a derivative thereof; further preferably, the hydrophilic substance comprises a modified hydroxyethyl cellulose, a carboxymethyl group One or more of cellulose, hydroxypropyl methylcellulose.

根据本公开的方法，其中，所述静置的时间为1～24h，优选3～6h。当黏附材料溶液平铺于所述纳米纤维膜上的时间在1～24h的范围内时，可以更好的使黏附材料溶液均匀的分布在纳米纤维膜表面，使黏附材料溶液嵌入到纳米纤维膜的孔隙中，分子与分子之间的接触面积增大，从而增加黏附材料溶液与纳米纤维膜之间的结合力。优选地，所述黏附材料溶液中，所述黏附材料的质量浓度为0.1～20％；优选为5～15％，所述黏附材料溶液的厚度为0.1～3mm，优选0.2～2mm。The method according to the present disclosure, wherein the standing time is from 1 to 24 h, preferably from 3 to 6 h. When the time of adhering the solution of the adhesive material on the nanofiber membrane is in the range of 1 to 24 hours, the solution of the adhesive material can be evenly distributed on the surface of the nanofiber membrane, and the solution of the adhesive material is embedded in the nanofiber membrane. In the pores, the contact area between the molecules and the molecules is increased, thereby increasing the binding force between the adhesion material solution and the nanofiber membrane. Preferably, in the solution of the adhesive material, the mass concentration of the adhesive material is 0.1 to 20%; preferably 5 to 15%, and the thickness of the solution of the adhesive material is 0.1 to 3 mm, preferably 0.2 to 2 mm.

在本实施方式中，所述改性处理包括：采用交联剂进行交联反应的步骤；优选地，所述交联剂包括醛类化合物，优选包括甲醛、乙醛、戊二醛中的一种或多种，更优选包括戊二醛。本公开中选用戊二醛作为交联剂时，对生物体的毒性相对较小，与蛋白质反应时具有活性高、反应快、结合量高、交联性能好、产品稳定等优点。In the present embodiment, the modifying treatment includes a step of performing a crosslinking reaction using a crosslinking agent; preferably, the crosslinking agent includes an aldehyde compound, preferably including one of formaldehyde, acetaldehyde, and glutaraldehyde. One or more, more preferably including glutaraldehyde. When glutaraldehyde is used as the crosslinking agent in the present disclosure, the toxicity to the living body is relatively small, and when reacted with the protein, the activity is high, the reaction is fast, the binding amount is high, the crosslinking property is good, and the product is stable.

在本实施方式中，所述改性处理还包括：在盐溶液中进行交联反应；优选地，所述盐包括中性盐，所述中性盐优选包括水溶性铝盐、钠盐、钙盐和铁盐中的一种或多种。In the present embodiment, the modifying treatment further comprises: performing a crosslinking reaction in a salt solution; preferably, the salt includes a neutral salt, and the neutral salt preferably includes a water-soluble aluminum salt, a sodium salt, and a calcium salt. One or more of a salt and an iron salt.

所述改性处理是在溶液中进行地，所述溶液的pH值呈酸性。The modification treatment is carried out in a solution, and the pH of the solution is acidic.

在本实施方式中，所述改性处理的温度为50～130℃，优选为60～80℃。所述改性处理的时间为20～240min，优选40～80min；所述黏附材料溶液中，所述亲水性物质的质量浓度的0.1～20％，优选5～15％。优选地，所述交联剂的体积为所述亲水性物质的质量的0.1～10体积/质量％，优选0.5～5体积/质量％。一般而言，所述交联剂的体积的单位为mL，所述亲水性物质的质量的单位为g。In the present embodiment, the temperature of the modification treatment is 50 to 130 ° C, preferably 60 to 80 ° C. The modification treatment time is 20 to 240 minutes, preferably 40 to 80 minutes; and the mass concentration of the hydrophilic substance in the adhesion material solution is 0.1 to 20%, preferably 5 to 15%. Preferably, the volume of the crosslinking agent is from 0.1 to 10% by volume, preferably from 0.5 to 5% by volume, based on the mass of the hydrophilic substance. In general, the unit of the volume of the crosslinking agent is mL, and the unit of the mass of the hydrophilic substance is g.

另外，所述冷冻干燥的预冻温度为-80～-10℃，优选-80～-50℃；干燥温度为-20～30℃，优选-10～25℃。当预冻温度在-80～-10℃之间时，有利于形成较高的孔隙率和更加均一的结构，能够增大材料的比表面积，从而使纳米纤维膜层和编织网片层有效的结合在一起。Further, the freeze-drying pre-freezing temperature is -80 to -10 ° C, preferably -80 to -50 ° C; and the drying temperature is -20 to 30 ° C, preferably -10 to 25 ° C. When the pre-freezing temperature is between -80 and -10 °C, it is advantageous to form a higher porosity and a more uniform structure, which can increase the specific surface area of the material, thereby making the nanofiber membrane layer and the woven mesh layer effective. integrate.

在另一种具体的实施方式中，所述涂覆工艺包括以下步骤：In another specific embodiment, the coating process comprises the following steps:

将所述亲水性物质溶解，得到黏附材料溶液；将所述黏附材料溶液均匀的涂覆在所述纳米纤维膜上，并静置；Dissolving the hydrophilic substance to obtain a solution of an adhesive material; uniformly coating the solution of the adhesive material on the nanofiber membrane, and standing still;

将所述编织网片平铺于所述黏附材料溶液上，挥发干燥后，得到所述复合组织修复补片。The woven mesh sheet is laid on the adhesive material solution, and after volatilization and drying, the composite tissue repair patch is obtained.

优选地，所述黏附材料溶液从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层，挥发干燥后，得到所述复合组织修复补片；使得该复合组织修复补片在所述编织网片的与纳米纤维膜所在侧相反的面上具有防粘连层。Preferably, the adhesive material solution overflows from the pores of the woven mesh sheet and forms an anti-blocking solution layer on a surface of the woven mesh sheet opposite to the side where the nanofiber membrane is located, and after evaporation and drying, the composite is obtained. The tissue repair patch is made such that the composite tissue repair patch has an anti-adhesion layer on a side of the woven mesh opposite the side on which the nanofiber membrane is located.

在本实施方式中，所述亲水性物质包括蛋白质类化合物和/或其衍生物，优选包括胶原蛋白、明胶中的一种或两种。更优选地，所述亲水性物质包括经改性处理的蛋白质类化合物和/或其衍生物。进一步优选地，所述亲水性物质包括经改性处理的胶原蛋白、明胶中的一种或两种。In the present embodiment, the hydrophilic substance includes a proteinaceous compound and/or a derivative thereof, and preferably includes one or both of collagen protein and gelatin. More preferably, the hydrophilic substance comprises a modified protein compound and/or a derivative thereof. Further preferably, the hydrophilic substance comprises one or both of modified collagen and gelatin.

优选的，所述黏附材料溶液的厚度为0.1～3mm，优选1～2mm；所述静置的时间为1～72h，优选24～48h；所述黏附材料溶液中，所述黏附材料的质量浓度为1～50％，优选为10～20％。当黏附材料溶液平铺于所述纳米纤维膜上的时间在1～72h的范围内时，可以更好的使黏附材料溶液均匀的分布在纳米纤维膜表面，使黏附材料溶液嵌入到纳米纤维膜的孔隙中，分子与分子之间的接触面积增大，从而增加黏附材料溶液与纳米纤维膜之间的结合力。Preferably, the thickness of the solution of the adhesive material is 0.1 to 3 mm, preferably 1 to 2 mm; the time of the standing is 1 to 72 hours, preferably 24 to 48 hours; and the mass concentration of the adhesive material in the solution of the adhesive material It is 1 to 50%, preferably 10 to 20%. When the adhesion material solution is laid on the nanofiber membrane for a time in the range of 1 to 72 h, the adhesion material solution can be better distributed on the surface of the nanofiber membrane, and the adhesion material solution is embedded in the nanofiber membrane. In the pores, the contact area between the molecules and the molecules is increased, thereby increasing the binding force between the adhesion material solution and the nanofiber membrane.

所述改性处理所采用的交联剂包括碳化二亚胺/N-羟基琥珀酰亚胺、京尼平、醛类化合物中的一种或多种，优选包括碳化二亚胺、碳化二亚胺/N-羟基琥珀酰亚胺的一种或两种，更优选包括碳化二亚胺/N-羟基琥珀酰亚胺。The crosslinking agent used in the modification treatment includes one or more of carbodiimide/N-hydroxysuccinimide, genipin, and an aldehyde compound, and preferably includes carbodiimide and carbonized di One or both of the amine/N-hydroxysuccinimide, more preferably including carbodiimide/N-hydroxysuccinimide.

在本实施方式中，所述改性处理的温度为10～70℃，优选25～50℃；改性处理的时间为1～72h，优选12～72h；所述黏附材料溶液中，所述亲水性物质的质量浓度为1～50％，优选为10～20％。优选地，所述交联剂的质量为所述亲水性物质的质量的10～50％，优选为10～20％。In the present embodiment, the temperature of the modification treatment is 10 to 70 ° C, preferably 25 to 50 ° C; the modification treatment time is 1 to 72 h, preferably 12 to 72 h; in the adhesion material solution, the pro The mass concentration of the aqueous substance is from 1 to 50%, preferably from 10 to 20%. Preferably, the mass of the crosslinking agent is 10 to 50%, preferably 10 to 20% by mass of the hydrophilic substance.

在又一种具体的实施方式中，所述流延工艺包括以下步骤：In still another specific embodiment, the casting process comprises the following steps:

将所述亲水性物质溶解得到黏附材料溶液；Dissolving the hydrophilic substance to obtain a solution of an adhesive material;

将所述黏附材料溶液均匀地流延在所述编织网片上并静置，挥发干燥后得到所述复合组织修复补片。优选地，所述黏附材料溶液从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层，挥发干燥后得到所述复合组织修复补片。使得该复合组织修复补片在所述编织网片的与纳米纤维膜所在侧相反的面上具有防粘连层。The adhesive material solution is uniformly cast on the woven mesh sheet and allowed to stand, and the composite tissue repair patch is obtained after volatilization and drying. Preferably, the adhesive material solution overflows from the pores of the woven mesh sheet and forms an anti-blocking solution layer on a surface of the woven mesh sheet opposite to the side where the nanofiber membrane is located, and the composite tissue is obtained after evaporation and drying. Repair the patch. The composite tissue repair patch is provided with an anti-blocking layer on a side of the woven mesh opposite the side on which the nanofiber membrane is located.

具体地，所述亲水性物质包括壳聚糖类化合物和/或其衍生物，优选包括羧甲基壳聚糖、羟丙基壳聚糖中的一种或两种。更优选地，所述亲水性物质包括经改性处理的壳聚糖类化合物和/或其衍生物。进一步优选地，所述亲水性物质包括经改性处理的羧甲基壳聚糖、羟丙基壳聚糖中的一种或两种。Specifically, the hydrophilic substance includes a chitosan compound and/or a derivative thereof, and preferably includes one or both of carboxymethyl chitosan and hydroxypropyl chitosan. More preferably, the hydrophilic substance includes a modified chitosan compound and/or a derivative thereof. Further preferably, the hydrophilic substance comprises one or both of modified modified carboxymethyl chitosan, hydroxypropyl chitosan.

在本实施方式中，所述黏附材料溶液的厚度为0.1～3mm，优选1～2mm；所述静置的处理时间为1～72h，优选24～48h；所述黏附材料溶液中，黏附材料的质量浓度为0.1～20％，优选5～15％。当静置时间在1～72h的范围内时，可以更好的使黏附材料溶液均匀的分布在纳米纤维膜表面，使黏附材料溶液嵌入到纳米纤维膜的孔隙中，分子与分子之间的接触面积增大，从而增加黏附材料溶液与纳米纤维膜之间的结合力。In the present embodiment, the thickness of the solution of the adhesive material is 0.1 to 3 mm, preferably 1 to 2 mm; the treatment time for the standing is 1 to 72 hours, preferably 24 to 48 hours; in the solution of the adhesive material, the adhesion material The mass concentration is from 0.1 to 20%, preferably from 5 to 15%. When the standing time is in the range of 1 to 72 h, the adhesion material solution can be evenly distributed on the surface of the nanofiber membrane, and the adhesion material solution is embedded in the pores of the nanofiber membrane, and the contact between the molecules and the molecules The area is increased to increase the bonding force between the adhesion material solution and the nanofiber membrane.

在本实施方式中，所述改性处理所采用的交联剂包括丙三醇和水；优选地，所述丙三醇和水的体积比为0.1～5:1，优选0.5～2:1，所述亲水性物质直接溶解在丙三醇和水组成的交联剂中，形成黏附材料溶液。所述黏附材料溶液中，所述亲水性物质的质量浓度为0.1～20％，优选5～15％。所述改性处理的温度为10～50℃，优选20～30℃；改性处理的时间为1～48h，优选12～24h。In this embodiment, the crosslinking agent used in the modification treatment includes glycerin and water; preferably, the volume ratio of the glycerin to water is 0.1 to 5:1, preferably 0.5 to 2:1. The hydrophilic substance is directly dissolved in a crosslinking agent composed of glycerin and water to form a solution of the adhesion material. In the solution of the adhering material, the hydrophilic substance has a mass concentration of 0.1 to 20%, preferably 5 to 15%. The temperature of the modification treatment is 10 to 50 ° C, preferably 20 to 30 ° C; and the modification treatment time is 1 to 48 h, preferably 12 to 24 h.

所述壳聚糖类化合物经丙三醇和水改性处理后得到的黏附材料溶液是无色透明、表面光洁、无气泡的。并且最终制备得到的复合组织修复补片能够使创伤位置的生理功能取得协同增效的作用，能够改善物化性能。The solution of the adhesion material obtained by modifying the chitosan compound by glycerin and water is colorless, transparent, smooth and bubble-free. And the finally prepared composite tissue repair patch can synergistically enhance the physiological function of the wound site and improve the physical and chemical properties.

另外，本公开所述的复合组织修复补片可以是三层结构，或者是多层结构，例如四层结构、五层结构等。当所述复合组织修复补片为五层结构时，优选依次由第一纳米纤维膜、第一黏附材料、编织网片、第二黏附材料、第二纳米纤维膜组成。In addition, the composite tissue repair patch of the present disclosure may be a three-layer structure or a multi-layer structure, such as a four-layer structure, a five-layer structure, or the like. When the composite tissue repair patch has a five-layer structure, it is preferably composed of a first nanofiber membrane, a first adhesive material, a woven mesh sheet, a second adhesive material, and a second nanofiber membrane.

本公开的复合组织修复补片通过微机控制电子万能材料拉力机(型号为HY-3080)测试纳米纤维膜与编织网片之间的剥离强度δ _T。具体方法为：将微机控制电子万能材料拉力机一端夹住纳米纤维膜，另一端夹住编织网片，设定测试隔距为25mm，拉伸速度为10mm/min，试验尺寸定为50mm×15mm，平行测试3次，取平均值。计算公式为：δ _T＝F/(B×T)，其中，F为剥离力，B为待测样品宽度，T为复合组织修复补片的厚度。 The composite tissue repair patch of the present disclosure tests the peel strength δ _T between the nanofiber membrane and the woven mesh sheet by a microcomputer controlled electronic universal material tensile machine (model HY-3080). The specific method is as follows: the microcomputer-controlled electronic universal material tensile machine is clamped on the nanofiber membrane at one end, and the braided mesh is clamped at the other end, and the test gauge is set to 25 mm, the tensile speed is 10 mm/min, and the test size is set to 50 mm×15 mm. , tested in parallel 3 times and averaged. The calculation formula is: δ _T = F / (B × T), where F is the peeling force, B is the width of the sample to be tested, and T is the thickness of the composite tissue repair patch.

根据本公开的复合组织修复补片的断裂强度的测定方法为：通过拉力机测试复合组织修复补片的断裂强度。将待测样品裁剪为40mm×10mm的条状结构，使用厚度仪测试出复合组织修复补片的厚度(T)，测定断裂强度(f)和断裂伸长量(E)，拉伸速度为10mm/min，隔距为25mm，平行测试3次，取平均值。计算公式为：f＝F’/(B×T)，其中，F’为断裂强力，T为复合组织修复补片的厚度，B为待测样品宽度。The method for determining the breaking strength of the composite tissue repair patch according to the present disclosure is to test the breaking strength of the composite tissue repair patch by a tensile machine. The sample to be tested was cut into a strip structure of 40 mm×10 mm, and the thickness (T) of the composite tissue repair patch was measured using a thickness gauge, and the breaking strength (f) and the elongation at break (E) were measured, and the stretching speed was 10 mm. /min, the gauge is 25mm, tested in parallel 3 times, and averaged. The calculation formula is: f = F' / (B × T), where F' is the breaking strength, T is the thickness of the composite tissue repair patch, and B is the width of the sample to be tested.

采用溶剂填充法测定出复合组织修复补片的孔隙率。由于乙醇容易渗透入复合组织修复补片内部而不引起材料收缩和溶胀，因此采用乙醇作为试剂。具体测定方法如下：在100mL的容器中注入无水乙醇溶液，称取烘干至衡重的复合组织修复补片(重量为m ₁)浸泡于乙醇中，循环抽真空至复合组织修复补片不再有气泡溢出，称取含有乙醇、复合组织修复补片以及烧杯总重量为m ₂，再将内部含有乙醇的复合组织修复补片取出，称取烧杯和剩余的乙醇的总重量为m ₃，平行3次。测得孔隙率P为： The porosity of the composite tissue repair patch was determined by solvent filling method. Ethanol is used as a reagent because ethanol easily penetrates into the interior of the composite tissue repair patch without causing material shrinkage and swelling. The specific measurement method is as follows: in a 100 mL container, an absolute ethanol solution is injected, and the composite tissue repair patch (weight m ₁ ) which is dried to balance weight is weighed in ethanol, and the vacuum is vacuumed until the composite tissue repair patch is not Then, the bubble overflows, and the composite tissue repairing patch containing ethanol, the composite tissue repair patch, and the total weight of the beaker is m ₂ , and then the internal tissue containing the ethanol is taken out, and the total weight of the beaker and the remaining ethanol is m ₃ . Parallel 3 times. The measured porosity P is:

P＝(m ₂-m ₃-m ₁)/(m ₂-m ₃)×100％ P=(m ₂ -m ₃ -m ₁ )/(m ₂ -m ₃ )×100%

其中：(m ₂-m ₃-m ₁)为复合组织修复补片中孔隙所含有的乙醇的质量； Wherein: (m ₂ -m ₃ -m ₁ ) is the mass of ethanol contained in the pores in the composite tissue repair patch;

(m ₂-m ₃)为含有乙醇的复合组织修复补片总质量。 (m ₂ -m ₃ ) is the total mass of the composite tissue repair patch containing ethanol.

实施例Example

下面将结合实施例对本公开的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本公开，而不应视为限定本公开的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The embodiments of the present disclosure will be described in detail below with reference to the embodiments, but those skilled in the art will understand that the following examples are only intended to illustrate the disclosure, and are not intended to limit the scope of the disclosure. Those who do not specify the specific conditions in the examples are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are conventional products that can be obtained commercially.

实施例1Example 1

<纳米纤维膜的制备><Preparation of nanofiber membrane>

将聚乳酸(PLLA)溶于六氟异丙醇溶液，其中，聚乳酸的浓度为5％(g/mL)，搅拌溶解得到均匀的聚合物溶液。将所述聚合物溶液置于静电纺丝注射器中，调节微量注射泵的速率为8mL/h，调节高压发生器的电压为15kV，调节接收装置的接收距离为15cm，进行静电纺丝，当膜层厚度达到0.15mm后关闭静电纺丝，得到纳米纤维膜。Polylactic acid (PLLA) was dissolved in a hexafluoroisopropanol solution in which the concentration of polylactic acid was 5% (g/mL), and the mixture was stirred to obtain a uniform polymer solution. The polymer solution was placed in an electrospinning syringe, the rate of the micro syringe pump was adjusted to 8 mL/h, the voltage of the high voltage generator was adjusted to 15 kV, and the receiving distance of the receiving device was adjusted to 15 cm, and electrospinning was performed as a film. After the layer thickness reached 0.15 mm, the electrospinning was turned off to obtain a nanofiber membrane.

<黏附材料溶液的制备><Preparation of Adhesive Material Solution>

称取20g羟乙基纤维素溶于100mL纯化水中，加入0.8g氯化钙，并用乙酸调节溶液pH为4，搅拌溶解均匀；加入0.8mL戊二醛溶液(质量浓度为25％)，并控制反应温度为65℃，改性处理60min；得到黏附材料溶液。Weigh 20g of hydroxyethyl cellulose dissolved in 100mL of purified water, add 0.8g of calcium chloride, adjust the pH of the solution to 4 with acetic acid, stir and dissolve evenly; add 0.8mL glutaraldehyde solution (mass concentration is 25%), and control The reaction temperature was 65 ° C, and the modification treatment was carried out for 60 minutes; a solution of the adhesive material was obtained.

<复合组织修复补片的制备><Preparation of composite tissue repair patch>

将纳米纤维膜放入容器中，然后将上述黏附材料溶液平铺在纳米纤维膜上，静置6h，待黏附材料溶液均匀地嵌入纳米纤维膜的孔隙中，并控制黏附材料溶液的厚度为1mm。The nanofiber membrane is placed in a container, and then the above adhesive material solution is laid on the nanofiber membrane and allowed to stand for 6 hours. The solution of the adhesive material is uniformly embedded in the pores of the nanofiber membrane, and the thickness of the solution of the adhesive material is controlled to be 1 mm. .

将编织网片平铺在黏附材料溶液上，然后放入冻干机中于-80℃的温度下预冻3h；在25℃下干燥36h，取出并延压成型，得到如图1所示的复合组织修复补片，其中，1为纳米纤维膜，2为编织网片，3为黏附材料。The woven mesh sheet is laid on the adhesive material solution, and then pre-frozen in a lyophilizer at a temperature of -80 ° C for 3 h; dried at 25 ° C for 36 h, taken out and stretch molded to obtain a composite as shown in FIG. Tissue repair patch, wherein 1 is a nanofiber membrane, 2 is a woven mesh, and 3 is an adhesive material.

实施例2Example 2

<纳米纤维膜的制备><Preparation of nanofiber membrane>

将聚DL-乳酸(PDLLA)溶于六氟异丙醇溶液，其中，聚DL-乳酸的浓度为10％(g/mL)，搅拌溶解得到均匀的聚合物溶液。将所述聚合物溶液置于静电纺丝注射器中，调节微量注射泵的速率为7mL/h，调节高压发生器的电压为20kV，调节接收装置的接收距离为15cm，进行静电纺丝，当膜层厚度达到0.2mm后关闭静电纺丝，得到纳米纤维膜。PolyDL-lactic acid (PDLLA) was dissolved in a hexafluoroisopropanol solution in which the concentration of polyDL-lactic acid was 10% (g/mL), and the mixture was stirred to obtain a uniform polymer solution. The polymer solution was placed in an electrospinning syringe, the rate of the micro syringe pump was adjusted to 7 mL/h, the voltage of the high voltage generator was adjusted to 20 kV, and the receiving distance of the receiving device was adjusted to 15 cm, and electrospinning was performed as a film. After the layer thickness reached 0.2 mm, the electrospinning was turned off to obtain a nanofiber membrane.

<黏附材料溶液的制备><Preparation of Adhesive Material Solution>

称取10g羧甲基纤维素钠溶于100mL纯化水中，加入0.5g氯化钙，并用稀盐酸调节溶液pH为3，搅拌溶解均匀。加入0.5mL戊二醛溶液(质量浓度为25％)，并控制反应温度为70℃，改性处理40min。得到黏附材料溶液。10 g of sodium carboxymethylcellulose was weighed and dissolved in 100 mL of purified water, 0.5 g of calcium chloride was added, and the pH of the solution was adjusted to 3 with dilute hydrochloric acid, and stirred and dissolved uniformly. 0.5 mL of glutaraldehyde solution (mass concentration: 25%) was added, and the reaction temperature was controlled to 70 ° C, and the modification treatment was carried out for 40 minutes. A solution of the adherent material is obtained.

将纳米纤维膜放入容器中，然后将上述黏附材料溶液平铺在纳米纤维膜上，静置4h，待黏附材料溶液均匀地嵌入纳米纤维膜的孔隙中，并控制黏附材料溶液的厚度为1mm。The nanofiber membrane is placed in a container, and then the above-mentioned adhesive material solution is laid on the nanofiber membrane and allowed to stand for 4 hours. The solution of the adhesive material is uniformly embedded in the pores of the nanofiber membrane, and the thickness of the solution of the adhesive material is controlled to be 1 mm. .

将编织网片平铺在黏附材料溶液上，且所述黏附材料溶液从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层。然后放入冻干机中于-80℃的温度下预冻3h；在20℃下干燥24h，取出并延压成型，得到如图2所示的复合组织修复补片。所述复合组织修复补片在所述编织网片的与纳米纤维膜所在侧相反的面上具有防粘连层。其中，1为纳米纤维膜，2为编织网片，3为黏附材料，4为防粘连层。Spreading the woven mesh sheet on the adhesive material solution, and the adhesive material solution overflows from the pores of the woven mesh sheet and forms an anti-adhesion solution layer on a surface of the woven mesh sheet opposite to the side where the nanofiber membrane is located . Then, it was pre-frozen in a lyophilizer at a temperature of -80 ° C for 3 h; dried at 20 ° C for 24 h, taken out and stretch molded to obtain a composite tissue repair patch as shown in FIG. 2 . The composite tissue repair patch has an anti-blocking layer on a side of the woven mesh opposite the side on which the nanofiber membrane is located. Among them, 1 is a nanofiber membrane, 2 is a woven mesh, 3 is an adhesive material, and 4 is an anti-blocking layer.

实施例3Example 3

<纳米纤维膜的制备><Preparation of nanofiber membrane>

将明胶(Gelatin)溶于三氟乙醇溶液，其中，明胶的浓度为7％(g/mL)，搅拌溶解得到均匀的聚合物溶液。将所述聚合物溶液置于静电纺丝注射器中，调节微量注射泵的速率为5mL/h，调节高压发生器的电压为30kV，调节接收装置的接收距离为20cm，进行静电纺丝，当膜层厚度达到0.5mm后关闭静电纺丝，得到纳米纤维膜。Gelatin was dissolved in a trifluoroethanol solution in which the concentration of gelatin was 7% (g/mL), and the mixture was stirred to obtain a uniform polymer solution. The polymer solution was placed in an electrospinning syringe, the rate of the micro syringe pump was adjusted to 5 mL/h, the voltage of the high voltage generator was adjusted to 30 kV, the receiving distance of the receiving device was adjusted to 20 cm, and electrospinning was performed as a film. After the layer thickness reached 0.5 mm, the electrospinning was turned off to obtain a nanofiber membrane.

<黏附材料溶液的制备><Preparation of Adhesive Material Solution>

称取15g羟乙基纤维素钠溶于100mL纯化水中，加入1g氯化钙，并用醋酸调节溶液pH为4，搅拌溶解均匀。加入1mL的戊二醛溶液(25％浓度)，并控制反应温度为50℃，改性处理60min。得到黏附材料溶液。15 g of sodium hydroxyethylcellulose was weighed and dissolved in 100 mL of purified water, 1 g of calcium chloride was added, and the pH of the solution was adjusted to 4 with acetic acid, and the mixture was stirred and dissolved uniformly. 1 mL of glutaraldehyde solution (25% strength) was added, and the reaction temperature was controlled to 50 ° C, and the modification treatment was carried out for 60 minutes. A solution of the adherent material is obtained.

将纳米纤维膜放入容器中，然后将上述黏附材料溶液平铺在纳米纤维膜上，静置2h，待黏附材料溶液均匀地嵌入纳米纤维膜的孔隙中，并控制黏附材料溶液的厚度为0.5mm。The nanofiber membrane is placed in a container, and then the above-mentioned adhesive material solution is laid on the nanofiber membrane and allowed to stand for 2 hours. The solution of the adhesive material is uniformly embedded in the pores of the nanofiber membrane, and the thickness of the adhesive material solution is controlled to be 0.5. Mm.

将编织网片平铺在黏附材料溶液上，且所述黏附材料溶液从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层。然后放入冻干机中于-50℃的温度下预冻4h；在25℃下干燥24h，取出并延压成型，得到复合组织修复补片。所述复合组织修复补片在所述编织网片的与纳米纤维膜所在侧相反的面上具有防粘连层。Spreading the woven mesh sheet on the adhesive material solution, and the adhesive material solution overflows from the pores of the woven mesh sheet and forms an anti-adhesion solution layer on a surface of the woven mesh sheet opposite to the side where the nanofiber membrane is located . Then, it was pre-frozen in a lyophilizer at a temperature of -50 ° C for 4 h; dried at 25 ° C for 24 h, taken out and stretch-formed to obtain a composite tissue repair patch. The composite tissue repair patch has an anti-blocking layer on a side of the woven mesh opposite the side on which the nanofiber membrane is located.

实施例4Example 4

<纳米纤维膜的制备><Preparation of nanofiber membrane>

将聚乳酸(PLA)溶于六氟异丙醇溶液，其中，聚乳酸的浓度为7％(g/mL)，搅拌溶解得到均匀的聚合物溶液。将聚合物溶液置于静电纺丝注射器中，调节微量注射泵的速率为15mL/h，调节高压发生器的电压为12kV，调节接收装置的接收距离为20cm，进行静电纺丝，当膜层厚度达到0.3mm后关闭静电纺丝，得到纳米纤维膜。Polylactic acid (PLA) was dissolved in a hexafluoroisopropanol solution in which the concentration of polylactic acid was 7% (g/mL), and the mixture was stirred to obtain a uniform polymer solution. The polymer solution was placed in an electrospinning syringe, the rate of the micro syringe pump was adjusted to 15 mL/h, the voltage of the high voltage generator was adjusted to 12 kV, the receiving distance of the receiving device was adjusted to 20 cm, and electrospinning was performed, when the film thickness was After reaching 0.3 mm, the electrospinning was turned off to obtain a nanofiber membrane.

<黏附材料溶液的制备><Preparation of Adhesive Material Solution>

称取10g明胶溶于100mL纯化水中，加热到40℃，搅拌得到均匀的明胶溶液。然后加入1g碳化二亚胺/N-羟基琥珀酰亚胺，其中，碳化二亚胺与N-羟基琥珀酰亚胺的质量比为1:1，25℃下改性处理48h，得到黏附材料溶液。10 g of gelatin was weighed and dissolved in 100 mL of purified water, heated to 40 ° C, and stirred to obtain a uniform gelatin solution. Then, 1 g of carbodiimide/N-hydroxysuccinimide was added, wherein the mass ratio of carbodiimide to N-hydroxysuccinimide was 1:1, and the modification treatment was carried out at 25 ° C for 48 hours to obtain an adhesive material solution. .

将纳米纤维膜放入容器中，然后将黏附材料溶液均匀涂覆在纳米纤维膜上，静置时间24h，待黏附材料溶液均匀地嵌入纳米纤维膜的孔隙中，并控制黏附材料溶液的厚度为1mm。The nanofiber membrane is placed in a container, and then the adhesive material solution is uniformly coated on the nanofiber membrane for 24 hours, the solution of the adhesive material is uniformly embedded in the pores of the nanofiber membrane, and the thickness of the solution of the adhesive material is controlled to be 1mm.

将编织网片平铺在黏附材料溶液上，且所述黏附材料从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层。在自然条件下静置，待黏附材料溶液中的溶剂挥发干燥，得到复合组织修复补片。复合组织修复补片在所述编织网片的与纳米纤维膜所在侧相反的面上具有防粘连层。A woven mesh sheet is tiled onto the adhesive material solution, and the adhesive material overflows from the pores of the woven mesh sheet and forms an anti-blocking solution layer on a side of the woven mesh sheet opposite to the side on which the nanofiber membrane is located. After standing under natural conditions, the solvent in the solution to be adhered is evaporated and dried to obtain a composite tissue repair patch. The composite tissue repair patch has an anti-blocking layer on a side of the woven mesh opposite the side on which the nanofiber membrane is located.

实施例5Example 5

<纳米纤维膜的制备><Preparation of nanofiber membrane>

将聚乙交-丙交酯(PLGA)溶于六氟异丙醇溶液，其中，聚乙交-丙交酯的浓度为5％(g/mL)，搅拌溶解得到均匀的聚合物溶液。将聚合物溶液置于静电纺丝注射器中，调节微量注射泵的速率为10mL/h，调节高压发生器的电压为25kV，调节接收装置的接收距离为15cm，进行静电纺丝，当膜层厚度达到0.5mm后关闭静电纺丝，得到纳米纤维膜。Polyethylidene-lactide (PLGA) was dissolved in a hexafluoroisopropanol solution in which the concentration of poly-glycolide was 5% (g/mL), and the mixture was stirred to obtain a uniform polymer solution. The polymer solution was placed in an electrospinning syringe, the rate of the micro syringe pump was adjusted to 10 mL/h, the voltage of the high voltage generator was adjusted to 25 kV, the receiving distance of the receiving device was adjusted to 15 cm, and electrospinning was performed, when the film thickness was After reaching 0.5 mm, the electrospinning was turned off to obtain a nanofiber membrane.

<黏附材料溶液的制备><Preparation of Adhesive Material Solution>

称取20g胶原蛋白粉溶于100mL纯化水中，常温下溶解，搅拌得到均匀的胶原溶液。然后加入3g碳化二亚胺，40℃下改性处理72h，得到黏附材料溶液。20 g of collagen powder was weighed and dissolved in 100 mL of purified water, dissolved at room temperature, and stirred to obtain a uniform collagen solution. Then, 3 g of carbodiimide was added and the modification treatment was carried out at 40 ° C for 72 hours to obtain a solution of the adhesive material.

将纳米纤维膜放入容器中，然后将黏附材料溶液均匀涂覆在纳米纤维膜上，静置时间36h，待黏附材料溶液均匀地嵌入纳米纤维膜的孔隙中，并控制黏附材料溶液的厚度为2mm。The nanofiber membrane is placed in a container, and then the adhesive material solution is uniformly coated on the nanofiber membrane, and the standing time is 36 h, the solution of the adhesive material is uniformly embedded in the pores of the nanofiber membrane, and the thickness of the solution of the adhesive material is controlled to be 2mm.

将编织网片平铺在黏附材料溶液上。且所述黏附材料溶液从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层。在自然条件下静置，待黏附材料溶液中的溶剂挥发干燥，得到复合组织修复补片。所述复合组织修复补片在所述编织网片的与纳米纤维膜所在侧相反的面上具有防粘连层。The woven mesh is tiled onto the adherent material solution. And the adhesion material solution overflows from the pores of the woven mesh sheet and forms an anti-blocking solution layer on a side of the woven mesh sheet opposite to the side on which the nanofiber membrane is located. After standing under natural conditions, the solvent in the solution to be adhered is evaporated and dried to obtain a composite tissue repair patch. The composite tissue repair patch has an anti-blocking layer on a side of the woven mesh opposite the side on which the nanofiber membrane is located.

实施例6Example 6

<纳米纤维膜的制备><Preparation of nanofiber membrane>

将聚己内酯(PCL)溶于四氢呋喃溶液，其中，聚己内酯的浓度为15％(g/mL)，搅拌溶解得到均匀的聚合物溶液；将聚合物溶液装入静电纺丝注射器中，调节微量注射泵的速率为6mL/h，调节高压发生器的电压为20kV，调节接收装置的接收距离为10cm，进行静电纺丝，当膜层厚度达到0.7mm后关闭静电纺丝，得到纳米纤维膜。The polycaprolactone (PCL) is dissolved in a tetrahydrofuran solution, wherein the concentration of the polycaprolactone is 15% (g/mL), and the mixture is stirred to obtain a uniform polymer solution; the polymer solution is charged into the electrospinning syringe. The rate of adjusting the micro-injection pump is 6mL/h, the voltage of the high-voltage generator is adjusted to 20kV, the receiving distance of the receiving device is adjusted to 10cm, and the electrospinning is performed. When the thickness of the film reaches 0.7mm, the electrospinning is turned off to obtain the nanometer. Fiber membrane.

<黏附材料溶液的制备><Preparation of Adhesive Material Solution>

称取5g羧甲基壳聚糖溶于100mL的混合溶液中，其中，所述混合溶液由50mL的纯化水和50mL的丙三醇组成，搅拌溶解得到均匀的壳聚糖溶液。然后在25℃的温度下，改性处理12h，得到黏附材料溶液。5 g of carboxymethyl chitosan was weighed and dissolved in 100 mL of a mixed solution composed of 50 mL of purified water and 50 mL of glycerin, and stirred to dissolve to obtain a uniform chitosan solution. Then, at a temperature of 25 ° C, the modification treatment was carried out for 12 hours to obtain a solution of the adhesive material.

<组织修复补片的制备><Preparation of tissue repair patch>

将纳米纤维膜放入容器中，然后将编织网片平铺在纳米纤维膜上。The nanofiber membrane is placed in a container and the woven mesh is then laid flat on the nanofiber membrane.

将黏附材料溶液流延在编织网片上，静置时间24h，并控制黏附材料溶液的厚度在1.5mm。The adhesive material solution was cast on the woven mesh sheet, allowed to stand for 24 hours, and the thickness of the adhesive material solution was controlled to be 1.5 mm.

黏附材料溶液通过编织网片的网孔渗透到纳米纤维膜上。且所述黏附材料从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层。然后在自然条件下，待黏附材料溶液中的溶剂挥发干燥，得到复合组织修复补片。所述复合组织修复补片在所述编织网片的与纳米纤维膜所在侧相反的面上具有防粘连层。The adhesive material solution penetrates the nanofiber membrane through the mesh of the woven mesh. And the adhesive material overflows from the pores of the woven mesh sheet and forms an anti-blocking solution layer on a side of the woven mesh sheet opposite to the side on which the nanofiber membrane is located. Then, under natural conditions, the solvent in the solution to be adhered is evaporated and dried to obtain a composite tissue repair patch. The composite tissue repair patch has an anti-blocking layer on a side of the woven mesh opposite the side on which the nanofiber membrane is located.

实施例7Example 7

<纳米纤维膜的制备><Preparation of nanofiber membrane>

将透明质酸(HA)溶于水，其中，透明质酸的浓度为3％(g/mL)，搅拌得到均匀的聚合物溶液；将聚合物溶液装入静电纺丝注射器中，调节微量注射泵的速率为3mL/h，调节高压发生器的电压为35kV，调节接收装置的接收距离为10cm，进行静电纺丝，当膜层厚度达到0.2mm后关闭静电纺丝，得到纳米纤维膜。The hyaluronic acid (HA) is dissolved in water, wherein the concentration of hyaluronic acid is 3% (g/mL), and the mixture is stirred to obtain a uniform polymer solution; the polymer solution is charged into the electrospinning syringe to adjust the microinjection. The pump speed is 3 mL/h, the voltage of the high-voltage generator is adjusted to 35 kV, the receiving distance of the receiving device is adjusted to 10 cm, and electrospinning is performed. When the film thickness reaches 0.2 mm, the electrospinning is turned off to obtain a nanofiber membrane.

<黏附材料溶液的制备><Preparation of Adhesive Material Solution>

称取3g羟丙基壳聚糖溶于100mL的混合溶液中，其中，所述混合溶液由50mL的纯化水和50mL的丙三醇组成，搅拌溶解得到均匀的壳聚糖溶液。然后在30℃的温度下，改性处理24h，得到黏附材料溶液。3 g of hydroxypropyl chitosan was weighed and dissolved in 100 mL of a mixed solution composed of 50 mL of purified water and 50 mL of glycerin, and stirred to dissolve to obtain a uniform chitosan solution. Then, it was modified at a temperature of 30 ° C for 24 hours to obtain a solution of the adhering material.

将黏附材料溶液流延在编织网片上，静置时间36h，并控制黏附材料溶液的厚度在2.5mm。The adhesive material solution was cast on the woven mesh sheet, allowed to stand for 36 h, and the thickness of the adhesive material solution was controlled to be 2.5 mm.

黏附材料溶液通过编织网片的网孔渗透到纳米纤维膜上。且所述黏附材料从所述编织网片的孔隙中溢出在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层。然后在自然条件下，待黏附材料溶液中的溶剂挥发干燥，得到复合组织修复补片。所述复合组织修复补片在所述编织网片的与纳米纤维膜所在侧相反的面上具有防粘连层。The adhesive material solution penetrates the nanofiber membrane through the mesh of the woven mesh. And the adhesion material overflows from the pores of the woven mesh sheet to form an anti-blocking solution layer on a surface of the woven mesh sheet opposite to the side on which the nanofiber membrane is located. Then, under natural conditions, the solvent in the solution to be adhered is evaporated and dried to obtain a composite tissue repair patch. The composite tissue repair patch has an anti-blocking layer on a side of the woven mesh opposite the side on which the nanofiber membrane is located.

对实施例1-7制备得到的复合组织修复补片进行性能测试，如表1所示：The composite tissue repair patch prepared in Examples 1-7 was tested for performance, as shown in Table 1:

表1Table 1

疝气修复实验Helium repair experiment

将实施例2、4制备得到的复合组织修复补片进行疝气修复实验。The composite tissue repair patch prepared in Examples 2 and 4 was subjected to a helium gas repair experiment.

取新西兰实验兔，5个月，体重2.5kg。将新西兰实验兔随机分成3组，每组5只新西兰实验兔。对新西兰实验兔进行麻醉、备皮、仰卧固定于木板上；消毒铺单后，于腹部正中，用20#手术刀顺着新西兰实验兔腹白线切开皮肤，长约10cm，暴露出肌肉，将大小为2cm×3cm的腹壁全层(包括腹膜、肌肉、筋膜组织)切除。分别采用实施例2的复合组织修复补片和实施例4的复合组织修复补片和市售编织网片，并用0#丝线将补片与周围的肌肉间断缝合，4#丝线间断缝合皮肤。New Zealand experimental rabbits were taken for 5 months and weighed 2.5 kg. New Zealand experimental rabbits were randomly divided into 3 groups of 5 New Zealand experimental rabbits. The New Zealand experimental rabbits were anesthetized, prepared for skin and fixed on the wooden board. After disinfection, the skin was cut in the middle of the abdomen, and the skin was cut with a 20# scalpel along the white line of the New Zealand experimental rabbit. The length was about 10 cm and the muscles were exposed. The entire abdominal wall (including peritoneum, muscle, fascia tissue) having a size of 2 cm x 3 cm was excised. The composite tissue repair patch of Example 2 and the composite tissue repair patch of Example 4 and a commercially available woven mesh sheet were respectively used, and the patch was sutured intermittently with the surrounding muscles with a 0# silk thread, and the skin was intermittently sutured by a 4# silk thread.

如图3-5所示，纳米纤维膜朝向腹腔内侧，编织网片层朝向外侧，其中，图3为采用本公开实施例2制备得到的复合组织修复补片进行疝气修复手术修补后的照片；图4为采用本公开实施例4制备得到的复合组织修复补片进行疝气修复手术修补后的照片；图5为采用编织网片进行疝气修复手术修补后的照片。As shown in FIG. 3-5, the nanofiber membrane is oriented toward the inner side of the abdominal cavity, and the woven mesh layer is oriented toward the outer side. FIG. 3 is a photograph of the composite tissue repair patch prepared by the embodiment 2 of the present disclosure after repairing the hernia repair operation; 4 is a photograph of a composite tissue repair patch prepared in Example 4 of the present disclosure after repairing a hernia repair operation; and FIG. 5 is a photograph of a hernia repair performed by a woven mesh.

术后对新西兰实验兔进行常规的观察和喂养。术后2周时，将新西兰实验兔的修复部位解剖，观察新西兰实验兔伤口的组织修复情况。New Zealand experimental rabbits were routinely observed and fed after surgery. At 2 weeks postoperatively, the repaired parts of New Zealand experimental rabbits were dissected to observe the tissue repair of New Zealand experimental rabbit wounds.

图6为采用实施例2制备得到的复合组织修复补片进行疝气修复手术后两周的修复效果图；图7为采用实施例4制备得到的复合组织修复补片进行疝气修复手术后两周的修复效果图；图8为采用编织网片进行疝气修复手术后两周的修复效果图。FIG. 6 is a view showing the effect of repairing the composite tissue repair patch prepared in Example 2 for two weeks after the hernia repair operation; FIG. 7 is a two-week period after the hernia repair operation using the composite tissue repair patch prepared in Example 4. The repair effect picture; Figure 8 is the repair effect of the two weeks after the hernia repair operation using the woven mesh.

解剖结果显示，实施例2、4的复合组织修复补片上新生了大量的血管和组织，植入部位周围与血管和组织结合紧密；即：复合组织修复补片内部及周围可见大量的血管和毛细血管，表现出良好的组织修复效果。因此，植入实施例2、4的复合组织修复补片后，新生组织生长快速，并能够长入复合组织修复补片中，与复合组织修复补片融为一体，且无皱缩现象。而对照组的编织网片，新生组织及血管少，且新生组织没有长入编织网片中，并且有严重皱缩的情况。The anatomical results showed that a large number of new blood vessels and tissues were newly added to the composite tissue repair patch of Examples 2 and 4. The surrounding part of the implant site was tightly bound to the blood vessels and tissues; that is, a large number of blood vessels and capillaries were visible inside and around the composite tissue repair patch. Blood vessels, showing good tissue repair effects. Therefore, after the composite tissue repairing patches of Examples 2 and 4 are implanted, the new tissue grows rapidly, and can grow into the composite tissue repair patch, and integrates with the composite tissue repair patch, and has no shrinkage phenomenon. In the control group, the woven mesh, the new tissue and the blood vessels were few, and the new tissue did not grow into the woven mesh, and there was a serious shrinkage.

另外，从图6-7可以看出，实施例2、4的复合组织修复补片与组织器官接触面没有发生任何粘连现象。而从图8可以看出，对照组编织网片与组织器官出现了多处粘连。In addition, as can be seen from Figures 6-7, the composite tissue repair patch of Examples 2 and 4 did not have any adhesion to the tissue-organ contact surface. As can be seen from Fig. 8, the control woven mesh and the tissues and organs showed multiple adhesions.

因此，本公开的复合组织修复补片不仅具有促进组织修复再生的功能，且有效的起到了防止材料皱缩、防止脏器粘连等作用，是一种理想的复合组织修复补片。Therefore, the composite tissue repair patch of the present disclosure not only has the function of promoting tissue repair and regeneration, but also effectively prevents the material from shrinking and prevents the adhesion of organs, and is an ideal composite tissue repair patch.

本公开的上述实施例仅仅是为清楚地说明本公开所作的举例，而并非是对本公开的实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。凡在本公开的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本公开权利要求的保护范围之内。The above-described embodiments of the present disclosure are merely illustrative of the present disclosure, and are not intended to limit the embodiments of the present disclosure. Other variations or modifications of the various forms may be made by those skilled in the art in light of the above description. There is no need and no way to exhaust all of the implementations. Any modifications, equivalent substitutions and improvements made within the spirit and scope of the present disclosure are intended to be included within the scope of the appended claims.

Claims

一种复合组织修复补片，其特征在于，所述复合组织修复补片包括：A composite tissue repair patch, characterized in that the composite tissue repair patch comprises:

纳米纤维膜、编织网片和黏附材料，其中，所述黏附材料位于所述纳米纤维膜与所述编织网片之间；a nanofiber film, a woven mesh sheet, and an adhesive material, wherein the adhesive material is located between the nanofiber film and the woven mesh sheet;

所述黏附材料包括亲水性物质，所述纳米纤维膜和所述编织网片通过所述黏附材料相结合，且所述黏附材料嵌入到所述纳米纤维膜和所述编织网片的孔隙中；The adhesion material includes a hydrophilic substance, the nanofiber membrane and the woven mesh sheet are combined by the adhesion material, and the adhesion material is embedded in the pores of the nanofiber membrane and the woven mesh sheet ;

所述纳米纤维膜与所述编织网片之间的剥离强度为20～75cN/mm；所述复合组织修复补片的断裂强度为8～12.5Mpa；优选地，所述复合组织修复补片的断裂伸长量为20～250％；更优选地，所述复合组织修复补片的孔隙率为50～90％。The peeling strength between the nanofiber membrane and the woven mesh sheet is 20 to 75 cN/mm; the breaking strength of the composite tissue repair patch is 8 to 12.5 MPa; preferably, the composite tissue repairing patch The elongation at break is 20 to 250%; more preferably, the composite tissue repair patch has a porosity of 50 to 90%.
根据权利要求1所述的复合组织修复补片，其特征在于，所述复合组织修复补片还包括防粘连层，所述防粘连层黏附于所述编织网片的与所述纳米纤维膜所在侧相反的面上。The composite tissue repair patch according to claim 1, wherein said composite tissue repair patch further comprises an anti-adhesion layer, said anti-adhesion layer being adhered to said woven mesh sheet and said nanofiber membrane On the opposite side of the side.
根据权利要求1或2所述的复合组织修复补片，其特征在于，所述亲水性物质的重均分子量为50000～2000000Da。The composite tissue repair patch according to claim 1 or 2, wherein the hydrophilic substance has a weight average molecular weight of 50,000 to 2,000,000 Da.
根据权利要求1-3任一项所述的复合组织修复补片，其特征在于，所述亲水性物质包括：含氮类化合物及其衍生物、纤维素类化合物及其衍生物、醇类化合物及其衍生物、壳聚糖类化合物及其衍生物、糖类化合物及其衍生物中的一种或多种。The composite tissue repair patch according to any one of claims 1 to 3, wherein the hydrophilic substance comprises: a nitrogen-containing compound and a derivative thereof, a cellulose compound and a derivative thereof, and an alcohol One or more of a compound and a derivative thereof, a chitosan compound and a derivative thereof, a saccharide compound, and a derivative thereof.
根据权利要求4所述的复合组织修复补片，其特征在于，所述含氮类化合物包括蛋白质类化合物，优选包括胶原蛋白、明胶中的一种或两种；所述壳聚糖类化合物包括：羧甲基壳聚糖、羟丙基壳聚糖中的一种或两种；所述纤维素类化合物包括：羧甲基纤维素、羧甲基纤维素钠中的一种或两种。The composite tissue repair patch according to claim 4, wherein the nitrogen-containing compound comprises a proteinaceous compound, preferably one or both of collagen and gelatin; and the chitosan compound comprises One or two of carboxymethyl chitosan and hydroxypropyl chitosan; and the cellulose compound includes one or both of carboxymethylcellulose and sodium carboxymethylcellulose.
根据权利要求1-5任一项所述的复合组织修复补片，其特征在于，所述亲水性物质包括改性的亲水性物质，优选包括经过交联剂改性得到的亲水性物质。The composite tissue repair patch according to any one of claims 1 to 5, wherein the hydrophilic substance comprises a modified hydrophilic substance, preferably comprising a hydrophilicity modified by a crosslinking agent. substance.
根据权利要求1-6任一项所述的复合组织修复补片，其特征在于，所述纳米纤维膜与编织网片之间的距离为0.1～3mm；优选为0.2～2mm。The composite tissue repair patch according to any one of claims 1 to 6, wherein the distance between the nanofiber membrane and the woven mesh sheet is 0.1 to 3 mm; preferably 0.2 to 2 mm.
根据权利要求1-7任一项所述的复合组织修复补片，其特征在于，所述纳米纤维膜采用包括静电纺丝步骤的方法制得。The composite tissue repair patch according to any one of claims 1 to 7, wherein the nanofiber membrane is produced by a method comprising an electrospinning step.
根据权利要求1-8任一项所述的复合组织修复补片，其特征在于，所述纳米纤维膜由直径为10nm～100μm的纤维丝交织而成，优选地，所述纤维丝由可降解材料制成，更优选地，所述可降解材料包括聚乳酸、聚DL-乳酸、聚己内酯、聚羟基脂肪酸酯、聚乙交酯、聚已交-丙交酯；胶原蛋白、明胶、壳聚糖、透明质酸、纤维素中的一种或多种。The composite tissue repair patch according to any one of claims 1 to 8, wherein the nanofiber membrane is interwoven by filaments having a diameter of 10 nm to 100 μm, preferably, the filament is degradable Made of a material, more preferably, the degradable material comprises polylactic acid, poly-DL-lactic acid, polycaprolactone, polyhydroxyalkanoate, polyglycolide, poly-glycolide; collagen, gelatin One or more of chitosan, hyaluronic acid, and cellulose.
根据权利要求1-9任一项所述的复合组织修复补片，其特征在于，所述纳米纤维膜中加载有药物，所述药物优选包括生长因子；更优选包括表皮生长因子、成纤维细胞生长因子中的一种或两种。The composite tissue repair patch according to any one of claims 1 to 9, wherein the nanofiber membrane is loaded with a drug, and the drug preferably comprises a growth factor; more preferably, an epidermal growth factor, a fibroblast One or two of the growth factors.
根据权利要求1-10任一项所述的复合组织修复补片，其特征在于，所述编织网片由不可降解材料制成，优选地，所述不可降解材料包括聚丙烯、聚偏二氟乙烯、聚对苯二四酸乙二醇酯、膨化聚四氟乙烯中的一种或多种。The composite tissue repair patch according to any one of claims 1 to 10, wherein the woven mesh sheet is made of a non-degradable material, preferably, the non-degradable material comprises polypropylene, polyvinylidene fluoride. One or more of ethylene, polyethylene terephthalate, and expanded polytetrafluoroethylene.
一种根据权利要求1-11任一项所述的复合组织修复补片的制备方法，其特征在于，包括：A method of preparing a composite tissue repair patch according to any one of claims 1-11, characterized in that it comprises:

复合步骤：制备黏附材料溶液，将所述纳米纤维膜和所述编织网片用所述黏附材料溶液复合得到所述复合组织修复补片；a composite step: preparing an adhesive material solution, and compounding the nanofiber membrane and the woven mesh sheet with the adhesive material solution to obtain the composite tissue repair patch;

优选地，利用所述黏附材料溶液，通过冷冻干燥工艺、涂覆工艺或流延工艺将所述纳米纤维膜与所述编织网片复合。Preferably, the nanofiber membrane is compounded with the woven mesh sheet by a freeze drying process, a coating process or a casting process using the adhesion material solution.
根据权利要求12所述的方法，其特征在于，调整所述黏附材料的分子量和/或所述黏附材料溶液的浓度，使得所述黏附材料溶液从所述编织网片的孔隙中溢出并在所述编织网片的与纳米纤维膜所在侧相反的面上形成防粘连溶液层。The method according to claim 12, wherein the molecular weight of the adhesion material and/or the concentration of the solution of the adhesion material is adjusted such that the solution of the adhesion material overflows from the pores of the woven mesh sheet and is An anti-blocking solution layer is formed on the surface of the woven mesh sheet opposite to the side on which the nanofiber film is located.
根据权利要求12或13所述的方法，其特征在于，所述冷冻干燥工艺包括以下步骤：A method according to claim 12 or claim 13 wherein the freeze drying process comprises the steps of:

将所述亲水性物质溶解，得到黏附材料溶液；Dissolving the hydrophilic substance to obtain a solution of an adhesive material;

将所述黏附材料溶液平铺于所述纳米纤维膜上，并静置；Laminating the adhesion material solution on the nanofiber membrane and standing still;

将所述编织网片平铺于所述黏附材料溶液上，通过冷冻干燥得到所述复合组织修复补片。The woven mesh sheet is laid flat on the adhesive material solution, and the composite tissue repair patch is obtained by freeze drying.
根据权利要求14所述的方法，其特征在于，所述黏附材料溶液的厚度为0.1～3mm，优选0.2～2mm；所述静置的时间为1～24h，优选3～6h；所述黏附材料溶液中，所述黏附材料的质量浓度为0.1～20％，优选为5～15％；优选地，所述冷冻干燥工艺的预冻温度为-80～-10℃，优选为-80～-50℃；干燥温度为-20～30℃，优选为-10～25℃。The method according to claim 14, wherein the thickness of the solution of the adhesive material is 0.1 to 3 mm, preferably 0.2 to 2 mm; the time of the standing is 1 to 24 hours, preferably 3 to 6 hours; the adhesion material In the solution, the mass concentration of the adhesive material is 0.1 to 20%, preferably 5 to 15%; preferably, the freeze-drying process has a pre-freezing temperature of -80 to -10 ° C, preferably -80 to -50 ° C; drying temperature is -20 to 30 ° C, preferably -10 to 25 ° C.
根据权利要求14或15所述的方法，其特征在于，所述亲水性物质包括纤维素类化合物和/或其衍生物，优选包括羟乙基纤维素、羧甲基纤维素、羟丙基甲基纤维素的一种或几种；优选地，所述亲水性物质包括经改性处理的纤维素类化合物和/或其衍生物，优选包括经改性处理的羟乙基纤维素、羧甲基纤维素、羟丙基甲基纤维素的一种或几种。The method according to claim 14 or 15, wherein the hydrophilic substance comprises a cellulose compound and/or a derivative thereof, preferably comprising hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl group. One or more of methyl cellulose; preferably, the hydrophilic substance comprises a modified cellulose compound and/or a derivative thereof, preferably comprising modified hydroxyethyl cellulose, One or more of carboxymethyl cellulose and hydroxypropyl methyl cellulose.
根据权利要求16所述的方法，其特征在于，所述改性处理包括：采用交联剂进行交联反应的步骤；优选地，所述交联剂包括醛类化合物，优选包括甲醛、乙醛、戊二醛中的一种或多种，更优选包括戊二醛。The method according to claim 16, wherein said modifying treatment comprises the step of performing a crosslinking reaction using a crosslinking agent; preferably, said crosslinking agent comprises an aldehyde compound, preferably comprising formaldehyde, acetaldehyde One or more of glutaraldehyde, more preferably glutaraldehyde.
根据权利要求17所述的方法，其特征在于，所述改性处理还包括：在盐溶液中进行交联反应；优选地，所述盐包括中性盐，更优选地，所述中性盐包括水溶性铝盐、钠盐、钙盐和铁盐中的一种或多种。The method according to claim 17, wherein said modifying treatment further comprises: performing a crosslinking reaction in a salt solution; preferably, said salt comprises a neutral salt, more preferably said neutral salt It includes one or more of a water-soluble aluminum salt, a sodium salt, a calcium salt, and an iron salt.
根据权利要求16-18任一项所述的方法，其特征在于，所述改性处理是在溶液中进行的，优选地，所述溶液的pH值呈酸性。A method according to any one of claims 16 to 18, wherein the modifying treatment is carried out in a solution, preferably the pH of the solution is acidic.
根据权利要求16-19任一项所述的方法，其特征在于，所述改性处理的温度为50～130℃，优选为60～80℃；所述改性处理的时间为20～240min，优选40～80min；所述黏附材料溶液中，所述亲水性物质的质量浓度的0.1～20％，优选5～15％。The method according to any one of claims 16 to 19, wherein the temperature of the modification treatment is 50 to 130 ° C, preferably 60 to 80 ° C; and the modification treatment time is 20 to 240 min. Preferably, it is 40 to 80 minutes; and the mass concentration of the hydrophilic substance in the adhesive material solution is 0.1 to 20%, preferably 5 to 15%.
根据权利要求12或13所述的方法，其特征在于，所述涂覆工艺包括以下步骤：A method according to claim 12 or claim 13 wherein the coating process comprises the steps of:

将所述亲水性物质溶解，得到黏附材料溶液；Dissolving the hydrophilic substance to obtain a solution of an adhesive material;

将所述黏附材料溶液涂覆在所述纳米纤维膜上，并静置；Coating the adhesion material solution on the nanofiber membrane and standing;

将所述编织网片平铺于所述黏附材料溶液上挥发干燥，得到所述复合组织修复补片。The woven mesh sheet is tiled on the adhesive material solution and evaporated to dryness to obtain the composite tissue repair patch.
根据权利要求21所述的方法，其特征在于，所述黏附材料溶液的厚度为0.1～3mm，优选1～2mm；所述静置的时间为1～72h，优选为24～48h；所述黏附材料溶液中，所述黏附材料的质量浓度为1～50％，优选为10～20％。The method according to claim 21, wherein the thickness of the solution of the adhesive material is 0.1 to 3 mm, preferably 1 to 2 mm; the time of the standing is 1 to 72 hours, preferably 24 to 48 hours; In the material solution, the mass concentration of the adhesion material is from 1 to 50%, preferably from 10 to 20%.
根据权利要求21或22所述的方法，其特征在于，所述亲水性物质包括蛋白质类化合物和/或其衍生物，优选包括胶原蛋白、明胶中的一种或两种；The method according to claim 21 or 22, wherein the hydrophilic substance comprises a proteinaceous compound and/or a derivative thereof, preferably one or both of collagen and gelatin;

优选地，所述亲水性物质包括经改性处理的蛋白质类化合物，优选包括经改性处理的胶原蛋白、明胶中的一种或两种。Preferably, the hydrophilic substance comprises a modified protein compound, preferably one or both of modified modified collagen and gelatin.
根据权利要求23所述的方法，其特征在于，所述改性处理包括：采用交联剂进行交联反应的步骤；优选地，所述交联剂包括碳化二亚胺/N-羟基琥珀酰亚胺、京尼平、醛类化合物中的一种或多种，优选包括碳化二亚胺、碳化二亚胺/N-羟基琥珀酰亚胺的一种或两种，更优选包括碳化二亚胺/N-羟基琥珀酰亚胺。The method according to claim 23, wherein said modifying treatment comprises the step of performing a crosslinking reaction using a crosslinking agent; preferably, said crosslinking agent comprises carbodiimide / N-hydroxysuccinyl One or more of the imine, genipin, and an aldehyde compound, preferably including one or both of carbodiimide, carbodiimide/N-hydroxysuccinimide, more preferably including carbonized secondary Amine/N-hydroxysuccinimide.
根据权利要求23或24所述的方法，其特征在于，所述改性处理的温度为10～70℃，优选25～50℃；所述改性处理的时间为1～72h，优选12～72h；所述黏附材料溶液中，所述亲水性物质的质量为1～50％，优选为10～20％。The method according to claim 23 or 24, wherein the temperature of the modification treatment is 10 to 70 ° C, preferably 25 to 50 ° C; and the modification treatment time is 1 to 72 h, preferably 12 to 72 h. In the solution of the adhesive material, the hydrophilic substance has a mass of 1 to 50%, preferably 10 to 20%.
根据权利要求12或13所述的方法，其特征在于，所述流延工艺包括以下步骤：The method according to claim 12 or 13, wherein the casting process comprises the following steps:

将所述亲水性物质溶解，得到黏附材料溶液；Dissolving the hydrophilic substance to obtain a solution of an adhesive material;

将所述编织网片平铺于所述纳米纤维膜上；Spreading the woven mesh sheet on the nanofiber membrane;

将所述黏附材料溶液流延在所述编织网片上并静置，挥发干燥得到所述复合组织修复补片。The adhesive material solution is cast on the woven mesh sheet and allowed to stand, and evaporated to obtain the composite tissue repair patch.
根据权利要求26所述的方法，其特征在于，所述黏附材料溶液的厚度为0.1～3mm，优选1～2mm；所述静置的处理时间为1～72h，优选24～48h；所述黏附材料溶液中，所述黏附材料的质量浓度为0.1～20％，优选5～15％。The method according to claim 26, wherein the thickness of the solution of the adhesive material is 0.1 to 3 mm, preferably 1 to 2 mm; and the treatment time for the standing is 1 to 72 hours, preferably 24 to 48 hours; In the material solution, the mass concentration of the adhesion material is from 0.1 to 20%, preferably from 5 to 15%.
根据权利要求26或27所述的方法，其特征在于，所述亲水性物质包括壳聚糖类化合物和/或其衍生物，优选包括羧甲基壳聚糖、羟丙基壳聚糖中的一种或两种；The method according to claim 26 or 27, wherein the hydrophilic substance comprises a chitosan compound and/or a derivative thereof, preferably comprising carboxymethyl chitosan or hydroxypropyl chitosan. One or two;

优选地，所述亲水性物质包括改性处理的壳聚糖类化合物，优选包括经改性处理的羧甲基壳聚糖、羟丙基壳聚糖中的一种或两种。Preferably, the hydrophilic substance comprises a modified chitosan compound, preferably one or both of modified modified carboxymethyl chitosan, hydroxypropyl chitosan.
根据权利要求28所述的方法，其特征在于，所述改性处理包括：采用交联剂进行交联反应的步骤；优选地，所述交联剂包括丙三醇和水；优选地，所述丙三醇和水的体积比为0.1～5:1，优选为0.5～2:1。The method according to claim 28, wherein said modifying treatment comprises the step of performing a crosslinking reaction using a crosslinking agent; preferably, said crosslinking agent comprises glycerin and water; preferably, said The volume ratio of glycerol to water is from 0.1 to 5:1, preferably from 0.5 to 2:1.
根据权利要求28或29所述的方法，其特征在于，所述改性处理的温度为10～50℃，优选20～30℃；所述改性处理的时间为1～48h，优选12～24h；所述黏附材料溶液中，所述亲水性物质的质量浓度为0.1～20％，优选5～15％。The method according to claim 28 or 29, wherein the temperature of the modification treatment is 10 to 50 ° C, preferably 20 to 30 ° C; and the modification treatment time is 1 to 48 h, preferably 12 to 24 h. In the solution of the adhesive material, the hydrophilic substance has a mass concentration of 0.1 to 20%, preferably 5 to 15%.
一种根据权利要求1-11任一项所述的复合组织修复补片在制备疝气修复补片、盆底修复补片、尿失禁悬吊带、肩袖修复补片、***补片、创面修复补片、瘘修复补片中的应用。A composite tissue repair patch according to any one of claims 1-11, in which a hernia repair patch, a pelvic floor repair patch, a urinary incontinence suspension strap, a rotator cuff repair patch, a breast patch, and a wound repair patch are prepared. The application in the patch and 瘘 repair patch.