Advisor:

Andrés García, PhD (Georgia Institute of Technology)

Committee Members:

Edward Botchwey, PhD (Georgia Institute of Technology)

Levi Wood, PhD (Georgia Institute of Technology)

Nick Willett, PhD (University of Oregon)

Esma Yolcu, PhD (University of Missouri)

Hydrogel-delivery of mesenchymal stem cells to modulate the local immune environment and direct tissue repair

Mesenchymal stem/stromal cells (MSC) are actively being explored for use in a variety of regenerative medicine applications due to their potent immunosuppressive and anti-inflammatory properties. Traditionally, these cells have been delivered by bolus injection, but the need to prolong the survival and retention of MSC at sites of injury has spurred the development of a variety of biomaterial-based MSC delivery vehicles. Many studies have explored how biomaterial properties modulate MSC behaviors in both in vitro and in vivo contexts. However, a majority of the in vivo studies were carried out in immunocompromised mice, neglecting the key interaction of the host immune system with these biomaterial-MSC constructs. Additionally, while many properties of synthetic biomaterials are well-defined, controlling biomaterial degradation rates in in vivo environments remains a significant, therapeutic-limiting challenge. The objective of this thesis is to utilize immunocompetent mouse models to evaluate the immunomodulatory and regenerative effects of engineered biomaterial-MSC constructs. In Aim 1, I demonstrate that subcutaneous delivery of murine MSC within synthetic hydrogels in immunocompetent mice modulates the local cytokine milieu and temporal recruitment of immune cells to the hydrogel. In Aim 2, I show that, when delivered subcutaneously in a hydrogel, the fetal bovine serum used for ex vivo MSC expansion elicits a robust type 2 immune response characterized by infiltration of eosinophils and CD4+ T cells and that this immune response impairs bone repair. Finally, in Aim 3, I utilize hydrolytically degradable ester linkage groups to engineer PEG hydrogels with tunable in vivo degradation kinetics for enhanced delivery of MSC to diabetic cutaneous wounds. Overall, this work yields critical insights into MSC-immune cell interactions in vivo and highlights strategies for modulating these interactions through the use of engineered biomaterial MSC delivery vehicles.