BME PhD Dissertation Defense: Anish Vasan

Title: "ECM DYSFUNCTION IN TISSUE REPAIR: A 3D MICROTISSUE APPROACH TO SENESCENCE"

Advisory Committee: Jeroen Eyckmans, PhD – BME (Research Advisor) Wilson Wong, PhD – BME (Chair) Andrés J. García, Ph.D. – MechE, BE (Georgia Tech) Christopher Chen, M.D., Ph.D. – BME, MSE Daniel S Roh, M.D., PhD – BMC

Abstract: Skin wound healing requires fibroblasts to migrate into the wound site, generate contractile forces, and assemble new extracellular matrix (ECM). When these processes fail, as in chronic wounds associated with aging and diabetes, tissue integrity is not restored. This dissertation investigates the fibroblast-ECM axis of wound closure, with the central argument that tissue integrity and mechanics due to differences in the ECM is a governing, and under-targeted, variable in tissue repair. In this dissertation, we developed a scalable, 96-well 3D microtissue platform integrated with an automated analysis pipeline, WoundCompute. Using this platform, we find that tissue gap closure and the mechanical tissue parameters of contractile force, and compaction are weakly correlated rather than intrinsically coupled outputs. We then used this platform to demonstrate that senescent ECM impairs wound closure independent of the continued presence of senescent cells, and that targeted restoration of collagen type I (COL1A1) is sufficient to rescue repair in vitro. Together, this work establishes that ECM dysfunction is not merely a consequence of cellular senescence but an independent barrier to tissue repair.