All ETDs from UAB

Advisory Committee Chair

Susan L Bellis

Advisory Committee Members

Michael S Reddy

Sasanka Ramanadham

Alan W Eberhardt

Palaniappan Sethu

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) School of Engineering

Abstract

Over 2 million bone grafting procedures are performed annually. To meet the high demand for these surgeries, commercial grafting materials sourced from allograft, xenograft, and synthetic calcium phosphate have become widely popular clinically. One limitation of these grafts, however, is their lack of growth factors that drive angiogenesis during bone tissue regeneration. Insufficient revascularization of the injured bone tissue leads to poor fracture healing. However, reincorporating angiogenic factors on grafting materials has proven challenging due to limited surface interactions between the protein and mineral graft surface. To address this challenge, we have synthesized a polyglutamate domain to the VEGF mimetic peptide, QK, in order to reliably deliver angiogenic factors on mineralized graft material. Polyglutamate domains anchor strongly through ionic interactions to the hydroxyapatite present within mineral graft materials. In this work, we have shown that a heptaglutamate (E7) domain synthesized to the QK peptide (E7-QK) greatly enriched the concentration (4-6 fold) of peptide coated onto graft materials. Moreover, enrichment of E7-QK on graft material led to enhanced activation of endothelial cells in direct contact with the scaffold over grafts coated with unmodified QK peptide. Furthermore, we have devised a method to deliver an angiogenic gradient of polyglutamate modified QK peptides. The length of polyglutamate domain on the peptide directly correlates to the time of release of the peptide from the graft material. We combined a mixture of varied lengths of polyglutamate domains (E2, E4, E7) to the QK peptide (PGM-QK) to create a constant release gradient from mineral graft material. In this study, we characterized the release kinetics of each individual component of PGM-QK (E2-QK, E4-QK, and E7-QK) and found the longer the domain length, the longer the retention of the peptide on the graft material. Additionally, we showed that PGM-QK released from graft material provided an extended angiogenic stimulus. Endothelial cells treated with PGM-QK peptides released from graft material over the course of 6 days exhibited activation of angiogenic signaling pathways and enhanced migration. These results demonstrate the utility of polyglutamate domains to deliver a constant stimulus of bone healing factor from commercial graft material.

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