Engineering Modular Oxygen-generating, Pro-vasculogenic Biomaterial Platforms for Cell-Based Therapies

项目总结/文摘

PROJECT SUMMARY/ABSTRACT In this proposal, we aim to develop two distinct biomaterial systems for improving nutrient and oxygen availability within cell-based clinical islet transplantation (CIT) platforms for the treatment of type 1 diabetes mellitus (T1DM). The motivation for this work is the lack of durable systems for oxygen supplementation of transplanted, insulin-producing cells, as well as the limited optimization of scaffolds for facilitating competent and complete implant vascularization. T1DM affects over 1.25 million Americans and is expected to quadruple by 2050. Previous attempts to treat T1DM through the transplantation of islets is limited due to hypoxic conditions and delayed graft vascularization. Published and preliminary data from our laboratory has demonstrated that the inclusion of a biocompatible, oxygen-generating composite material, termed OxySite, alongside transplanted insulin-producing cells can lead to prolonged cell survival and insulin production post-transplantation. By delivering local oxygen immediately post-transplantation, this approach should bridge the gap between initial transplant and the establishment of competent vascularization. Herein, we seek to manipulate the geometry and material properties of the original OxySite prototypes to enhance geometric flexibility and oxygen kinetic control. In addition, it is recognized that traditional vascularization techniques fail to provide timely support for cells at the site of transplant due to the prolonged process for endogenous cell infiltration and organization into cell-based grafts. Herein, we seek to identify an optimal geometry for guiding vascularization. Overall, we hypothesize that through engineering a modular oxygen-generating microbead platform to fit multiple transplant sites and release requirements, in conjunction with a flexible scaffolding that utilizes geometry and pore size to accelerate the process of vascularization, transplanted cells can be supported at all time periods post transplantation. Fabrication and implementation of these two platforms would provide a significant improvement to CIT applications, as well as other cell-based therapies. Furthermore, we anticipate they will also give valuable insight into the design of materials for controlled therapeutic release and into the mechanisms of vascularization. Our laboratory has previously used biomaterials to not only improve CIT platforms but also reveal crucial relationships involved in cell engraftment and long-term function. The techniques outlined in these previous studies will serve as a starting point for the proposed work. In Aim 1, we will explore whether generating porosity, modulating OxySite material formulation, and applying a rate limiting polymer can permit fabrication of a modular, oxygen- generation platform. We will further characterize this new platform utilizing a model islet transplantation platform. For Aim 2, we will design and fabricate a flexible, scaffolding using 3D printing to allow for configurable pore size and geometry. We will use an in vitro pre-vascularization method for rapid testing of varying pore sizes for optimal vasculature formation before proceeding to a subcutaneous biocompatibility model.