Pericapsular fibrosis of encapsulated pancreatic islets has remained a major roadblock to the clinical translation of islet therapy to treat type 1 diabete (T1D). Although there have been tremendous research efforts to design new super-biocompatible materials, no truly anti-fibrotic encapsulation material exists. Building polymeric drug delivery systems into existing cell encapsulation materials could delay the fibrotic response and promote stable vascular access to maintain islet cell viability after the maturation of pericapsular tissue. We propose to use polymer science and drug delivery technologies to improve the efficacy of transplanted islets. We hypothesize that the orchestrated, spatiotemporal release of specific cytokines, angiogenic proteins, and anti-inflammatory molecules at the microcapsule-host interface could be used to promote the growth of a stable perivascular network which could in turn, circumvent the deleterious effects of downstream pericapsular fibrosis. Our goal is to engineer spatially distinct hydrogel microcapsules that can simultaneously prevent fibrosis and enhance vascular access. As part of our research plan, we will first determine how to design polymeric delivery systems for the localized delivery of putative therapeutics. Subsequent release kinetics, bioactivity, and material properties will be analyzed to determine optimal loading formulations. Drug delivery systems will then be co-encapsulated within cell-laden microcapsules and evaluated in vitro prior to in vivo studies.
Our specific aims are:
Aim 1. To fabricate and characterize controlled release systems capable of delivering active interleukin 4 (IL-4), vascular endothelial growth factor (VEGF), and dexamethasone at biologically relevant rates. Formulation parameters will be varied to achieve target therapeutic concentrations. Bioactivity of release moieties will be evaluated using the appropriate in vitro cell culture systems.
Aim 2. To develop methods for the co-encapsulation of polymeric delivery systems and islet cells within multi-layered hydrogel matrices. Hydrogel microcapsules will be fabricated using modified electro-jetting methods developed in our laboratory and drug-laden release kinetics will be characterized prior to co-encapsulation with islets.
Aim 3. To evaluate the therapeutic potential of engineered capsules in vivo. Engineered capsules will first be evaluated in a subcutaneous model to access the ability to recruit stable vasculature. Formulations will then be implanted into the intraperitoneal cavity of streptozotocin (STZ)-induced diabetic C57/BL/6 mice to evaluate ability of drug-eluting cell-laden capsules to achieve a long-term cure (>6 months).
Type 1 diabetes (T1D) has a prevalence of 3 million Americans and accounts for $14.9 billion in healthcare costs in the United States alone. The results of this work will lead to significant progress towards designing a bio-artificial pancreas, thus improving the quality of life for many people.
