生物活性形状记忆人工骨及其预防骨不连的力学生物学机理研究

Nonunion is a common syndrome during the therapy process of bone fracture and defects. Current studies for nonunion are mainly focused on the clinical therapies after nonunion has been formed; however, for prevention of nonunion, there is no effective technology. This project provides an innovative idea to prevent nonunion by using bioactive shape memory bone (BASM bone), with a final goal to establish a novel nonunion-preventive technology. It has been proven that unstable fixation, gap between the implanted bone and native bone, and stress-shielding are primary factors resulting in nonunion in addition to insufficient blood supply. Our hypothesis is that BASM bone may eliminate these factors or attenuate their effects and thus prevent nonunion. The principle is that BASM bone can axially expand in response to temperature (i.e. body temperature), fully filling the gap, and exerting an axial compressive stress on the native bone to weaken stress-shielding and stabilize BASM bone. To test our hypothesis, a novel shape memory polymer with enhanced cell adhesion activity and mechanical properties is designed and compounded with hydroxyapatite (HAp) to form BASM bone; then an in vitro bone defect model based on a cantilever-beam tensometer is constructed and the shape recovery stress and local stress distribution of BASM bone are characterized; the obtained data together with the results from cellular experiments and animal tests are integrated to evaluate the nonunion-prevention potential of BASM bone and understand the possible mechanobiological mechanisms underlying the nonunion-prevention. The success of this project will develop an innovative approach and technology to prevent non-union and facilitate the application of biomaterials and biomechanics in bone repair and regeneration.

骨不连是骨修复常见并发症，相关研究主要集中在骨不连形成后的治疗上，尚缺乏预防骨不连的有效技术。本项目拟开展基于生物活性形状记忆人工骨(BASM骨)预防骨不连的基础研究，以期研发出一种防骨不连的新技术。固定不稳定、骨折间隙和应力遮挡是诱发骨不连的三大因素。本课题假设：BASM骨可以消除或削弱这些诱因，从而防止骨不连。其原理是：BASM骨在热刺激下发生形状回复，轴向膨胀而完全填充间隙，并对本体骨施加轴向压力，稳定人工骨，削弱应力遮挡。为验证此假设，拟设计一种具促细胞粘附活性的形状记忆聚合物，与羟基磷灰石HAp复合形成BASM骨；构建基于悬臂梁式张力计的体外骨缺损模型，定量表征BASM骨回复应力和应力分布，并结合细胞实验和动物试验评价BASM骨预防骨不连的能力，解析其防骨不连的力学生物学机制。本课题的成功实施将提供一条预防骨不连的新思路，对促进生物材料、生物力学在骨修复与再生中的应用有重要意义。

骨不连是骨修复常见并发症，目前尚缺乏预防骨不连的有效技术。本项目旨在设计制备一种基于形状记忆聚氨酯的生物活性形状记忆人工骨（BASM骨）并建立一种基于BASM骨预防骨不连的新技术。本项目首先设计制备了一种侧链带-COOH的反应性形状记忆聚氨酯，并共价引入RGDS多肽制得了具有促细胞粘附活性的SMP-PU-RGD。但由于其力学性能欠佳，本项目进一步设计合成了一种基于刚性环状异山梨醇（ISO）的高力学性能聚氨酯材料（ISO-PUs），并与具有骨传导活性的β-磷酸三钙（β-TCP）复合，采用3D plotting技术构建了ISO-PUs/β-TCP多孔复合支架，即BASM骨。该BASM骨的孔隙率大于70%，具有与天然骨相似的大孔（400 ~600 μm）套小孔（约15 μm）的多级孔隙结构，其压缩强度和模量明显优于ISO-PU支架和PDLLA支架，且能显著促进成骨细胞向支架孔隙内部长入、增殖和分化。为了体外评价BASM骨预防骨不连形成的潜力，我们成功设计加工了一套基于悬臂梁张力计的体外骨缺损模型和形状回复力定量检测装置。研究发现，BASM骨在形状回复时可以完全填充自体骨与BASM骨间的间隙并对自体骨施加回复应力，且回复应力大小和回复速率与材料赋形时的变形方式和变形率密切相关，证明BASM骨可以消除或缓解引起骨不连形成的固定不稳定、骨折间隙和应力遮挡因素，有预防骨不连的潜力。动物实验结果也证实BASM骨能够有效防止骨不连的发生。同时，我们还创新性地发现：形状回复应变作为一种力学刺激，也可调控细胞形态并促进细胞后期增殖，提示回复应变是预防骨不连形成的另一重要机制。据此，我们提出了BASM骨预防骨不连的力学生物学机制：BASM骨在热刺激下形状回复所产生的回复应力和回复应变可分别对自体骨和BASM骨细胞施加力学刺激，促进细胞生长和成骨分化，防止骨不连；BASM骨自身的骨传导活性和仿生骨组织结构可进一步促进新骨长入和骨组织再生，预防骨不连。本研究的成功实施不仅提供了一种可以预防骨不连的新型BASM骨支架，而且为临床预防骨不连形成提供了一条全新的思路。

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