基于pH响应性PMMA-锂皂石复合微凝胶的水凝胶构筑及力学性能优化研究

Injectable hydrogel possesses the characteristic of deformation behavior, porous structure and excellent biocompatibility, is an ideal material for soft tissue repair and regeneration. Limited to the very poor mechanical performance, injectable hydrogel is difficult to meet the multiple physiological needs. This proposal intends to use injectable pH-responsive poly(methyl methacrylate-methacrylic acid)/Laponite RD nanocomposite microgels as precursors, biocompatible nanocomposite hydrogels are constructed by ionic bond crosslinking or by coordination of covalent bond and ionic bond. The mechanical properties of hydrogels are adjustable. The main contents of this proposal : 1)Biocompatible Laponite RD platelets replacing of conventional surfactants, pH-responsive poly(methyl methacrylate-methacrylic acid)/Laponite RD nanocomposite microgels with adjustable swelling ratio are synthesized by Pickering emulsion polymerization; 2) Design of cationic copolymers, self-healing nanocomposite hydrogel is formed by the ionic bond coupling of the copolymers and microgels. Stress deformation and self-recovery ability of the hydrogel are controlled mainly by Laponite platelet orientation. Their action mechanism is also discussed; 3) Thiol-substituted cationic crosslinking agent and acryloyl modified nanocomposite microgel are designed. Thiol-Michael addition happens while mixing of crosslinking agent and modified microgel at higher pH value. Mechanical performance optimization of hydrogel is constructed. The effect of covalent / ionic bond coordination on the mechanical properties of the hydrogel is investigated. The proposal optimizes the mechanical properties of injectable hydrogel radically. The products are expected to be used for intervertebral disc repair and medical plastic etc.

可注射水凝胶形状可塑、结构多孔、生物相容性好，是理想的软组织再生、修复材料。限于其力学性能较弱，难以满足多重生理需求，课题以具有pH响应性的聚(甲基丙烯酸甲酯-甲基丙烯酸)/ 锂皂石（Laponite RD）纳米复合微凝胶为前体，经共价键、离子键交联，得可注射用，生物友好、力学性能可调的复合水凝胶。内容涉及：1）利用生物相容性的锂皂石纳米圆片代替常规表面活性剂，经Pickering乳液聚合，合成溶胀性能变化的pH响应性复合微凝胶；2）设计阳离子聚合物，与微凝胶前体交联，合成具备自修复功能的复合水凝胶，进而探讨结构和锂皂石取向制约水凝胶应力形变、弹性恢复能力的机理；3）设计巯基化阳离子交联剂，与丙烯酰氧基化微凝胶进行迈克尔加成，构建机械性能优化的复合水凝胶, 研究共价/离子键协同效应对水凝胶力学性能的影响。课题从根本上优化了可注射水凝胶的力学性能，产品可望用于腰椎间盘修复、医疗整形等领域。

以具有pH响应性的微凝胶为可注射材料，克服了常规可注射的水凝胶固含量低、黏度大、力学性能较弱的缺点。但以往报道的pH响应性的微凝胶制备时添加的大量阴离子乳化剂（如SDS）增加了微凝胶的生物毒性，在使用前要经过严格的去除乳化剂步骤，限制了其作为生物医用材料的进一步研究。. 本项目以无生物毒性的无机纳米微粒锂皂石（Laponite RD）或SiO2代替生物毒性的乳化剂，采用Pickering乳液聚合法分别合成了pH响应性的甲基丙烯酸甲酯（MMA）和甲基丙烯酸（MAA）共聚物微凝胶poly(MMA-MAA)/Laponite RD（聚集体粒径大多在2-5 um）、poly(MMA-MAA)/SiO2（干态粒径约350 nm），以及未加交联剂的乳胶粒。这些微凝胶或乳胶粒在低浓度的分散体系、4⁓10的pH范围内，粒径大小随pH的升高与降低呈现很好的可逆性溶胀与收缩；高浓度时，pH低于6为流动性很好的可注射材料，升高pH值到7.5以上转变为固态的凝胶状。甲基丙烯酸缩水甘油酯（GMA）共价连接上述微粒，获得表面烯基修饰的微凝胶或乳胶粒，修饰后的微凝胶或乳胶粒与母体具有相似的pH响应性。. 以甲基丙烯酸--羟乙酯和甲基丙烯酰氧乙基三甲基氯化铵为主要单体进行共聚，合成了阳离子共聚物(HD)、侧基含有巯基的阳离子共聚物(SH-HD)，以及侧基含有烯基的阳离子共聚物（V-HD）。上述阳离子共聚物为不同形式的交联剂，与微凝胶、乳胶粒及表面烯基修饰的微凝胶或乳胶粒复合，形成不同形式的共价/离子键协同效应的复合水凝胶。. 改变浓度、聚合物分子量、共价键形成方式、组成和组成比例，均可在宽广的范围调节凝胶的性能，其储能模量的变化从临界凝胶时的100 Pa左右变化到约4.0 × 105 Pa。复合凝胶体系中，添加不到1%质量分数的阳离子聚合物，形成的复合凝胶的模量即可升高2⁓3倍，凝胶的临界应变最高可提升1.5倍。因而，课题的展开优化了可注射水凝胶的力学性能，为可注射凝胶的构筑提供了理论和材料基础，产品也可望用于腰椎间盘修复、医疗整形等领域。另外值得提出的是，以二氧化硅为稳定剂制备的未添加交联剂的乳胶粒，若调节pH到11，体系变为具有粘结性质的弹性体状态，今后将会进一步展开相关的研究。