Injectable Osteoinductive Biodegradable Composites

描述（由申请人提供）：许多临床情况，如脊柱关节固定术、全关节置换术、骨不全性骨折和骨骼创伤后骨丢失，可以通过可原位注射和交联的生物可降解支架来解决。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、凝固时间、压缩、扭转和弯曲的机械性能以及促进组织形成。对于微创应用，需要可通过化学氧化还原引发原位交联、可促进组织生长并具有改善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可影响可注射系统的生物相容性的交联剂。我们假设：1）如果富马酰氯，其中含有碳-碳双键的原位交联，与具有柔性骨架的生物相容性大分子单体共聚，如聚2）羟基磷灰石填料与聚合物基质的共价键合将显著改善可注射系统的扭转和弯曲强度; 3）使用水凝胶微球代替盐作为致孔剂将显著改善注射前材料的流变性质;和4）生长因子的受控递送将促进原位组织形成。因此，我们建议解决的问题，自交联，可注射性，羟基磷灰石的聚合物支架和共价键合。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（ε-己内酯富马酸酯）（PCLF）大分子单体的自交联和降解特性的影响，以消除在注射系统中使用交联剂。在第二个目标中，羟基磷灰石纳米颗粒将与甲基丙烯酰氧基二甲基氯硅烷接枝，以通过接枝物的碳-碳双键与PCLF基质中的富马酸酯基团的碳-碳双键反应将颗粒相共价键合到基质上。该目的的目标是提高复合材料的扭转和弯曲强度。在第三个目的中，明胶或油（聚（乙二醇）富马酸酯）水凝胶微球将代替盐用作致孔剂以改善可注射制剂的流变学性质。第四个目标是将复合材料作为重组人骨形态发生蛋白-2（rhBMP-2）的载体，并确定复合材料的组成和负载量对rhBMP-2的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.