SUBJECT: Ph.D. Proposal Presentation
BY: Jose Garcia
TIME: Monday, December 14, 2015, 11:00 a.m.
TITLE: Vascularization of Constructs for Improved Survival of Human Mesenchymal Stem Cells for Bone Repair
COMMITTEE: Dr. Andres J. Garcia, Ph.D., Chair (ME)
Dr. Edward Botchwey, Ph.D. (BME)
Dr. Robert Guldberg, Ph.D. (ME)
Dr. W. Robert Taylor, M.D., Ph.D. (Emory)
Dr. Alberto Fernandez-Nieves, Ph.D. (Physics)


Repair of non-healing bone defects through tissue engineering strategies remains a challenging feat in the clinic due to the aversive microenvironment surrounding the injured tissue. The vascular damage that occurs following a bone injury causes extreme ischemia and a loss of circulating cells that contribute to regeneration. Tissue engineered constructs aimed at regenerating the injured bone suffer from complications based on the slow progression of endogenous vascular repair and often fail at bridging the bone defect. Furthermore, stem cell-based strategies aimed at regenerating the critical-size defect routinely demonstrate subpar performance due to the extreme ischemic environment causing massive loss of implanted cell viability. To that end, various strategies have been explored to increase blood vessel regeneration within defects to facilitate both tissue engineered and natural repair processes.

This project aims to engineer biomaterials that understand and accelerate the vascularization of critical-size defects for the purposes of enhanced bone regeneration and heightened implanted stem-cell survival. We have engineered polyethylene-glycol (PEG)-based hydrogels that can be functionalized with differing cell adhesive ligands and proteins through a facile Michael-addition reaction between a maleimide moiety on the PEG macromer and a free thiol on the biological molecule. These protease-degradable hydrogels have been previously shown to have the ability to incorporate vascular endothelial growth factor (VEGF) for enhanced vascularization when implanted subcutaneously in mice. We propose to utilize this platform to investigate how integrin-specificity affects vascularization within critical-size defects and how incorporation of VEGF or small molecules to increase expression of hypxoxia inducible factor 1-alpha work in conjunction with integrin-specificity to promote vascularization. Our hypothesis is that integrin-specificity plays a role in vascularization of tissue engineered constructs. By exploiting the role integrins play in vascularization, the efficacy of other strategies such as protein or small molecule delivery can be enhanced and vasculogenesis increased. The significance of this work is the development of synthetic biomaterials that allow for increased stem cell survival and enhance the efficacy of stem cell-mediated therapies.