Examination of Microvascular Remodeling to Enhance Autologous Fat Grafting

There exists a clinical need for repairing soft tissue defects resulting from pathological conditions, trauma, congenital disorders, and post-operative cancer resections. Autologous fat has been regarded as an appealing tissue for these surgeries due to its innate biocompatibility, high degree of vascularity, and low risk for immune rejection. Indeed, autologous fat grafting in plastic and reconstructive surgery is increasing and typically manifests in two different practices/scenarios: (i.) fat grafting, which typically involves non-surgical injection of micro-volumes of fat, and (ii.) flap transfer, which involves surgical composite tissue transfer of macro-volumes of fat, muscle, and often skin. Despite the popularity of using autologous fat in reconstructive surgery, graft survival and long-term volume retention is highly variable and unpredictable. Further, resorption rates of grafted fat ranges from 25-80% strengthening the need for investigation into fat graft survival. This resorption process is poorly understood and the underlying mechanism(s) responsible for long-term volume retention of fat grafts remains to be elucidated. I submit that fat engraftment and resorption are dynamic processes resulting from the intersection of key mechanisms, including adipocyte adaptations, vascular remodeling, and inflammation. Using a comprehensive and integrative strategy, my dissertation evaluates these three mechanisms in culture systems and in different murine models. I develop and employ novel imaging strategies, transgenic mice, and analysis metrics, with the ultimate goal of designing therapeutic interventions for enhancing adipose tissue regeneration and graft survival. Toward this end, my research makes four key contributions: (i) determining how vascular network remodeling in flaps (macro-grafts) and fat grafts (micro-grafts) both affect and are affected by perfusion and inflammation, (ii) identifying macrophages as a novel drug target and evaluating a new pharmacological treatment for improving long-term survival of fat grafts, (iii) evaluating and optimizing enzymatic digestion and stromal vascular fraction enhancement for micro-graft volume retention and adipocyte viability, and (iv) validating a novel imaging approach for monitoring oxygen perfusion in tissues. Together, my insights and innovations substantially advance the nascent field of adipose tissue engineering and motivate new tools and approaches that could have significant clinical impact.