Current bone grafting materials such as allograft and alloplast have limited osteoinductivity. The proposed research aims to reintroduce bone-healing factors to these materials to improve bone regeneration. Our group has identified a polyglutamate domain that can be added to growth factor mimetic peptides to control the binding and release of the peptides from calcium-containing bone grafting materials. In the proposed research, we will use variable-length polyglutamate domains (E2, E4, & E7) to create a gradient release of the proangiogenic QK peptide (angiogenic signaling domain of VEGF) known as PGM-QK from bone grafts. We hypothesize that the controlled release of PGM-QK will increase vascularization within the implant site, thereby improving bone regeneration. In addition to PGM-QK peptide delivery, we will investigate the co-delivery of PGM-QK with the osteogenic peptide, E7-BMP2pep. In previous studies, E7-BMP2pep delivered on grafting material was able to localize within the injury site and induce an osteogenic response comparable to rBMP-2, without any deleterious side effects. We propose that co-delivery of these two therapeutics on bone grafts will greatly enhance new bone synthesis. In this proposal, there are two major objectives: (1) develop a gradient release of PGM-QK from bone grafts to induce angiogenesis, and (2) co-deliver PGM-QK and E7-BMP2pep on bone grafting materials to accelerate bone regeneration.
AIM 1 : Use of PGM-QK peptides to stimulate angiogenic endothelial cell behavior.
Aim 1 will develop a gradient release of PGM-QK from bone grafting materials to elicit proangiogenic endothelial cell responses including migration and tubule formation. As well, graft materials with PGM-QK will be evaluated for angiogenic potential using the chorioallantoic membrane assay. We postulate that controlled release of PGM- QK peptide from grafting materials will elicit greater neovascularization compared with rVEGF and QK peptide.
AIM 2 : Co-delivery of PGM-QK and E7-BMP2pep peptides to stimulate bone regeneration. Bone grafts treated with PGM-QK will be implanted into subcutaneous pouches to evaluate vascularization from gradient release of PGM-QK. In addition, bone grafts coated with both PGM-QK and E7-BMP2pep will be implanted into cranial defects to determine whether increased vascularization mediated by PGM-QK improves osteogenesis. Excised tissue will be evaluated for angiogenesis, new bone formation, immune and foreign body response, and fibrosis. We hypothesize that the osteogenic potency of E7-BMP2pep in conjunction with the increased vessel network formed in response to PGM-QK peptide will greatly accelerate bone regeneration mediated by bone grafting materials.
Current bone grafting materials used in craniofacial, orthopedic, and dental applications lack the necessary growth and signaling factors necessary for proper bone repair. Several researchers have sought to reintroduce these factors onto bone graft materials with limited success. This proposed research will introduce a novel method of delivering/releasing bone promoting factors on implanted commercial bone grafts within the injury site to enhance bone regeneration.
