Improved Survival of Pancreatic Islets through Delivery of Alanine from Pegdma Microparticles

Authors: 
Long, A., University of California, Berkeley
Desai, T., University of California, San Francisco
Type 1 diabetes is an autoimmune disease characterized by the selective destruction of insulin producing β-cells within the pancreas. The disease has no established cure, with typical treatments ranging from insulin therapy to whole pancreas and islet transplantation. Cell replacement therapy through transplantation of islets or stem cell-derived β-cells can facilitate complete insulin independence, and is thus a promising treatment for type 1 diabetes. However, protecting these cells from the body’s inflammatory response represents a formidable challenge to the success of the transplantation process. Recent studies have shown that amino acid supplementation promotes islet survival in high-density cultures that mimic the hostile transplant environment. Thus, a biocompatible, injectable nutrient delivery system may hold the key to in vivo islet longevity during the post-transplantation period. In this work, we present two therapies engineered to satisfy the role of nutrient supplementation in islet survival. First, photolithography was used to generate poly(ethylene glycol) dimethacrylate (PEGDMA) hydrogel microparticles that are loaded with alanine. The release profile of alanine from these microstructures was optimized by changing microparticle cross-linking densities and amino acid concentrations. Our data suggest that 20% PEGDMA microparticles with a 600 mM loading concentration of alanine are effective in preventing islet death. Second, PEGDMA microparticles and beta cells were functionalized with complementary DNA strands to promote cell adhesion and nutrient delivery. Efficient targeting of fatty-acid modified oligonucleotides to β-cell membranes was achieved through stepwise assembly, and cell-particle adhesion was examined. Both of these therapies satisfy the role of nutrient supplementation in islet survival and can enhance the therapeutic benefits of islet transplantation as a treatment for type 1 diabetes.