Injectable Osteoinductive Biodegradable Composites

描述（由申请人提供）：许多临床情况，如脊柱固定术、全关节置换术、骨质增生性不全骨折和骨骼创伤后的骨质流失，可以通过可注射和原位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、凝胶时间、凝固时间、压缩、扭转和弯曲力学性能以及促进组织形成。对于微创应用，注射系统可以通过化学氧化还原引发原位交联，可以促进组织生长，并提高扭转和弯曲强度。最近开发的注射材料使用的交联剂会影响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）与具有柔性骨架（如聚己内酯）的生物相容性大分子共聚，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体的共价键能显著提高注射体系的扭转和弯曲强度；3)用水凝胶微球代替盐作为孔隙剂，可显著改善注射前材料的流变性能；4)生长因子的控制递送可促进原位组织形成。因此，我们建议解决羟基磷灰石与聚合物支架的自交联、可注射性和共价键问题。该项目的第一个目的是研究共聚和交联参数对新型聚富马酸己内酯（PCLF）大分子自交联和降解特性的影响，以消除注射系统中交联剂的使用。在第二个目标中，羟基磷灰石纳米颗粒将与甲基丙烯氧基二甲基氯硅烷接枝，通过接枝的碳-碳双键与PCLF基质中的富马酸基团的双键反应，将颗粒相与基体共价结合。目的是提高复合材料的抗扭和抗弯强度。在第三个目标中，明胶或olio（聚（乙二醇）富马酸酯）水凝胶微球将被用作孔隙剂来代替盐，以改善可注射制剂的流变特性。在第四个目标中，复合材料将作为重组人骨形态发生蛋白-2 （rhBMP-2）的载体，研究复合材料的组成和负载对rhBMP-2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.