Grant: Operating Grant

While islet transplantation is a promising treatment for the 1% of Canadians who live with insulin dependent (type 1) diabetes, the majority of islets (perhaps 60%) in current protocols are lost almost immediately upon transplantation. This is due to inflammatory responses and the lack of blood vessels near the islet which impairs islet survival and function. We have pioneered an approach ("modular tissue engineering") to create uniform, scaleable and most importantly vascularized constructs. Small collagen rods ("modules") are embedded with functional cells along with support cells derived from fat tissue and surface seeded with endothelial cells, the cells that line blood vessels. Random packing of many modules creates a construct where the gaps among modules form interconnected channels lined with endothelial cells. Once injected, the endothelialized channels connect with the host vessels (through a remodeling process) and enable blood flow to nourish the transplanted cells and thereby maintain their viability and function. However vessel formation is slow and the resulting vessels are imperfect. Hence, this proposal addresses the rate limiting barriers to successful construct vascularization in order to accelerate mature, functional vessel formation. We exploit the ability of the cells to respond to hypoxia (low oxygen) and the ability of the inflammatory response to be biased towards vessel formation. Then we use insulin delivery in diabetic mice as a "readout" to show that the vessels are indeed functional.