Chris and Lorraine Stiehl have committed to raise funds to name an entire Research Grant titled the Stiehl Legacy Project. Chris is a survivor of type 1 diabetes. At age 10, his physician said he wouldn’t make it to 50. At 70, he has beaten the odds. Why? Because of the advances being made in diabetes research!

PROJECT DESCRIPTION

Novel engraftment strategies for a bioengineered pancreas in the treatment of Type 1 Diabetes

Beta-cell replacement therapy restores normal glucose homeostasis by replenishing the lost beta cells through transplantation in the treatment of patients suffering from Type 1 Diabetes. Although this therapy can restore normoglycemia without ongoing insulin supplementation in preclinical models, much development and translational work are yet to be done before the full potential of this therapy can be realized.

Some of the most formidable challenges include (a) the acute shortage of donor islets which limit the treatment to only a few patients with the most severe diabetes, (b) the need for lifelong immunosuppression, and (c) graft failures due to deprivation of essential nutrients, ischemia caused by lack of oxygen, and immune-mediated rejection. Researchers are exploring novel strategies to address these challenges, such as using more readily available cell sources (e.g., xenogeneic islets, stem cell-derived beta cells) and developing immunoprotective cell-encapsulation platforms.

While encapsulation devices can be beneficial in diminishing an immune attack, these devices create a formidable barrier for the vasculature to reach beta cells, leading to nutrient starvation and ischemia, which can impair long term physiologic performance and lead to consequential loss of the graft. Patients lose nearly 70-80% of the graft in the first week of implantation.

My research is focused on developing a bioengineered pancreas that incorporates novel engraftment strategies which can (a) promote vascularization around beta cells and minimize ischemic injury, and (b) create a local immune protective zone by increasing immune tolerance for the graft to preserve the beta-cell mass and long-term normal physiologic performance. Renewable sources of beta cells (derived from human stem cells) from our collaborators will be used to address the acute shortage of donor islet.

Our proposed encapsulation strategies present a biomimetic spatial arrangement for transplanted islets and facilitate a more homogenous distribution of nutrients and oxygen while preventing the accumulation of metabolic waste. The approach allows for direct contact with blood vessels by allowing the ingrowth of new vasculature. The local release of essential amino acids and resident oxygen generation further aids the survival and functional maintenance of the graft. The local delivery of immunomodulatory drugs as part of our engraftment strategies will help to mitigate the risk of immune attack by creating a local protective zone around the islet grafts. Thus, our novel engraftment strategies for this bioengineered pancreas ensures long-term graft survival and preserves functional performance.

The anticipated outcome of our research would lead to a significant leap toward clinical translation of the beta cell replacement therapy for patients suffering primarily from autoimmune T1D diabetes.