Injectable Osteoinductive Biodegradable Composites

描述(申请人提供)：许多临床情况，如脊柱融合术、全关节置换术、骨质疏松性骨折和骨骼创伤后的骨丢失，可以通过可原位注射和交联的可生物降解支架来解决。对于用于骨组织工程的可注射生物降解材料，设计参数包括生物相容性、粘度、凝胶化时间、凝结时间、压缩、扭转和弯曲的力学性能以及促进组织形成。对于微创应用，需要能够通过化学氧化还原引发原位交联、能够促进组织生长并具有更高的扭转和弯曲强度的可注射系统。最近开发的可注射材料使用的交联剂会影响可注射系统的生物相容性。我们假设：1)如果富马酰氯(含有用于原位交联的碳-碳双键)与具有灵活主链的生物相容大单体(如聚己内酯)共聚，则共聚物可以在没有交联剂的情况下自交联；2)羟基磷灰石填料与聚合物基质的共价键合将显著提高可注射体系的扭转和弯曲强度；3)使用水凝胶微球代替盐作为致孔剂，在注射前将显著改善材料的流变性能；以及4)生长因子的受控传递将促进原位组织形成。因此，我们建议解决羟基磷灰石与聚合物支架的自交联性、可注入性和共价键的问题。在本项目的第一个目标中，将研究共聚和交联参数对新型聚己内酯富马酸酯(PCLF)大分子单体自交联和降解特性的影响，以消除注射体系中交联剂的使用。第二个目的是将羟基磷灰石纳米颗粒与甲基丙烯酰氧基二甲基氯硅烷接枝，通过接枝的碳-碳双键与PCLF基质中富马酸基的碳-碳双键反应，使颗粒相与基质共价键合。这一目标是为了提高复合材料的扭转和弯曲强度。第三个目的是用明胶或富马酸聚乙二醇酯水凝胶微球代替食盐作为致孔剂，以改善注射制剂的流变性。第四个目的是将该复合材料作为重组人骨形态发生蛋白-2(rhBMP-2)的载体，考察复合材料的组成和载药量对其释放动力学和生物活性的影响。

DESCRIPTION (provided by applicant): Many clinical situations, such as spinal arthodesis, total joint arthroplasty, osteoprotic insufficiency fractures, and bone loss after skeletal trauma, may be addressed by biodegradable scaffolds that can be injected and crosslinked in situ. For injectable biodegradable materials for bone tissue engineering, design parameters include biocompatibility, viscosity, gelation time, setting time, mechanical properties in compression, torsion, and bending, and promotion of tissue formation. For minimally invasive applications, injectable systems that can be crosslinked in situ by chemical redox initiation, can promote tissue growth, and have improved torsional and bending strength are required. Recently developed injectable materials use crosslinking agents that can affect the biocompatibility of the injectable system. We hypothesized that 1) if fumaryl chloride, which contains carbon-carbon double bonds for in situ crosslinking, is copolymerized with a biocompatible macromer that has a flexible backbone such as poly(caprolactone), the copolymer may self-crosslink in the absence of a crosslinking agent; 2) covalent bonding of hydroxyapatite filler to the polymer matrix would significantly improve the torsional and bending strength of the injectable system; 3) the use of hydrogel microspheres in place of salt as porogen would significantly improve the rheological properties of the material before injection; and 4) controlled delivery of growth factors would promote tissue formation in situ. Therefore, we propose to address the issues of self-crosslinking, injectability, and covalent bonding of hydroxyapatite to the polymer scaffold. In the first aim of this project, the effect of copolymerization and crosslinking parameters on self-crosslinking and degradation characteristics of a novel poly(epsilon-caprolactone fumarate) (PCLF) macromer will be investigated to eliminate the use of a crosslinking agent in injectable systems. In the second aim, hydroxyapatite nanoparticles will be grafted with methacryloxydimethylchlorosilane to covalently bond the particulate phase to the matrix by reacting the carbon-carbon double bonds of the graft with those of the fumarate groups in the PCLF matrix. The goal of this aim is to improve the torsional and bending strengths of the composite. In the third aim, gelatin or olio(poly(ethylene glycol) fumarate) hydrogel microspheres will be used as porogen in place of salt to improve the rheological properties of the injectable formulation. In the fourth aim, the composite material will serve as a carrier for recombinant human bone morphogenic protein-2 (rhBMP-2), and the effects of composite composition and loading on release kinetics and bioactivity of rhBMP-2 will be determined.