技术领域technical field
本发明属于生物基材料技术领域，尤其涉及一种3D打印人工生物可降解硬脑膜及其制备方法。The invention belongs to the technical field of bio-based materials, and in particular relates to a 3D printing artificial biodegradable dura mater and a preparation method thereof.
背景技术Background technique
硬脑膜是介于颅骨和脑组织之间的一种厚而坚韧的双层膜性组织，它在保护脑组织、防止脑脊液漏、颅内感染、脑膨出、癫痫等并发症具有重要的作用，是保护脑组织的一道重要屏障。硬脑膜在外伤、肿瘤侵蚀或是颅内手术的过程中都极有可能受到损伤，这时就需要应用硬脑膜缺损的修复材料来进行修补，以确保硬脑膜解剖结构的完整性。据研究资料表明10%～30%的脑部手术需要行硬膜修补术处理。The dura mater is a thick and tough double-layered membranous tissue between the skull and brain tissue. It plays an important role in protecting brain tissue, preventing cerebrospinal fluid leakage, intracranial infection, encephalocele, epilepsy and other complications. , is an important barrier to protect brain tissue. The dura mater is very likely to be damaged during trauma, tumor erosion or intracranial surgery. At this time, it is necessary to use repair materials for dura mater defects to repair to ensure the integrity of the dura anatomy. According to research data, 10% to 30% of brain surgeries require dural repair.
胶原是动物结缔组织和细胞间质的纤维蛋白成分。它利用牛跟腱I型胶原纤维进行特殊理化生物改性制备而成。它组织结构稳定、相容性好，可被机体完全降解，免疫反应轻微，无毒性反应，能有效预防术后组织粘连、感染及脑脊液漏。细菌纤维素（BC）膜由葡萄糖分子以β-l，4糖苷键聚合而成的，具有多孔性结构及相当纳米级孔径分布的天然纤维网状高分子材料。纤维素膜内表面形成了只有1～2层成纤维细胞的被膜，外表面也被结缔组织膜包裹，但比内层厚。这样形成的内膜不易与脑组织黏连，局部也没有炎症细胞浸润，不存在排斥反应。Collagen is a fibrin component of animal connective tissue and interstitial cells. It is prepared by using bovine Achilles tendon type I collagen fibers through special physical and chemical biological modification. It has stable tissue structure, good compatibility, can be completely degraded by the body, mild immune response, no toxic reaction, and can effectively prevent postoperative tissue adhesion, infection and cerebrospinal fluid leakage. Bacterial cellulose (BC) membrane is a natural fibrous network polymer material with porous structure and fairly nano-scale pore size distribution, which is formed by the polymerization of glucose molecules with β-l, 4 glycosidic bonds. The inner surface of the cellulose membrane forms a capsule with only 1-2 layers of fibroblasts, and the outer surface is also wrapped by a connective tissue membrane, but it is thicker than the inner layer. The intima formed in this way is not easy to adhere to the brain tissue, there is no local infiltration of inflammatory cells, and there is no rejection reaction.
3D打印技术应用于骨组织支架可以个性打印形状，精准吻合缺损；可以通过特定的程序设定打印出有利于细胞增值的孔隙，增强支架的骨诱导性、骨传导性、骨再生。美国维克森林大学成功打印出了人体肾脏、耳、鼻等器官。并且应用3D打印技术制备的个性化纯钛根性和根形带螺纹种植体应力分布更为均匀，对初期稳定性更为有利。然而目前3D打印在人工硬脑膜方面的应用还比较空白。The application of 3D printing technology to bone tissue scaffolds can print individual shapes and accurately fit defects; pores that are conducive to cell proliferation can be printed through specific program settings to enhance the scaffold’s osteoinductivity, osteoconductivity, and bone regeneration. Wake Forest University in the United States has successfully printed organs such as human kidneys, ears, and nose. And the personalized pure titanium root and root-shaped threaded implants prepared by 3D printing technology have more uniform stress distribution, which is more beneficial to the initial stability. However, the application of 3D printing in artificial dura mater is still relatively blank.
因此，本发明提出一种三层复合结构硬脑膜修复材料，以人工合成降解材料作为基材，细菌纤维素/.聚乳酸复合膜作为增强层，胶原蛋白海绵膜层作为生物膜，利用3D打印技术制备的人工硬脑膜内部结构和人体脑膜高度相似，可直接贴合在患者的脑膜破损处，实现伤口缝合的效果。与传统方法相比，更利于硬脑膜细胞的生长，降低了与颅盖骨的粘连概率，为硬脑膜修复，防止癫痫的发生提供了有力保障。Therefore, the present invention proposes a three-layer composite structure dura mater repair material, which uses synthetic degradable material as the base material, bacterial cellulose/polylactic acid composite membrane as the reinforcing layer, and the collagen sponge membrane layer as the biological membrane. The internal structure of the artificial dura mater prepared by technology is highly similar to the human meninges, and can be directly attached to the damaged meninges of patients to achieve the effect of wound suturing. Compared with the traditional method, it is more conducive to the growth of dural cells, reduces the adhesion probability to the calvaria, and provides a strong guarantee for the repair of the dura mater and the prevention of epilepsy.
发明内容SUMMARY OF THE INVENTION
本发明针对现有硬脑膜修复材料存在的问题和不足提供一种三层复合结构硬脑膜修复材料的制备方法，该方法制备的复合型硬脑膜具有良好的力学性能、生物相容性和生物可降解性，膜内部结构和人体脑膜高度相似，能够承受较高的颅内高压而防止脑脊液渗漏，降低了与颅盖骨的粘连概率，为硬脑膜修复，防止癫痫的发生提供了有力保障。Aiming at the problems and deficiencies of existing dura mater repair materials, the present invention provides a method for preparing a three-layer composite structure dura mater repair material. The composite dura mater prepared by the method has good mechanical properties, biocompatibility and biocompatibility. Degradability, the internal structure of the membrane is highly similar to the human meninges, and it can withstand high intracranial high pressure to prevent cerebrospinal fluid leakage, reduce the probability of adhesion to the calvaria, and provide a strong guarantee for the repair of the dura and the prevention of epilepsy.
本发明专利的技术方案是：以人工合成降解材料作为基材，BC/PLA复合膜作为增强层，胶原蛋白海绵膜层作为生物膜，再利用3D打印技术打印出适合患者的人工硬脑膜基体，最后将BC/PLA复合膜和胶原蛋白海绵膜层依次覆盖到基体表面，具体方法如下：The technical scheme of the patent of the present invention is: using synthetic degradable material as the base material, BC/PLA composite membrane as the reinforcing layer, and collagen sponge membrane layer as the biological membrane, and then using 3D printing technology to print the artificial dura mater matrix suitable for patients, Finally, the BC/PLA composite membrane and the collagen sponge membrane layer are sequentially covered on the surface of the substrate. The specific methods are as follows:
（1）基材的制备：称取人工合成降解材料、过氧化二苯甲酰、丙酮加入反应釜中，充入氮气进行保护，升温至40~60℃，压力0.4~0.6Mpa，反应2.5~3.5小时，反应完毕，离心分离产品，得到基材共聚物。根据患者的CT数据打印出硬脑膜基体。(1) Preparation of base material: Weigh artificially synthesized degradable material, dibenzoyl peroxide and acetone into the reaction kettle, fill with nitrogen for protection, heat up to 40~60℃, pressure 0.4~0.6Mpa, and react for 2.5~ After 3.5 hours, the reaction was completed, and the product was centrifuged to obtain the substrate copolymer. The dura mater is printed from the patient's CT data.
其中人工合成降解材料为TecoflexEG-85树酯、聚己内酯纳米纤维、壳聚糖、聚乳酸、聚丁二酸乙二醇酯、聚羟基丁酸酯的一种或几种。The synthetic degradable material is one or more of TecoflexEG-85 resin, polycaprolactone nanofiber, chitosan, polylactic acid, polyethylene succinate, and polyhydroxybutyrate.
（2）细菌纤维素/.聚乳酸复合膜制备：(2) Preparation of bacterial cellulose/polylactic acid composite membrane:
a）将聚乳酸（PLA）溶解于复合溶剂中，得到质量分数为5~15%的PLA溶液。利用静电纺丝仪在20kV，45℃下纺膜，PLA溶液用量5.0mL，纺膜速率0.15~0.3mm/s，制得直径为0.5~1mm的PLA膜。a) Dissolve polylactic acid (PLA) in a composite solvent to obtain a PLA solution with a mass fraction of 5-15%. The electrospinning machine was used to spin films at 20kV and 45°C, the amount of PLA solution was 5.0mL, and the spinning rate was 0.15~0.3mm/s to obtain PLA films with diameters of 0.5~1mm.
b）将保存于4℃条件下的木醋杆菌接种于平板培养基，26℃下恒温好氧培养48h，使菌种完全活化。将活化后的菌落转移到到种子培养液，26℃下恒温好氧静置培养7d。在250mL三角瓶中装入30mL发酵培养基，加入0.30g无菌PLA膜，按体积分数20%接种量接入种子液，30℃、160r/min振荡培养30~36h，收集发酵液中湿膜，刀片剥离外层细菌纤维素层，取BC/PLA复合层，用去离子水反复冲洗至pH为7.0，–50℃下冷冻干燥得BC/PLA复合膜。b) Inoculate the Acetobacter xylinum stored at 4°C on the plate medium, and incubate at 26°C for 48 hours under constant temperature and aerobic conditions to fully activate the strain. The activated colonies were transferred to the seed culture solution and cultured at 26°C for 7 days under constant temperature and aerobic culture. Put 30mL fermentation medium in a 250mL conical flask, add 0.30g sterile PLA film, insert the seed solution according to the volume fraction of 20% of the inoculum, 30 ℃, 160r/min shaking culture for 30~36h, collect the wet film in the fermentation liquid , peel off the outer bacterial cellulose layer with a blade, take the BC/PLA composite layer, rinse it with deionized water repeatedly to pH 7.0, and freeze-dry it at –50 °C to obtain the BC/PLA composite film.
其中平板培养基的成分为葡萄糖、蛋白胨、酵母粉、磷酸氢二钠、柠檬酸和琼脂按质量分数为（20：5：5：2.7：1.15：20）的混合物。The composition of the plate medium is a mixture of glucose, peptone, yeast powder, disodium hydrogen phosphate, citric acid and agar in a mass fraction (20:5:5:2.7:1.15:20).
其中种子培养基的成分为葡萄糖、蛋白胨、酵母粉、磷酸氢二钠和柠檬酸按质量分数为（20：5：5：2.7：1.15）的混合物。The components of the seed medium are a mixture of glucose, peptone, yeast powder, disodium hydrogen phosphate and citric acid in a mass fraction (20:5:5:2.7:1.15).
其中复合溶剂为氯仿和乙醇按17∶5的体积分数混合溶液。The composite solvent is a mixed solution of chloroform and ethanol in a volume fraction of 17:5.
（3）胶原蛋白海绵膜层的制备：将胶原蛋白、BMP生长因子和复合粒子按质量分数为（20~23.5：3.2~5.3：7.5~10.3）分散于去离子水中，45℃水浴缓慢搅拌至体系均匀得胶原蛋白凝胶液，继续水浴1h。加入一定甘油，磁力搅拌转速为100r/min，搅拌均匀，浇注进培养皿。置于冷冻干燥机中，在−80℃预冻24h，设置温度曲线为-80℃，2h后抽真空，以5℃/h的速率增至35℃，恒温15h，得胶原蛋白海绵。(3) Preparation of collagen sponge membrane layer: Disperse collagen, BMP growth factor and composite particles in deionized water according to the mass fraction (20~23.5:3.2~5.3:7.5~10.3), and stir slowly in a 45°C water bath until The collagen gel solution was obtained uniformly in the system, and the water bath was continued for 1 h. A certain amount of glycerol was added, the magnetic stirring speed was 100 r/min, the stirring was uniform, and it was poured into a petri dish. Placed in a freeze dryer, pre-frozen at −80 °C for 24 h, set the temperature curve to -80 °C, vacuumed after 2 h, increased to 35 °C at a rate of 5 °C/h, and held at a constant temperature for 15 h to obtain collagen sponge.
其中复合粒子为药物和纳米银粒子的混合物。The composite particles are a mixture of drugs and nano-silver particles.
（4）人工合成硬脑膜：(4) Synthetic dura mater:
a）采用涂膜器将上述制备好的BC/PLA复合膜覆于打印好的基材上，待溶液挥发1~3h后，进行下一次涂覆，如此重复6~10次；将得到的双层硬脑膜材料加入不锈钢转鼓中，加入2~4份常温水，水洗10~30min，弃去废液，如此重复水洗3~6次；加入2~4份常温水，水洗30~60min，弃去废液，如此重复水洗2~5次；加入2~4份常温水，水洗60~90min，弃去废液，如此重复水洗2~5次；将水洗后的双层硬脑膜材料置于20~40℃真空干燥箱中干燥4~8h；a) Use a film applicator to coat the prepared BC/PLA composite film on the printed substrate. After the solution volatilizes for 1 to 3 hours, perform the next coating, and repeat this for 6 to 10 times; The layer of dura mater material is added to the stainless steel drum, add 2~4 parts of room temperature water, wash with water for 10~30min, discard the waste liquid, repeat the washing for 3~6 times; add 2~4 parts of room temperature water, wash with water for 30~60min, discard To remove the waste liquid, repeat the washing 2~5 times; add 2~4 parts of normal temperature water, wash with water for 60~90min, discard the waste liquid, repeat the washing 2~5 times; put the double-layer dura mater material after washing in 20 Dry in a vacuum drying oven at ~40℃ for 4~8h;
b）再将胶原蛋白海绵按上述步骤涂覆在双层硬脑膜材料，得到半成品可降解复合层硬脑膜半成品。b) The collagen sponge is then coated on the double-layer dura mater material according to the above steps to obtain the semi-finished degradable composite layer dura mater semi-finished product.
c）将采用Co60所产生的γ射线或环氧乙烷进行消毒灭菌，成型包装，即制得可降解复合层硬脑膜成品。c) Sterilize and sterilize the γ-ray or ethylene oxide produced by Co60, and form and package to obtain the finished product of the degradable composite dura mater.
与现有的硬脑膜材料相比，具备以下优点：Compared with existing dura mater materials, it has the following advantages:
（1）采用生物相容性和生物可降解的高分子聚合物制备引导膜，组织反应小，不会引起机体免疫反应和验证反应；(1) Using biocompatible and biodegradable macromolecular polymers to prepare the guiding membrane, the tissue reaction is small, and it will not cause the immune response and verification reaction of the body;
（2）无机成分和BMP生长因子的加入增加的引导膜的成骨生物活性，促进成骨细胞的生长；(2) The addition of inorganic components and BMP growth factors increases the osteogenic biological activity of the guiding membrane and promotes the growth of osteoblasts;
（3）本发明制备的复合硬脑膜具有良好的生物活性，抗菌性，较好的力学强度，降解速率可调，促进伤口愈合等优点，在体内降解或被机体完全吸收的时间为4~12个月。(3) The composite dura mater prepared by the present invention has the advantages of good biological activity, antibacterial property, good mechanical strength, adjustable degradation rate, and promotion of wound healing. months.
具体实施方式Detailed ways
以下结合实施例对本发明做进一步详细说明。所用试剂或者仪器设备未注明生产厂商的，均视为可以通过市场购买的常规产品。The present invention will be described in further detail below in conjunction with the embodiments. If the reagents or equipment used are not marked with the manufacturer, they are regarded as conventional products that can be purchased through the market.
实施例1Example 1
第一步：制备基体Step 1: Preparing the Matrix
称取聚羟基丁酸酯、聚己内酯纳米纤维、过氧化二苯甲酰、丙酮加入反应釜中，充入氮气进行保护，升温至40℃，压力0.4Mpa，反应2.5小时，反应完毕，离心分离产品，得到基材共聚物。根据患者的CT数据打印出硬脑膜基体。Weigh polyhydroxybutyrate, polycaprolactone nanofiber, dibenzoyl peroxide and acetone into the reaction kettle, fill with nitrogen for protection, heat up to 40°C, pressure 0.4Mpa, react for 2.5 hours, and the reaction is completed, The product is centrifuged to obtain the substrate copolymer. The dura mater is printed from the patient's CT data.
第二步：制备细菌纤维素/.聚乳酸复合膜Step 2: Preparation of bacterial cellulose/polylactic acid composite membrane
1）将聚乳酸（PLA）溶解于复合溶剂[V（氯仿）：V（乙醇）=17∶5]中，得到质量分数为15%的PLA溶液。利用静电纺丝仪在20kV，45℃下纺膜，PLA溶液用量5.0mL，纺膜速率0.15mm/s，制得直径为0.5mm的PLA膜；1) Dissolve polylactic acid (PLA) in a composite solvent [V (chloroform):V (ethanol)=17:5] to obtain a PLA solution with a mass fraction of 15%. A PLA film with a diameter of 0.5 mm was prepared by using an electrospinning machine at 20 kV and 45 °C to spin the film, the amount of PLA solution was 5.0 mL, and the spinning speed was 0.15 mm/s;
2）将保存于4℃条件下的木醋杆菌接种于平板培养基，26℃下恒温好氧培养48h，使菌种完全活化。将活化后的菌落转移到到种子培养液，26℃下恒温好氧静置培养7d。在250mL三角瓶中装入30mL发酵培养基，加入0.30g无菌PLA膜，按体积分数20%接种量接入种子液，30℃、160r/min振荡培养36h，收集发酵液中湿膜，刀片剥离外层细菌纤维素层，取BC/PLA复合层，用去离子水反复冲洗至pH为7.0，–50℃下冷冻干燥得BC/PLA复合膜。2) Inoculate the Acetobacter xylinum stored at 4°C on the plate medium, and incubate it under constant temperature and aerobic conditions at 26°C for 48 hours to fully activate the strain. The activated colonies were transferred to the seed culture solution and cultured at 26°C for 7 days under constant temperature and aerobic culture. Put 30mL fermentation medium in a 250mL conical flask, add 0.30g sterile PLA film, insert the seed solution according to the volume fraction of 20% inoculum, 30 ℃, 160r/min shaking culture for 36h, collect the wet film in the fermentation solution, insert the blade The outer bacterial cellulose layer was peeled off, and the BC/PLA composite layer was taken, washed repeatedly with deionized water to pH 7.0, and freeze-dried at –50 °C to obtain the BC/PLA composite membrane.
第三步：制备胶原蛋白海绵膜层：Step 3: Preparation of collagen sponge membrane layer:
将胶原蛋白、BMP生长因子和药物与纳米银粒子的混合粒子按质量分数为（23.5： 5.3：10.3）分散于去离子水中，45℃水浴缓慢搅拌至体系均匀得胶原蛋白凝胶液，继续水浴1h。加入一定甘油，磁力搅拌转速为100r/min，搅拌均匀，浇注进培养皿。置于冷冻干燥机中，在−80℃预冻24h，设置温度曲线为-80℃，2h后抽真空，以5℃/h的速率增至35℃，恒温15h，得胶原蛋白海绵。Disperse the mixture of collagen, BMP growth factor, drug and nano-silver particles in deionized water according to the mass fraction (23.5: 5.3: 10.3), stir slowly in a water bath at 45 °C until the system is uniform to obtain a collagen gel solution, and continue the water bath. 1h. A certain amount of glycerol was added, the magnetic stirring speed was 100 r/min, the stirring was uniform, and it was poured into a petri dish. Placed in a freeze dryer, pre-frozen at −80 °C for 24 h, set the temperature curve to -80 °C, vacuumed after 2 h, increased to 35 °C at a rate of 5 °C/h, and held at a constant temperature for 15 h to obtain collagen sponge.
第四步：人工合成硬脑膜Step 4: Synthetic dura mater
1）采用涂膜器将上述制备好的BC/PLA复合膜覆于打印好的基材上，待溶液挥发1h后，进行下一次涂覆，如此重复6~10次；将得到的双层硬脑膜材料加入不锈钢转鼓中，加入2份常温水，水洗10min，弃去废液，如此重复水洗3次；加入2份常温水，水洗30min，弃去废液，如此重复水洗2次；加入2份常温水，水洗60min，弃去废液，如此重复水洗2次；将水洗后的双层硬脑膜材料置于20℃真空干燥箱中干燥4h；1) Use a film applicator to coat the BC/PLA composite film prepared above on the printed substrate. After the solution volatilizes for 1 hour, the next coating is performed, and this is repeated 6 to 10 times; The meningeal material was added to the stainless steel drum, 2 parts of room temperature water was added, washed with water for 10 minutes, and the waste liquid was discarded, and the washing was repeated 3 times; 2 parts of room temperature water was added, and the waste liquid was washed for 30 minutes. Parts of room temperature water, washed with water for 60 min, discarded the waste liquid, and repeated the washing twice; the washed double-layer dura mater material was placed in a 20 ℃ vacuum drying box to dry for 4 hours;
2）再将胶原蛋白海绵按上述步骤涂覆在双层硬脑膜材料，得到半成品可降解复合层硬脑膜半成品；2) The collagen sponge is then coated on the double-layer dura mater material according to the above steps to obtain the semi-finished degradable composite layer dura mater semi-finished product;
3）将采用Co60所产生的γ射线或环氧乙烷进行消毒灭菌，成型包装，即制得可降解复合层硬脑膜成品。3) Sterilize and sterilize the gamma rays or ethylene oxide produced by Co60, form and package, and obtain the finished product of the degradable composite layer dura mater.
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| CN201910229258.1ACN109954166A (en) | 2019-03-25 | 2019-03-25 | A 3D printed artificial biodegradable dura mater and its preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110464876A (en)* | 2019-08-30 | 2019-11-19 | 河南亚都实业有限公司 | A kind of growth factor-loaded bacteria cellulose/bioceramic composite membrane |
| CN110917402A (en)* | 2019-11-29 | 2020-03-27 | 中国人民解放军总医院第六医学中心 | Multifunctional artificial dura mater |
| CN111420123A (en)* | 2020-03-16 | 2020-07-17 | 江西光至金辉医疗制品有限公司 | Degradable anti-adhesion double-layer dura mater patch and preparation method thereof |
| CN113150517A (en)* | 2021-03-11 | 2021-07-23 | 惠州市浩明科技股份有限公司 | Biodegradable plastic film material and preparation method thereof |
| CN115531610A (en)* | 2022-11-09 | 2022-12-30 | 贵州医科大学附属医院 | Fiber composite membrane, its preparation method and application |
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| CN101692986A (en)* | 2009-03-10 | 2010-04-14 | 广州迈普再生医学科技有限公司 | Artificial dura mater with bioactivity and preparation method thereof |
| CN104414772A (en)* | 2013-09-06 | 2015-03-18 | 山东百多安医疗器械有限公司 | In-vivo degradable and absorbable artificial medical tissue repairing film |
| CN107177048A (en)* | 2017-05-12 | 2017-09-19 | 陕西科技大学 | A kind of bacteria cellulose polymeric lactic acid compound film and preparation method thereof and load medicine gauze and preparation method based on the composite membrane |
| WO2018050092A1 (en)* | 2016-09-14 | 2018-03-22 | 四川蓝光英诺生物科技股份有限公司 | Artificial tissue precursor and preparation method therefor |
| CN108744063A (en)* | 2018-06-08 | 2018-11-06 | 苏州卡夫思曼医疗科技有限公司 | A kind of degradable artificial endocranium and preparation method thereof |
| CN108815578A (en)* | 2018-07-09 | 2018-11-16 | 北京诺康达医药科技股份有限公司 | A kind of artificial bio-membrane's endocranium and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101692986A (en)* | 2009-03-10 | 2010-04-14 | 广州迈普再生医学科技有限公司 | Artificial dura mater with bioactivity and preparation method thereof |
| CN104414772A (en)* | 2013-09-06 | 2015-03-18 | 山东百多安医疗器械有限公司 | In-vivo degradable and absorbable artificial medical tissue repairing film |
| WO2018050092A1 (en)* | 2016-09-14 | 2018-03-22 | 四川蓝光英诺生物科技股份有限公司 | Artificial tissue precursor and preparation method therefor |
| CN107177048A (en)* | 2017-05-12 | 2017-09-19 | 陕西科技大学 | A kind of bacteria cellulose polymeric lactic acid compound film and preparation method thereof and load medicine gauze and preparation method based on the composite membrane |
| CN108744063A (en)* | 2018-06-08 | 2018-11-06 | 苏州卡夫思曼医疗科技有限公司 | A kind of degradable artificial endocranium and preparation method thereof |
| CN108815578A (en)* | 2018-07-09 | 2018-11-16 | 北京诺康达医药科技股份有限公司 | A kind of artificial bio-membrane's endocranium and preparation method thereof |
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110464876A (en)* | 2019-08-30 | 2019-11-19 | 河南亚都实业有限公司 | A kind of growth factor-loaded bacteria cellulose/bioceramic composite membrane |
| CN110464876B (en)* | 2019-08-30 | 2022-03-29 | 东营凤起生物科技发展有限公司 | Growth factor-loaded bacterial cellulose/biological ceramic composite membrane |
| CN110917402A (en)* | 2019-11-29 | 2020-03-27 | 中国人民解放军总医院第六医学中心 | Multifunctional artificial dura mater |
| CN111420123A (en)* | 2020-03-16 | 2020-07-17 | 江西光至金辉医疗制品有限公司 | Degradable anti-adhesion double-layer dura mater patch and preparation method thereof |
| CN113150517A (en)* | 2021-03-11 | 2021-07-23 | 惠州市浩明科技股份有限公司 | Biodegradable plastic film material and preparation method thereof |
| CN115531610A (en)* | 2022-11-09 | 2022-12-30 | 贵州医科大学附属医院 | Fiber composite membrane, its preparation method and application |
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| WD01 | Invention patent application deemed withdrawn after publication | Application publication date:20190702 | |
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