All ETDs from UAB

Advisory Committee Chair

Susan L Bellis

Advisory Committee Members

Nicolaas C Geurs

Mia L Geisinger

Amjad Javed

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Bone grafting procedures are common practice. Autogenous bone is considered optimal, however, complications associated with bone harvesting often lead clinicians to use off-the-shelf materials that have limited osteoinductivity. Alternatively, bioactive factors passively adsorbed onto various carriers are available. These materials, while effective, are expensive to produce, require supraphysiological doses, and have adverse side effects due to dissemination from the graft site. This dissertation aims to reintroduce osteoinductive factors to bone grafts to enhance regenerative capacity. Specifically, we utilized negatively-charged calcium-binding domains (polyglutamate) to anchor two osteoinductive peptides bone graft materials including an allograft, xenograft, alloplast, and bone cement. The peptides utilized were: 1) DGEA (collagen-mimetic peptide) and 2) BMP2pep (BMP2-derived peptide). When these peptides were modified with heptaglutamate (E7) we observed greater loading and retention in vitro and peptides were retained for 2 months in vivo. We also evaluated the effect of varying the number of glutamates to achieve tapered release kinetics. We found greater peptide loading and slower release with increased number of glutamates. This release effect was seen on four distinct graft materials demonstrating the versatility of the technology as a potential tool to deliver other bioactive molecules that would benefit from controlled release. The osteoinductive potential of E7-peptides was then evaluated utilizing two in vivo models. First, in a subcutaneous pouch model, comparable amounts of ectopic bone were observed when E7BMP2pep or recombinant Bone Morphogenetic Protein-2 (rBMP2) was utilized. These 2 groups formed significantly more bone than all other peptides and uncoated graft. Second, a critical-size defect in the mandible was used. PET/CT imaging showed at 8-weeks E7BMP2pep induced significantly more radioisotope resorption than all other groups including rBMP2. At 12-weeks comparable new bone growth was observed histologically when E7BMP2pep and rBMP2 were utilized. However, the rBMP2 group had more adipogenesis than all other groups. Importantly, the rBMP2 group had more side effects than other groups. Taken together, our data show that E7BMP2pep is easy and cost-effective to produce. It significantly improved regenerative potential without the high cost, inflammation, ectopic bone formation, or other deleterious effects of passively absorbed products that disseminate from the graft site.

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