Osteoinductive Injectable Degradable Polymeric Scaffold

骨诱导可注射可降解聚合物支架

• 批准号: 7120377
• 负责人: Michael J Yaszemski
• 金额: $ 5.3万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-24 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120377
• 关键词: alkaline phosphatase; biodegradable product; biomaterial development /preparation; biomaterial evaluation; biotechnology; bone morphogenetic proteins; bone regeneration; chemical kinetics; copolymer; crosslink; dicarboxylate; injection /infusion; laboratory rabbit; laboratory rat; lactones; microcapsule; osteoblasts; osteocalcin; polypropylenes; tissue support frame

DESCRIPTION (provided by applicant): Biodegradable polymeric scaffolds that can be injected into a bone defect and crosslinked in situ may provide surgeons with minimally invasive treatment options for several clinical situations, among them segmental skeletal defects and posterior spinal fusion. Scaffold design parameters include biocompatibility, rheologic properties that determine injectability, degradation rate and end products, mechanical properties, and osteoinductivity. We hypothesize that (1) interpenetrating polymer networks (IPN) formed by inter-crosslinking of poly(propylene fumarate) (PPF), which contains unsaturated double bonds for in situ crosslinking, and a novel poly(caprolactone fumarate) (PCLF), which contains flexible poly(caprolactone) macromers in its backbone, may self-crosslink in the absence of a crosslinking agent, (2) the use of degradable hydrogel microspheres as the porosity generating method would both improve the scaffold's injectability and eliminate the step of solid porogen diffusion from the scaffold needed in leaching techniques for pore generation, and (3) controlled delivery of bone morphogenic protein (BMP-2) from the scaffold at the bone regeneration site could be optimized to take maximum advantage of this molecule's osteoinductive properties. Therefore, we propose to address the issues of self-crosslinking, degradation, injectability, and controlled delivery of growth factors. In the first aim, the self-crosslinking and degradation characteristics of a novel PPF/PCLF IPN will be investigated to eliminate the use a crosslinking agent in injectable systems. In this aim, we will also synthesize natural and synthetic biodegradable hydrogels for use as porogens to improve the scaffold's rheological properties during injection. In the second aim, BMP-2 will be encapsulated in biodegradable PPF/PLGA blend microspheres, the microspheres will be immobilized in the IPN/hydrogel composite scaffold, and we will study the release kinetics of the growth factor as well as its bioactivity. In the third aim, the composition of the hydrogel as the porogen will be optimized by measuring the in vitro migration rate of marrow stromal cells (MSC) through candidate porogens. The function of MSCs in vitro will be used to optimize the loading dose of BMP-2 microspheres in the composite scaffold. This will occur by measuring the MSC's proliferation and secretion of both alkaline phosphatase and osteocalcin in response to BMP released from the scaffold. In the fourth aim, a rat segmental defect model and a rabbit posterolateral spine fusion model will be used to assess the ability of the IPN/hydrogel composite scaffold with loaded BMP-2 microspheres to induce bone formation in vivo.

描述（由申请人提供）：可生物降解聚合物支架可以注射到骨缺损中并原位交联，可为外科医生提供几种临床情况的微创治疗选择，其中包括节段性骨骼缺损和后路脊柱融合。支架设计参数包括生物相容性、决定可注射性的流变性、降解率和最终产物、机械性能和成骨性。我们假设(1)聚富马酸丙烯（PPF）（含有用于原位交联的不饱和双键）与新型聚富马酸己内酯（PCLF）（其主链中含有柔性聚己内酯大分子）可以在没有交联剂的情况下自交联形成互穿聚合物网络（IPN）；(2)使用可降解的水凝胶微球作为孔隙生成方法，既可以提高支架的可注射性，又可以消除浸出技术中产生孔隙所需的支架固体孔隙扩散步骤；(3)可以优化支架在骨再生部位的骨形态发生蛋白（BMP-2）的控制递送，以最大限度地利用该分子的成骨诱导特性。因此，我们建议解决生长因子的自交联、降解、注射性和控制递送等问题。在第一个目标中，将研究一种新型PPF/PCLF IPN的自交联和降解特性，以消除交联剂在注射系统中的使用。为此，我们还将合成天然的和合成的可生物降解的水凝胶作为孔隙剂，以改善支架在注射过程中的流变性能。在第二个目标中，我们将BMP-2包裹在可生物降解的PPF/PLGA混合微球中，将微球固定在IPN/水凝胶复合支架中，我们将研究生长因子的释放动力学及其生物活性。第三，通过测定骨髓基质细胞（MSC）通过候选致孔剂的体外迁移率，优化水凝胶作为致孔剂的组成。利用MSCs的体外功能优化BMP-2微球在复合支架中的负载剂量。这将通过测量MSC的增殖和碱性磷酸酶和骨钙素的分泌来响应从支架释放的BMP。在第四个目标中，将使用大鼠节段性缺损模型和兔后外侧脊柱融合模型来评估IPN/水凝胶复合支架加载BMP-2微球在体内诱导骨形成的能力。