Michelle Javier Quizon


BioE Ph.D. Defense Presentation

Monday, June 17, 2024

10:00 AM

Location: EBB CHOA Seminar Room

Zoom Link: https://gatech.zoom.us/j/96301545149?pwd=RXR6TGxaRzJFOXdkdkU1Y1ZYcVlaQT09  


Andrés García, Ph.D. (Advisor) (School of Mechanical Engineering, Georgia Institute of Technology)

Edward Botchwey, Ph.D. (Department of Biomedical Engineering, Georgia Institute of Technology and Emory University)

Rebecca Levit, M.D. (School of Medicine, Emory University)

Edward Phelps, Ph.D. (Department of Biomedical Engineering, University of Florida)

Krish Roy, Ph.D. (Department of Biomedical Engineering, Vanderbilt University)


Synthetic hydrogels for islet vascularization and engraftment in the subcutaneous space

Type 1 diabetes (T1D) is a chronic, debilitating disease characterized by the autoimmune destruction of insulin-producing beta cells within pancreatic islets. The gold standard for T1D cell therapy is clinical islet transplantation (CIT), the infusion of islets through the hepatic portal vein. While CIT recipients demonstrate enhanced blood glucose control, the procedure is limited to a marginal subset of T1D patients due to 1) the lack of donor islets and 2) the absolute immunosuppression required to overcome the inhospitable nature of the intrahepatic site. Indeed, an expected >60% loss of islets is expected within three days following transplantation. Thus, there is a significant need to establish an alternative extrahepatic transplant site that supports islet engraftment.

The subcutaneous space is an attractive extrahepatic transplant site for T1D cell therapy given its high clinical potential in terms of surgical accessibility, ease of monitoring, and convenience for replenishment and/or retrieval of therapeutic cargo. However, the unmodified subcutaneous space lacks the necessary vascularization to preserve islets. An elegant, facile strategy to promote vascularization is the biomaterial-mediated delivery of proangiogenic factors such as vascular endothelial growth factor (VEGF). The objective of my project was to engineer VEGF-delivering synthetic poly(ethylene glycol) hydrogels (VEGF-PEG) that promoted islet vascularization, engraftment, and function in the subcutaneous space. My central hypothesis was that VEGF-PEG can be tuned to do so. 

To test my hypothesis, I completed three specific aims. In Aim 1, I employed an in vitro co-culture of rat islets, human umbilical vein endothelial cells, and human mesenchymal stromal cells to screen key hydrogel parameters – namely, polymer density, tethered VEGF concentration, and adhesive peptide type – for endothelial cell network formation and islet-network interactions. In Aim 2, I demonstrated that my engineered VEGF-PEG platform supported rat islet survival, engraftment, and function upon subcutaneous delivery in immunocompromised, diabetic mice. Importantly, VEGF-PEG achieved normoglycemia and maintained islet graft function in diabetic mice for 12 weeks, aligning in performance to a leading natural biomaterial platform (islet viability matrix).  In Aim 3, I established a large animal model to evaluate the vasculogenic capabilities of engineered biomaterials. In healthy, nondiabetic Yucatan miniature pigs (n = 5), I demonstrated that a VEGF-PEG coating induced vascularization and local perfusion in the porcine subcutaneous space without detrimental health effects. I then successfully delivered neonatal Yorkshire pig islets in VEGF-PEG to an immunosuppressed, nondiabetic Yucatan miniature pig.

My work has resulted in an optimized synthetic hydrogel for islet vascularization, engraftment, and function in the subcutaneous space. My three-pronged, multi-model approach (in vitro co-culture of cells - in vivo studies in rodents - in vivo studies in pigs)  has provided a novel, logically translational strategy to engineer vasculogenic materials. This work provides a foundation for future studies in a translational, diabetic large animal model – recapitulating the human subcutaneous space more so than preclinical rodent models that comprise majority of the field.