Project Summary/Abstract Type 1 diabetes mellitus is an autoimmune disorder in which the patient’s pancreatic islets are destroyed by their own immune system, leaving them unable to produce insulin to manage their blood glucose levels. Currently, this disease affects about 1.6 million people in the United States and roughly 180 new patients are diagnosed each day. Clinical islet transplantation is a potential solution that involves injecting donor islets into the patient’s liver to secrete insulin and regain blood glucose control. A challenge of this therapy, however, is decreased islet viability due to mechanical stress and adverse inflammation at the infusion site. The utilization of islet encapsulation or islet-loaded porous scaffolds can provide a means to protect islets from these stresses; however, encapsulation can result in insufficient engraftment and incomplete immunosuppression, while traditional scaffold fabrication methods generate inconsistent pores and rough surfaces that can lead to unfavorable and unpredictable host responses to the implant. To address these challenges, this proposal seeks to develop a multi-functional biomaterial scaffold that improves the vascularization, engraftment, and immunoprotection of transplanted pancreatic islets for the treatment of Type 1 diabetes mellitus. In Aim 1, we will alter scaffold porosity and rung thickness to identify the specific geometric features that will result in robust host engraftment with minimal fibrosis. For Aim 2, we will incorporate depots of synergistic immunosuppressants into the 3D-printed scaffold material for controlled local drug delivery. We will characterize the kinetic release curves of the drug eluting scaffold in vitro and optimize the drug loading parameters necessary for sufficient local immune protection. Islet-loaded, therapeutic scaffolds should provide local drug release resulting in the suppression of adverse immune reactions in an allograft rat transplant model, preventing rejection of the cell cargo. Broadly, results from this work will provide a better understanding of the roles that scaffold geometry and local therapeutic release play in cell-based therapies, while improving experimental outcomes in islet transplantation.