All ETDs from UAB

Advisory Committee Chair

Susan L Bellis

Advisory Committee Members

Kathleen Berecek

Ho-Wook Jun

Dennis Kucik

Joseph Messina

Document Type

Dissertation

Date of Award

2008

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Hydroxyapatite (HA) coatings of hard tissue implants have been shown to increase osseointegration, but the mechanisms by which HA improves implant integration are not well understood. Numerous studies have shown that modifying HA with adhesive peptides, including RGD, and the collagen I mimetics, DGEA and P15, stimulates the adhesion of mesenchymal stem cells (MSCs), a cell type that differentiates along the osteoblast lineage. However, HA is a highly adsorptive biomaterial, and therefore it is unlikely that cells at the implant site would ever encounter a peptidemodified HA surface in the absence of an adsorbed protein layer. In fact, our laboratory hypothesizes that the ability of HA to rapidly adsorb proadhesive proteins such as fibronectin and vitronectin from blood plays a key role in promoting MSC attachment. To better understand the role of adsorbed proteins in regulating MSC behavior, cell adhesion was evaluated on peptide-modified HA disks that were either overcoated with serum or implanted briefly into rat tibiae to allow deposition of native adhesive proteins. Surprisingly, these studies indicated that RGD inhibited MSC adhesion. Conversely, collagen mimetics were not inhibitory, although they did not enhance cell adhesion either. We hypothesize that RGD peptides, but not collagen mimetics, compete with adsorbed adhesive proteins for binding to cell surface integrins, given that blood adhesive proteins bind through an RGD-dependent mechanism. Interestingly, although collagen mimetics did not improve cell adhesion, they did increase osteoblastic differentiation, iii presumably due to activation of collagen-selective integrins that are known to stimulate MSC differentiation along the osteoblast lineage. Importantly, our in vitro studies of the effects of adhesive peptides, when presented in combination with adsorbed blood proteins, were very predictive of the effects of these peptides on bone repair. RGD peptides inhibited, while collagen I mimetics enhanced, bone formation and bone-implant contact on HA disks implanted into rat tibiae. In sum, our collective studies highlight a potential role for collagen mimetic peptides in enhancing the performance of HA biomaterials, and further suggest that in vitro studies incorporating a protein modeling step provide a reliable indicator of the efficacy of biomimetic peptides in promoting implant osseointegration.

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