Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by the T cell-mediated destruction of the insulin-secreting beta cells located within the pancreatic islets of Langerhans. Current treatments for T1D include daily blood glucose monitoring and exogenous insulin injections, however, the only treatment that can return endogenous insulin production is islet transplant. For this procedure, islet cells are isolated from a donor cadaver pancreas and then infused into the patient’s portal vein where they lodge in the liver and secrete insulin. However, this procedure only has a 50-70% success rate since there is substantial islet loss immediately after transplantation, which is initiated by the instant blood mediated inflammatory response and ischemic conditions in the liver. In order to facilitate successful transplant outcomes, insulin-producing cells (i.e., islets, induced pluripotent stem cell derived-beta cells, dissociated islets, etc.) must have sufficient immunoprotection from the autoimmune response, revascularization to support metabolic function, and cell clustering to maintain required paracrine signaling for cell survival. There has been interest in using biomaterials, such as hydrogels, to address these criteria for the delivery of insulin-producing cells. However, hydrogels can be susceptible to the foreign body response (FBR), which is a host immune response to foreign materials that can lead to the formation of a dense fibrous encapsulation and lack of sufficient tissue integration around the implant. When designing a hydrogel material that can serve as a platform for the delivery of insulin-producing cells, it is important to consider if the material itself will elicit a fibrotic encapsulation that would inhibit the diffusion of oxygen and nutrients to the implanted cells.
There are many strategies to reduce the FBR to hydrogel implants, such as low-fouling surface modification, release of anti-inflammatory drugs, and immunomodulatory protein conjugation. However, biomaterial porosity has been shown to have the highest impact on successful implant-tissue integration. Microporous annealed particle (MAP) scaffolds are a class of injectable, porous biomaterials composed of a slurry of microgel particles that undergo a secondary light-based crosslinking reaction which “anneals” the microgels together to form a scaffold with cell-scale porosity. Compared to nanoporous hydrogels, MAP scaffolds have been shown to promote extensive cell infiltration and revascularization with no detectable fibrous encapsulation. We believe that MAP scaffolds are favorable for clustering cells within the pores, promoting angiogenesis at the implant site, and modulating the immune response while avoiding a FBR, which addresses the criteria for the delivery of insulin-producing cells to treat T1D.
In this dissertation, we present an immunomodulatory MAP scaffold which can support the delivery of insulin-producing cells. We first characterize the host immune response to subcutaneous implants of MAP scaffolds and nanoporous (NP) hydrogels using high-dimensional analysis techniques. We then investigate the delivery of syngeneic insulin-producing cells (e.g., whole islets, dissociated islets, and a commercial beta cell line) within the pores of MAP scaffold in a mouse model of type 1 diabetes (streptozotocin-induced) to three clinically-relevant implant sites. Next, we characterize the immune response to an immunomodulatory MAP scaffold, IL33-MAP, and deliver xenogeneic insulin-producing cells within the pores of IL33-MAP scaffolds which can expand T cell populations that are beneficial for immune tolerance. Finally, we develop methods for the encapsulation of insulin-producing cells within the microgel-building blocks of MAP scaffold to offer increased immunoprotection. Overall, we believe the work outlined in this dissertation establishes a novel, immunomodulatory MAP scaffold which has high impact for clinical translation to restore endogenous insulin production in patients with T1D.
