There are ~ 15 million diagnosed diabetics in the US, 5-10% of whom are type 1 (insulin dependent). Islet transplantation could have a large impact on preventing the degenerative complications of diabetes (here and in developing countries), but the majority of islets (perhaps 60%) in current protocols are lost upon transplantation due to the host response. Our approach (""""""""modular tissue engineering"""""""") enables the creation of uniform, scaleable and most importantly vascularized constructs. It is based on the porous structure that is created when solid objects on to which endothelial cells (EC) are seeded, randomly assemble to fill a space (an implant site or a tube), creating a perfuseable construct. The interstitial gaps among the modules form interconnected channels which are lined by the endothelial cells. The resulting endothelial cell lining enables whole blood to flow around the rods and through these interstitial channels. Current efforts have demonstrated the principle of modular tissue engineering and that blood can be perfused through the channels in vitro. While our long-term objective is to enable islet transplantation to be successful through tissue engineering, we propose now to show the utility of this approach in vivo, with particular emphasis on (a) the assessment of EC thrombogenicity and (b) minimizing the loss of islet viability due to the blood mediated inflammatory response.
Specific aims : (1) Demonstrate that whole blood (without anticoagulant) can be perfused through an EC covered modular construct and assess thrombosis in a canine AV shunt model. Canine EC seeded modular constructs will be inserted in a parallel flow test section within the AV shunt. (3) Restore normoglycemia in diabetic rats using implanted rat EC seeded modules containing embedded pancreatic islets. We expect to ameliorate the adverse local host response through the presence of the transplanted endothelial cells. Rat EC covered modules will be implanted in both the omental pouch and by portal vein infusion (used clinically). We will address these questions: What happens to the EC lined channels once the modules are implanted? Are the vessels functional? Does EC seeding and modular tissue engineering confer an advantage for insulin secretion and diabetes therapy? We will measure thrombogenicity, perfusion, assess remodeling, and measure changes in glycemia.
Showing the most recent 10 out of 15 publications
