Committee:
Andrés J. García, Ph.D. (Georgia Institute of Technology) – Chair
Thomas Barker, Ph.D. (Georgia Institute of Technology)
Edward A. Botchwey, Ph.D. (Georgia Institute of Technology)
Robert E. Guldberg, Ph.D. (Georgia Institute of Technology)
Todd C. McDevitt, Ph.D. (Georgia Institute of Technology)

Cell-based strategies have emerged as promising therapies for the treatment of diseased organs. Adult human mesenchymal stem cells (hMSC) constitute a critical component of the hematopoietic stem cell niche in the bone marrow, and although hMSCs have shown promising results in clinical trials for bone repair, inadequate control of cell fate and cell engraftment in host tissues limits the success of this cell-based therapy. Integrin-mediated cell adhesion plays a central role in tissue formation, maintenance, and repair by providing anchorage forces and triggering signals that regulate cell function. I hypothesize that biomaterials presenting integrin-specific adhesive peptides will direct hMSC signaling and specification. My objective is to engineer bioartificial hydrogels presenting integrin-specific ligands to create biomimetic niches for hMSC differentiation as well as injectable cell delivery vehicles for enhanced in vivo engraftment and function.

Three ligands will be used to examine the role of integrin specificity on hMSC differentiation: RGD for αVβ3 integrin, recombinant fibronectin FNIII7-10 for α5β1 integrin, and collagen-mimetic GFOGER peptide for α2β1 integrin. To incorporate these ligands and protease-degradable crosslinks, Michael addition chemistry will be utilized in a four-arm 20 kDa polyethylene glycol-maleimide (PEG-mal) system in which ligands and peptides are functionalized with cysteine residues. Using hydrogels presenting pro-osteogenic ligands and protease-degradable sites, hMSCs will be delivered to a non-healing segmental defect in the radii of immunodeficient mice. Bone formation and repair will be fully characterized by immunohistochemistry, micro-CT, and mechanical testing. The survival, engraftment, and differentiation of hMSCs transplanted in my hydrogels within into the defect will be monitored using a dual luciferase reporter system. This system reduces the number of animals, animal-to-animal variability, and permits direct correlations between hydrogel formulations, transplanted or differentiated cell numbers, and bone repair. The integration of innovative in vivo imaging approaches with my engineered hydrogels will generate new insights into transplanted hMSC survival, engraftment and function in a relevant non-healing bone repair model and allow for direct correlations among hydrogel formulation, transplanted cell numbers and differentiation, and bone repair outcomes.