技术领域technical field
本发明涉及无机-有机杂化复合材料技术领域，具体涉及溶胶凝胶生物活性玻璃-高分子杂化材料的制备方法。The invention relates to the technical field of inorganic-organic hybrid composite materials, in particular to a preparation method of sol-gel bioactive glass-polymer hybrid materials.
背景技术Background technique
骨组织是人体重要的组织器官，其主要功能是运动、支持和保护身体，同时也是人体重要的造血器官，以及贮存钙磷矿物的重要器官。骨组织的缺损将对人体健康及日常生活产生重大的影响。Bone tissue is an important tissue and organ of the human body. Its main function is to exercise, support and protect the body. It is also an important hematopoietic organ of the human body and an important organ for storing calcium and phosphorus minerals. The defect of bone tissue will have a significant impact on human health and daily life.
但由于先天性和创伤性的原因，在骨科、牙科、颌面外科、整形外科等临床上，由骨肿瘤、骨囊肿等原因导致骨切除造成的骨缺损病例非常多。骨组织切除后，不但造成相关功能的缺失，同时由于骨组织的切除，与周围组织的解剖结构、力学结构关系发生改变，也容易引起周围组织相应的并发症发生。如上颌骨切除后导致的听力丧失；桡骨头切除术后出现肘骨关节炎、关节对合异常等；胸椎肿瘤切除后，脊椎可能出现屈曲畸形、脱位等，再次导致截瘫。因此，在骨切除术中，通常需要相应的骨填充材料来替代切除的骨组织，以保证相应缺损组织的部分功能在术后仍然得以保存。However, due to congenital and traumatic reasons, in orthopedics, dentistry, maxillofacial surgery, orthopedic surgery, there are many cases of bone defects caused by bone tumors and bone cysts caused by bone resection. After the bone tissue is resected, it not only causes the loss of related functions, but also changes the anatomical structure and mechanical structure relationship with the surrounding tissue due to the resection of the bone tissue, which may also easily cause the corresponding complications of the surrounding tissue. For example, hearing loss after maxillary resection; elbow osteoarthritis and joint apposition abnormalities after radial head resection; after thoracic tumor resection, spinal flexion deformity and dislocation may occur, leading to paraplegia again. Therefore, during osteotomy, corresponding bone filling materials are usually required to replace the resected bone tissue, so as to ensure that some functions of the corresponding defect tissue are preserved after the operation.
目前临床常用的骨填充修复材料主要有生物源性的骨组织如自体骨、同种异体骨或异种骨；天然材料如改性处理的珊瑚等；以及合成无机材料，如硫酸钙、碳酸钙、羟基磷灰石、磷酸三钙以及生物玻璃等。总体而言，自体填充修复材料修复效果最好，但存在供应有限的问题。同种异体以及异种材料也有较好的修复效果，但由于存在免疫及病理的问题，在临床上也未得到广泛的应用。天然来源的钙磷材料，以及合成类的无机材料来源广泛，化学结构稳定，目前在临床上应用广泛。但在应用过程中也发现，无机材料由于自身分子结构的特性，修复材料存在脆性大、加工难、粉末应用不方便等缺点，也不是最好的骨修复材料。生物活性玻璃是一种具有优良生物相容性的及生物活性的无机类生物活性材料，它能够在植入部位迅速发生一系列表面反应，形成与骨和软组织都能产生良好结合的羟基磷灰石层，促进骨组织的再生，受到了相关研究人员的重视。但生物玻璃属于无机材料，仍然存在脆性大、加工难、粉末应用不方便等问题。At present, the bone filling materials commonly used in clinical practice mainly include biologically derived bone tissue such as autologous bone, allograft bone or xenograft bone; natural materials such as modified coral, etc.; and synthetic inorganic materials such as calcium sulfate, calcium carbonate, Hydroxyapatite, tricalcium phosphate, and bioglass, etc. In general, autologous filling restorative materials have the best restoration results, but there is a problem of limited supply. Allogeneic and heterogeneous materials also have good repair effects, but due to immune and pathological problems, they have not been widely used clinically. Calcium-phosphorus materials from natural sources and synthetic inorganic materials have a wide range of sources and stable chemical structures, and are currently widely used clinically. However, in the process of application, it is also found that due to the characteristics of its own molecular structure, inorganic materials have disadvantages such as high brittleness, difficult processing, and inconvenient powder application, and are not the best bone repair materials. Bioactive glass is an inorganic bioactive material with excellent biocompatibility and bioactivity. It can rapidly undergo a series of surface reactions at the implant site to form hydroxyapatite that can be well combined with bone and soft tissue. The stone layer, which promotes the regeneration of bone tissue, has attracted the attention of relevant researchers. However, bioglass is an inorganic material, and there are still problems such as high brittleness, difficult processing, and inconvenient powder application.
有机无机复合材料能够在一定程度上改善材料的成型性，调控材料的力学性能与生物学性能。但目前研究的复合材料都是大尺寸的杂化材料，如目前研究较多的可降解聚酯类高分子与羟基磷灰石、磷酸三钙、生物玻璃等无机材料形成的复合材料。仅仅停留在大尺度上的杂化仍然无法满足对骨填充修复材料同时必须具备生物学活性、可降解性能、力学适配性能提出的要求。小尺度的杂化，即在纳米尺度及分子水平上的杂化，才是最终解决对上述多功能需求的生物活性可降解复合材料的方法。Organic-inorganic composite materials can improve the formability of materials to a certain extent, and regulate the mechanical and biological properties of materials. However, the composite materials currently studied are all large-scale hybrid materials, such as the composite materials formed by degradable polyester polymers and inorganic materials such as hydroxyapatite, tricalcium phosphate, and bioglass, which have been studied more. Hybridization that only stays on a large scale still cannot meet the requirements for bone filling and repair materials that must have biological activity, degradability, and mechanical adaptability at the same time. Small-scale hybridization, that is, hybridization at the nanoscale and molecular levels, is the final solution to the above-mentioned multifunctional requirements for bioactive degradable composite materials.
虽然大尺度杂化和小尺度杂化的材料在组成和原子或分子的排布上是一样的，但有机高分子与无机材料在分子水平上形成的杂化材料，由于其特殊的分子结构特点，能够在材料内部同时实现不同类型化学键的共存与结合，如高分子的共价键与无机材料的离子键的化学结合，并且这种结合是在分子水平、纳米尺度上的结合，使得材料能够既具有无机材料的特性，同时也能够具有有机高分子的特点，作为组成物质聚集态的有机、无机相小尺度杂化的纳米结构表现出特有的纳米协同效应，形成的新材料还能够具有比以往单独的高分子、无机材料更加优异的性能，从而得到性能独特的新材料，表现出许多人们所需求的优良的性能。Although the large-scale hybrid and small-scale hybrid materials are the same in composition and arrangement of atoms or molecules, the hybrid materials formed by organic polymers and inorganic materials at the molecular level, due to their special molecular structure characteristics , can realize the coexistence and combination of different types of chemical bonds inside the material at the same time, such as the chemical combination of covalent bonds of polymers and ionic bonds of inorganic materials, and this combination is at the molecular level and on the nanometer scale, so that the material can It not only has the characteristics of inorganic materials, but also has the characteristics of organic polymers. As the aggregated state of organic and inorganic phases, the small-scale hybrid nanostructures show unique nano-synergistic effects, and the new materials formed can also have relatively In the past, single polymers and inorganic materials had more excellent properties, so that new materials with unique properties were obtained, showing many excellent properties that people demand.
溶胶凝胶生物玻璃的制备是通过硅氧烷前驱体中烷氧键水解成硅羟基，再通过硅羟基的缩合脱水，形成生物玻璃的大分子硅氧网络复合体。基于上述溶胶凝胶生物玻璃的合成原理，将高分子端基用含有硅烷氧基的基团进行端基修饰，通过硅烷氧基的水解反应形成硅羟基，并与溶胶凝胶玻璃前驱体中的硅羟基团进行共缩合，实现高分子与生物玻璃网络复合体的分子杂化。通过有机-无机分子杂化比例，以及有机成分分子链长短的控制，实现对杂化材料生物活性及力学性能的综合调节，制备具有临床应用意义的分子杂化无机-有机生物活性玻璃复合材料。Sol-gel bioglass is prepared by hydrolyzing alkoxy bonds in siloxane precursors to form silanol groups, and then dehydrating silanol groups to form macromolecular siloxane network complexes of bioglass. Based on the synthesis principle of the above sol-gel bioglass, the terminal group of the polymer is modified with a group containing a siloxyl group, and the silanol group is formed through the hydrolysis reaction of the siloxyl group, and is combined with the silanol group in the sol-gel glass precursor. The co-condensation of the silanol group realizes the molecular hybridization of the polymer and the bioglass network complex. Through the control of the ratio of organic-inorganic molecular hybridization and the length of the molecular chain of the organic component, the comprehensive adjustment of the biological activity and mechanical properties of the hybrid material can be realized, and the molecular hybrid inorganic-organic bioactive glass composite material with clinical application significance can be prepared.
发明内容Contents of the invention
本发明的目的在于克服现有溶胶凝胶生物活性玻璃的脆性大、粉末应用不便的不足，提供溶胶凝胶生物活性玻璃-高分子杂化复合材料的制备方法。The purpose of the present invention is to overcome the shortcomings of high brittleness and inconvenient powder application of the existing sol-gel bioactive glass, and provide a preparation method of the sol-gel bioactive glass-polymer hybrid composite material.
本发明的目的通过以下技术方案实现：The object of the present invention is achieved through the following technical solutions:
溶胶凝胶生物活性玻璃-高分子杂化材料的制备方法，包括如下步骤：A method for preparing a sol-gel bioactive glass-polymer hybrid material, comprising the steps of:
（1）将高分子与异氰酸基烷基烷氧基硅烷进行反应，得到烷氧基硅氧烷基封端的高分子；(1) Reacting the polymer with isocyanatoalkylalkoxysilane to obtain an alkoxysiloxane-terminated polymer;
（2）将步骤（1）得到的烷氧基硅氧烷基封端的高分子与生物活性玻璃的前躯体的水溶液进行搅拌混合，进行共水解及脱水聚合反应；(2) stirring and mixing the alkoxysiloxane-terminated polymer obtained in step (1) with the aqueous solution of the precursor of the bioactive glass, and performing co-hydrolysis and dehydration polymerization;
其中烷氧基硅氧烷基封端的高分子的质量百分比为60%~10%，生物玻璃的前驱体的质量百分比为40%~90%；Among them, the mass percentage of alkoxysiloxane-terminated polymer is 60%~10%, and the mass percentage of the precursor of bioglass is 40%~90%;
（3）对步骤（2）得到的产物进行陈化处理后进行干燥处理；(3) Drying the product obtained in step (2) after aging;
（4）将步骤（3）得到的产物进行热处理，得到生物玻璃-高分子杂化材料。(4) Heat-treating the product obtained in step (3) to obtain a bioglass-polymer hybrid material.
步骤（2）所述共水解及脱水聚合反应的反应温度为4℃~40℃，pH值范围为4~9，反应时间不少于2小时。The reaction temperature of the co-hydrolysis and dehydration polymerization in step (2) is 4°C-40°C, the pH range is 4-9, and the reaction time is not less than 2 hours.
所述pH值采用盐酸、氨水、氢氧化钠或者氢氧化钾进行调节。The pH value is adjusted with hydrochloric acid, ammonia water, sodium hydroxide or potassium hydroxide.
步骤（3）所述陈化处理的反应温度为4℃~100℃。The reaction temperature of the aging treatment in step (3) is 4°C to 100°C.
步骤（4）所述热处理的温度为100℃~800℃。The temperature of the heat treatment in step (4) is 100°C to 800°C.
步骤（1）所述高分子为双羟基、氨基端基高分子或多羟基、氨基端基高分子，数均分子量为100~20000。The polymer in step (1) is a dihydroxyl, amino-terminated polymer or a polyhydroxyl, amino-terminated polymer, with a number average molecular weight of 100-20,000.
步骤（2）还加入具有治疗作用的药物、生物活性分子溶液、缓释制剂、基因载体或负电性高分子。In step (2), drugs with therapeutic effects, bioactive molecule solutions, sustained-release preparations, gene carriers or negatively charged polymers are added.
步骤（1）所述异氰酸基烷基烷氧基硅烷为单烷氧基、双烷氧基或三烷氧基。The isocyanatoalkylalkoxysilane in step (1) is monoalkoxy, dialkoxy or trialkoxy.
生物活性玻璃的前躯体包含质量百分比为30%~80%的SiO2，质量百分比为10%~40%的CaO，质量百分比为1%~10%的P2O5，质量百分比为0~20%的NaO。The precursor of the bioactive glass contains 30%-80% by mass of SiO2 , 10%-40% by mass of CaO, 1%-10% by mass of P2 O5 , and 0-20% by mass % NaO.
步骤（3）所述干燥为冷冻干燥或者超临界干燥。The drying in step (3) is freeze drying or supercritical drying.
与现有材料相比，本发明具有如下优点和效果：Compared with existing materials, the present invention has the following advantages and effects:
（1）传统溶胶凝胶生物玻璃在陈化排水过程中，容易开裂，难以制备大块材料，而采用有机分子进行杂化后，高分子分子链能够在陈化过程中稳定硅氧网络结构，减少并避免材料的塌陷及开裂，利于制备大块的材料。其次，由于体系中存在高分子的结构，材料的脆性大大降低，韧性及加工性能得到改善。(1) The traditional sol-gel bioglass is easy to crack during the aging and drainage process, and it is difficult to prepare bulk materials. After hybridization with organic molecules, the polymer molecular chain can stabilize the silicon-oxygen network structure during the aging process. Reduce and avoid the collapse and cracking of materials, which is beneficial to the preparation of bulk materials. Secondly, due to the presence of a polymer structure in the system, the brittleness of the material is greatly reduced, and the toughness and processing performance are improved.
（2）本发明制备的溶胶凝胶生物活性玻璃-高分子杂化复合材料保留了溶胶凝胶生物玻璃的优异性能（体外矿化实验结果表明该修复材料在模拟体液中能够在表面形成钙磷沉积），预期能够在植入部位发生一系列表面反应，形成与骨产生良好结合的类骨钙磷沉积，促进骨组织的再生。(2) The sol-gel bioactive glass-polymer hybrid composite material prepared by the present invention retains the excellent properties of sol-gel bioglass (the results of in vitro mineralization experiments show that the repair material can form calcium phosphorus on the surface in simulated body fluid It is expected that a series of surface reactions will occur at the implant site to form bone-like calcium and phosphorus deposits that are well combined with bone and promote the regeneration of bone tissue.
附图说明Description of drawings
图1为本实施例制备的溶胶凝胶生物玻璃-高分子杂化材料与聚乙二醇（PEG）的红外图谱。Figure 1 is the infrared spectrum of the sol-gel bioglass-polymer hybrid material and polyethylene glycol (PEG) prepared in this example.
图2为PEG在模拟体液中矿化7天表面SEM图。Figure 2 is the surface SEM image of PEG mineralized in simulated body fluid for 7 days.
图3为本实施例制备的胶凝胶生物玻璃-高分子杂化材料在模拟体液中矿化7天表面SEM图片。Fig. 3 is the SEM picture of the surface of the gel bioglass-polymer hybrid material prepared in this example after mineralization in simulated body fluid for 7 days.
图4为本实施例制备的胶凝胶生物玻璃-高分子杂化材料的表面沉积物的能谱图。Fig. 4 is an energy spectrum diagram of the surface deposits of the gelatin bioglass-polymer hybrid material prepared in this example.
具体实施方式Detailed ways
下面结合实施例及附图，对本发明作进一步地详细说明，但本发明的实施方式不限于此。The present invention will be described in further detail below in conjunction with the embodiments and the accompanying drawings, but the embodiments of the present invention are not limited thereto.
实施例1Example 1
将16g的双端基为羟基的聚乙二醇（PEG）200与37.2g异氰酸基三乙氧基硅烷进行反应，得到53.4g端基含有乙氧基硅基的聚乙二醇。将53.4g该分子与15.6g四乙氧基硅烷、1.8g磷酸三乙酯、18.8g硝酸钙一同放入50毫升水中，用1M的稀盐酸调pH值至6.8，在15℃时，用磁力搅拌器800转/分钟搅拌3h，进行共水解反应。取共水解产物10ml，加入0.2g透明质酸，100ng骨形态发生蛋白BMP于溶液中，混合均匀。4℃陈化10天后，置于-20℃冰箱中7d，然后冷冻干燥处理48小时，再于800℃热处理3小时后，得到最终产物。16 g of polyethylene glycol (PEG) 200 whose double terminal groups are hydroxyl groups were reacted with 37.2 g of isocyanatotriethoxysilane to obtain 53.4 g of polyethylene glycol with ethoxysilyl groups at the terminal groups. Put 53.4g of this molecule together with 15.6g of tetraethoxysilane, 1.8g of triethyl phosphate, and 18.8g of calcium nitrate into 50ml of water, adjust the pH value to 6.8 with 1M dilute hydrochloric acid, and at 15°C, use magnetic The stirrer was stirred at 800 rev/min for 3 hours to carry out the co-hydrolysis reaction. Take 10ml of the co-hydrolyzed product, add 0.2g of hyaluronic acid and 100ng of bone morphogenetic protein BMP into the solution, and mix well. After aging at 4°C for 10 days, it was placed in a -20°C refrigerator for 7 days, then freeze-dried for 48 hours, and then heat-treated at 800°C for 3 hours to obtain the final product.
图1为本实施例制备的溶胶凝胶生物玻璃-高分子杂化材料与PEG的红外图谱（图中曲线A对应本实施例制备的溶胶凝胶生物玻璃-高分子杂化材料，曲线B对应PEG），从红外图谱中可以看出波数为1719cm-1处的吸收峰为PEG与生物玻璃杂化过程中，其化学键酰胺基团的特征吸收峰。Fig. 1 is the infrared spectrum of the sol-gel bioglass-polymer hybrid material prepared in this example and PEG (curve A in the figure corresponds to the sol-gel bioglass-polymer hybrid material prepared in this example, and curve B corresponds to PEG), it can be seen from the infrared spectrum that the absorption peak at the wavenumber of 1719cm-1 is the characteristic absorption peak of the chemical bond amide group in the hybridization process of PEG and bioglass.
图2为PEG在模拟体液中矿化7天表面SEM图。图3为本实施例制备的胶凝胶生物玻璃-高分子杂化材料在模拟体液中矿化7天表面SEM图片，由图3可知，本实施例制备的胶凝胶生物玻璃-高分子杂化材料表面有明显的矿物沉积。图4为本实施例制备的胶凝胶生物玻璃-高分子杂化材料的表面矿物沉积物的能谱图，能谱分析表明，该沉积物中主要成分为钙磷元素。表明本实施例制备的胶凝胶生物玻璃-高分子杂化材料能够在植入部位发生一系列表面反应，形成与骨和软组织都能产生良好结合的钙磷沉积物，促进骨组织的再生。Figure 2 is the surface SEM image of PEG mineralized in simulated body fluid for 7 days. Fig. 3 is the SEM image of the surface of the gelatin bioglass-polymer hybrid material prepared in this example after mineralization in simulated body fluid for 7 days. As can be seen from Fig. 3, the gelatin bioglass-polymer hybrid material prepared in this embodiment There are obvious mineral deposits on the surface of the chemical material. Fig. 4 is an energy spectrum diagram of the mineral deposits on the surface of the colloidal bioglass-polymer hybrid material prepared in this example. Energy spectrum analysis shows that the main components of the deposits are calcium and phosphorus elements. It shows that the gel bioglass-polymer hybrid material prepared in this example can undergo a series of surface reactions at the implantation site to form calcium and phosphorus deposits that are well combined with bone and soft tissue and promote bone tissue regeneration.
实施例2Example 2
将12g分子量为400的双端基为羟基的聚乙二醇（PEG）与14g异氰酸基三乙氧基硅烷进行反应，得到26g端基含有乙氧基硅基的聚乙二醇。将25g该分子与16.6g四乙氧基硅烷、1.8g磷酸三乙酯、15g四水硝酸钙，3g氧化钠一同放入70毫升水中，用1M的稀盐酸调pH值至4，在15℃时，用磁力搅拌器600转/分钟搅拌5h，进行共水解反应。取共水解产物10ml，加入一定量的壳聚糖和氧氟沙星的缓释微球，并混合均匀。在25℃陈化7天，然后经过逐级脱水干燥，再在100℃热处理24小时，得到最终产物。12 g of polyethylene glycol (PEG) with a molecular weight of 400 and double-terminal hydroxyl groups were reacted with 14 g of isocyanatotriethoxysilane to obtain 26 g of polyethylene glycol with ethoxysilyl groups at the end. Put 25g of this molecule together with 16.6g of tetraethoxysilane, 1.8g of triethyl phosphate, 15g of calcium nitrate tetrahydrate, and 3g of sodium oxide into 70ml of water, adjust the pH value to 4 with 1M dilute hydrochloric acid, and set the temperature at 15°C , stirred with a magnetic stirrer at 600 rpm for 5 h to carry out a co-hydrolysis reaction. Take 10ml of the co-hydrolyzed product, add a certain amount of slow-release microspheres of chitosan and ofloxacin, and mix well. Aged at 25°C for 7 days, then dehydrated and dried step by step, and then heat-treated at 100°C for 24 hours to obtain the final product.
实施例3Example 3
将20g分子量为1000的双端基为羟基的聚己内酯（PCL）与9.3g异氰酸基三乙氧基硅烷进行反应，得到29.3g端基含有乙氧基硅基的聚己内酯。将含25g该分子的溶液与16.6g四乙氧基硅烷、2g磷酸三乙酯、14g硝酸钙,1g氧化钠一同放入60毫升水中，用1M的稀盐酸调pH值至4，在15℃时，用磁力搅拌器800转/分钟搅拌8小时，进行共水解反应。取10ml的共水解产物，加入一定量负电性高分子透明质酸再搅拌0.5h，然后在15℃陈化14天，再在200℃热处理24小时，得到最终产物。React 20g of polycaprolactone (PCL) with a molecular weight of 1000 and 9.3g of isocyanatotriethoxysilane to obtain 29.3g of polycaprolactone with an ethoxysilyl group at the end . Put the solution containing 25g of this molecule together with 16.6g of tetraethoxysilane, 2g of triethyl phosphate, 14g of calcium nitrate, and 1g of sodium oxide into 60ml of water, adjust the pH value to 4 with 1M dilute hydrochloric acid, and set the temperature at 15°C , stirred with a magnetic stirrer at 800 rpm for 8 hours to carry out a co-hydrolysis reaction. Take 10ml of the co-hydrolyzed product, add a certain amount of negatively charged polymer hyaluronic acid and stir for 0.5h, then age at 15°C for 14 days, and then heat-treat at 200°C for 24 hours to obtain the final product.
实施例4Example 4
将18g分子量为600的双端基为羟基的聚乙二醇（PEG）与13.5g异氰酸基三乙氧基硅烷进行反应，得到31.5g端基含有乙氧基硅基的聚乙二醇。将20g该分子与16.6g四乙氧基硅烷、1g磷酸三乙酯、10g硝酸钙，0.5g氧化钠一同放入100毫升水中，用4M的氨水调pH值至8，在15℃时，用磁力搅拌器800转/分钟搅拌4小时，进行共水解反应。取共水解产物10ml，加入一定量负电性高分子海藻酸钠，庆大霉素缓释微球，混合均匀，然后产物在50℃陈化2天，冷冻干燥处理48h，再在150℃热处理24小时，得到杂化材料。React 18g of polyethylene glycol (PEG) with a molecular weight of 600 and double-terminal hydroxyl groups with 13.5g of isocyanatotriethoxysilane to obtain 31.5g of polyethylene glycol with ethoxysilyl groups at the end . Put 20g of this molecule together with 16.6g of tetraethoxysilane, 1g of triethyl phosphate, 10g of calcium nitrate, and 0.5g of sodium oxide into 100ml of water, adjust the pH value to 8 with 4M ammonia water, and at 15°C, use A magnetic stirrer was stirred at 800 rpm for 4 hours to carry out the co-hydrolysis reaction. Take 10ml of the co-hydrolyzed product, add a certain amount of negatively charged polymer sodium alginate, and gentamicin sustained-release microspheres, mix well, then age the product at 50°C for 2 days, freeze-dry for 48 hours, and then heat-treat at 150°C for 24 hours. hours, a hybrid material is obtained.
实施例5Example 5
将16g分子量为8000的双端基为羟基的PLA-PGA（PLGA）与1g异氰酸基三乙氧基硅烷进行反应，得到17g端基含有乙氧基硅基的PLGA。将含15g该分子的溶液与16.6g四乙氧基硅烷、0.9g磷酸三乙酯、15g硝酸钙一同放入50毫升水中，用1M的氢氧化钠调pH值至9，在15℃时，用磁力搅拌器1200转/分钟搅拌4小时，进行共水解反应。取共水解产物10ml，加入极少量促成骨蛋白、高分子1g壳聚糖、0.5g透明质酸，混合均匀。将产物在45℃陈化3天，冷冻干燥48h，再在200℃热处理48小时，得到最终产物。16 g of PLA-PGA (PLGA) with a molecular weight of 8000 and double-terminated hydroxyl groups was reacted with 1 g of isocyanatotriethoxysilane to obtain 17 g of PLGA with ethoxysilyl groups at its terminals. Put the solution containing 15g of this molecule together with 16.6g of tetraethoxysilane, 0.9g of triethyl phosphate, and 15g of calcium nitrate into 50ml of water, adjust the pH value to 9 with 1M sodium hydroxide, and at 15°C, Stir with a magnetic stirrer at 1200 rpm for 4 hours to carry out co-hydrolysis reaction. Take 10ml of the co-hydrolyzed product, add a very small amount of osteogenic protein, 1g of macromolecule chitosan, and 0.5g of hyaluronic acid, and mix well. The product was aged at 45°C for 3 days, freeze-dried for 48 hours, and then heat-treated at 200°C for 48 hours to obtain the final product.
实施例6Example 6
将15g分子量为3000的双端基为羟基的PEG-PCL共聚物与2.4g异氰酸基三乙氧基硅烷进行反应，得到17.4g端基含有乙氧基硅基的PEG-PCL。将10g该分子与16.6g四乙氧基硅烷、1.2g磷酸三乙酯、12g硝酸钙一同放入50毫升水中，用1M的稀盐酸调pH值至5，在15℃时，用磁力搅拌器1200转/分钟搅拌6小时，进行共水解反应，然后将pH调为中性（7左右即可）。取共水解产物10ml，加入促成骨蛋白BMP、0.5g胶原蛋白，搅拌混合均匀。将上述产物放置在100℃下陈化1天，逐级脱水，然后常温干燥，再在100℃热处理24小时，得到目的产物。15g of PEG-PCL copolymer with a molecular weight of 3000 and double-terminated hydroxyl groups were reacted with 2.4g of isocyanatotriethoxysilane to obtain 17.4g of PEG-PCL whose terminal groups contained ethoxysilyl groups. Put 10g of this molecule together with 16.6g of tetraethoxysilane, 1.2g of triethyl phosphate, and 12g of calcium nitrate into 50ml of water, adjust the pH value to 5 with 1M dilute hydrochloric acid, and at 15°C, use a magnetic stirrer Stir at 1200 rpm for 6 hours to carry out the co-hydrolysis reaction, and then adjust the pH to neutral (about 7 is enough). Take 10ml of co-hydrolyzed product, add osteogenic protein BMP, 0.5g collagen, stir and mix evenly. The above product was aged at 100°C for 1 day, dehydrated step by step, then dried at room temperature, and then heat-treated at 100°C for 24 hours to obtain the target product.
实施例7Example 7
将12g分子量为4000的双端基为羟基的PLA-PEG-PLA三嵌段共聚物与1.4g异氰酸基三乙氧基硅烷进行反应，得到13.4g端基含有乙氧基硅基的高分子。将8g该分子与16.6g四乙氧基硅烷、0.5g磷酸三乙酯、13g硝酸钙一同放入60毫升水中，用1M的稀盐酸调pH值至3，在15℃时，用磁力搅拌器800转/分钟搅拌4小时，进行共水解反应。加入缓冲液，调节pH至6.8。取10ml调pH后的共水解产物，加入药物缓释微球、RGD修饰的壳聚糖、透明质酸再混合搅拌均匀。将制备的产物放置在35℃下陈化5天，再在200℃热处理24小时，得到最终产物。12g of PLA-PEG-PLA three-block copolymers with a molecular weight of 4000 and 1.4g of isocyanatotriethoxysilane were reacted to obtain 13.4g of high molecular. Put 8g of this molecule together with 16.6g tetraethoxysilane, 0.5g triethyl phosphate, and 13g calcium nitrate into 60ml water, adjust the pH value to 3 with 1M dilute hydrochloric acid, and at 15°C, use a magnetic stirrer Stir at 800 rpm for 4 hours to carry out co-hydrolysis reaction. Buffer was added to adjust the pH to 6.8. Take 10ml of the co-hydrolyzed product after pH adjustment, add drug sustained-release microspheres, RGD-modified chitosan, and hyaluronic acid, and mix and stir evenly. The prepared product was aged at 35° C. for 5 days, and then heat-treated at 200° C. for 24 hours to obtain the final product.
实施例8Example 8
将20g分子量为2000的双端基为羟基的PCL-PEG-PCL三嵌段共聚物与4.7g异氰酸基三乙氧基硅烷进行反应，得到24.7g端基含有乙氧基硅基的高分子。将10g该分子与16.6g四乙氧基硅烷、0.4g磷酸三乙酯、6g硝酸钙一同放入70毫升水中，用1M的稀盐酸调pH值至6，在15℃时，用磁力搅拌器800转/分钟搅拌2小时，进行共水解反应，加入氧氟沙星缓释微球和5g胶原再搅拌0.5h。搅拌均匀后，上述反应物置于100毫升塑料烧杯中，在15℃陈化20天，超临界干燥48h，再在200℃热处理24小时，即得产物。20g of PCL-PEG-PCL tri-block copolymer with a molecular weight of 2000 and 4.7g of isocyanatotriethoxysilane were reacted to obtain 24.7g of polyethoxysilane containing ethoxysilyl. molecular. Put 10g of this molecule together with 16.6g tetraethoxysilane, 0.4g triethyl phosphate, and 6g calcium nitrate into 70ml water, adjust the pH value to 6 with 1M dilute hydrochloric acid, and at 15°C, use a magnetic stirrer Stir at 800 rpm for 2 hours to carry out co-hydrolysis reaction, add ofloxacin sustained-release microspheres and 5 g of collagen and stir for 0.5 h. After stirring evenly, the above reactants were placed in a 100ml plastic beaker, aged at 15°C for 20 days, supercritically dried for 48h, and then heat-treated at 200°C for 24 hours to obtain the product.
实施例9Example 9
将20g分子量为10000的聚氨酯与0.5g异氰酸基三乙氧基硅烷进行反应，得到20.5g端基含有乙氧基硅基的聚氨酯。将3克该分子与16.6g四乙氧基硅烷、0.8g磷酸三乙酯、8g硝酸钙一同放入60毫升水中，用1M的稀盐酸调pH值至4，在15℃时，用磁力搅拌器1200转/分钟搅拌4小时，进行共水解反应。加入缓冲液，调节pH至6.8，取10ml加入0.2g负电性高分子透明质酸和0.5g胶原，混合搅拌均匀。将上述反应物在4℃陈化14天，冷冻干燥处理48h，再在200℃热处理24小时，得到最终产物。20 g of polyurethane with a molecular weight of 10,000 was reacted with 0.5 g of isocyanatotriethoxysilane to obtain 20.5 g of polyurethane with ethoxysilyl groups at its terminals. Put 3 grams of this molecule together with 16.6g of tetraethoxysilane, 0.8g of triethyl phosphate, and 8g of calcium nitrate into 60ml of water, adjust the pH value to 4 with 1M dilute hydrochloric acid, and stir with magnetic force at 15°C The device was stirred at 1200 rpm for 4 hours to carry out the co-hydrolysis reaction. Add buffer to adjust the pH to 6.8, take 10ml, add 0.2g negatively charged polymer hyaluronic acid and 0.5g collagen, mix and stir evenly. The above reactants were aged at 4°C for 14 days, freeze-dried for 48 hours, and then heat-treated at 200°C for 24 hours to obtain the final product.
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受所述实施例的限制，如共水解及脱水聚合反应中还可加入其他具有治疗作用的药物、生物活性分子溶液、缓释制剂、基因载体或负电性高分子等，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。The above-mentioned examples are preferred implementations of the present invention, but the implementation of the present invention is not limited by the examples, as co-hydrolysis and dehydration polymerization can also add other therapeutic drugs, biologically active molecule solutions , sustained-release preparations, gene carriers or negatively charged polymers, etc., and any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods, including Within the protection scope of the present invention.
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