(169g) Engineering a Bioartifical Pancreas: Tuning Device Geometry Prevents Foreign Body Immune Responses and Fibrosis to Enable Prolonged Efficacy in Diabetic Rodents
Introduction: Transplantation of donor pancreatic islet cells into diabetics to restore normoglycemia has been common practice for decades. However, major hurdles still exist that drastically limit the efficacy of this treatment for patients. One major problem is the need for immunosuppressive therapies to prevent rejection of transplanted cells. To overcome this barrier efforts have been placed in developing a bioartificial pancreas, whereby islets are encapsulated within a semi-permeable immunoprotective barrier and then transplanted into diabetic patients. The long-term function of the bioartificial pancreas is dependent on its interaction with the host immune system. Immune recognition initiates a cascade of cellular processes leading to foreign body reactions, which include persistent inflammation, fibrosis (walling-off), and damage to the surrounding tissue. These unwanted effects are deleterious to the function and viability of the encapsulated islet cells. Towards the development of more biocompatible hydrogels we investigated the influence of hydrogel geometry on host recognition and fibrosis.
Materials and Methods: To investigate our hypothesis we fabricated a series of Ba cross-linked SLG20 alginate microcapsules of varying geometries with precise dimensions. Using wild type C57BL/6 mice, a robust model for fibrosis we interrogated the effects of fibrosis formation on our capsules to identify a unique geometry that proved to be most efficacious at resisting fibrosis. Rat and human derived pancreatic islet cells where then encapsulated lead capsule formulations and transplanted to Streptozocin (STZ) treatment diabetes induced C57BL/6 mice and monitored ability to restore normoglycemia over time.
Results and Discussion: Alginate based hydrogels of tuned geometry significantly abrogated foreign body reactions and fibrosis when compared to conventional alginate microcapsules. Tuned hydrogel capsules resisted fibrosis for at least 6 months when transplanted in the intraperitoneal space, a common site for bioartifical pancreas transplantation. Our study of probing immune cells recruited to transplanted materials implicates the limited activation of macrophages, a key driver of host recognition, as central to these truncated foreign body responses. Most significantly, diabetic mice treated with tuned format bioartificial pancreas maintained normoglycemic for over 6 months, producing a 3-fold improvement over mice treated with conventional format alginate based bioartificial pancreas.
Conclusions: We have demonstrated that by simply tuning the geometry of transplanted materials we can drastically influence their host recognition and propagation of foreign body reactions. Using these findings we fabricated a tuned format alginate based bioartificial pancreas, which was demonstrated to be significantly longer lasting and more efficacious than conventional format bioartificial pancreas systems. As such, we believe tuned format capsules could lead to a much improved cell encapsulation therapy strategy for type 1 diabetes. Furthermore, we believe that our findings have significant implications on the design of in vivo-transplanted biomedical devices for a range of applications including cell transplantation, controlled drug release, implantable sensors, and prosthesis for tissue engineering.