(511b) The Foreign Body Immune Response to Implanted Scaffolds Is Dependent on Size and Shape in Rodents and Non-Human Primates

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 semipermeable 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 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. Through in vivo screening for biocompatibility we identified a unique geometry that proved to be most efficacious at resisting fibrosis. We then validated that our observations related to geometry influencing biocompatibility translated across a broad spectrum of materials, including hydrogels, ceramics, metals, and plastics. Further, we studied whether these observations would translate to non-human primates and multiple transplantation sites. Finally, to highlight the implications the implications 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: In rodent and non-human primate animal models, spheres 1.5 mm and above in diameter significantly abrogated foreign body reactions and fibrosis when compared to smaller-sized spherical counterparts. Remarkably, these findings translated across a broad spectrum of materials including hydrogels, ceramics, metals, and plastics. To highlight the implications of these findings we studied the effect of hydrogel capsule size on the survival of encapsulated pancreatic islet cells. In a xenogeneic treatment model of transplanting encapsulated rat islets into streptozotocin (STZ)-induced diabetic C57BL/6 mice, islets prepared in 1.5 mm alginate capsules were able to restore blood glucose control in diabetic mice for up to 180 days, a greater than 5-fold longer duration than transplanted grafts encapsulated within conventionally sized 0.5 mm diameter alginate capsules.

Conclusions:  In summary, we have demonstrated that by tuning the geometry of implanted materials we can influence their host recognition. Spherical materials that are of 1.5mm in diameter or greater proved to be significantly more biocompatible than their smaller-sized or differently shaped counterparts months. Modulating the spherical dimensions of a broad spectrum of materials, encompassing hydrogels, ceramics, metals and plastics, also showed that spheres of 1.5mm in diameter or greater significantly mitigated foreign reactions and fibrosis. We believe these findings have important implications for the design of in vivo-implanted biomedical devices for a range of applications, including cell transplantation, controlled drug release, implantable sensors, and prosthesis for tissue engineering.