Islet transplantation (ITX) is experiencing increasing clinical success, but its applicability for type 1 diabetes (T1D) is currently limited by the need for lifelong chronic immunosuppression (IS) and the high number of islets from deceased organ donors needed to reverse T1D. Islet encapsulation is a possibility to reduce or eliminate chronic IS, but, so far, traditional 1000 m fixed-diameter capsules implanted in the peritoneal cavity failed to provide sufficiently effective and long-lasting outcomes. Most likely, this is because large and avascular capsules limit nutrient transport and delay glucose-stimulated insulin release (GSIR) causing loss of graft functionality. Recently, we developed an encapsulation technology that allows ?wrapping? each individual islet with a uniformly thin (15 m) layer of biomaterial, generating capsules that ?conform? to the size and shape of the islet rather than enclosing them in fixed-diameter traditional capsules. By reducing the diffusion distance 10-fold, this conformal coating (CC) allows increased nutrient transport. By reducing the overall graft volume more than 100-fold (from ~500 to ~3 mL), CC also makes possible transplantation in well vascularized confined sites, including pre-vascularized devices, and is no longer limited to the intraperitoneal cavity, further maximizing nutrient transport. Contrary to islets in traditional microcapsules, CC islets display no delay in GSIR, and our computational model predicts that CC grafts placed in confined sites will provide physiological insulin release (GSIR) after revascularization. We were able to confirm long-term euglycemia after transplantation of fully MHC-mismatched CC grafts in diabetic mice without immunosuppression. To address another main shortcoming of current ITX protocols, we recently found that our CC platform is also suitable for use with essentially unlimited insulin-secreting cell sources derived from stem cells (SC-b). Accordingly, we hypothesize that our unique CC technology can allow long-term function of primary islets and SC-b cell grafts without the need for immunosuppression using clinically applicable coating hydrogels (aim 1). Further, we hypothesize that by using innovative nanomaterials, we can provide local immunomodulation and higher oxygen tension at the CC graft site in the immediate post-transplant period minimizing the number of cells needed to reverse T1D and maximizing long-term graft function (aim 2). The work in preclinical mouse models proposed here is needed before we can test our base and nanomaterial-refined CC platform in primates and then in humans.
Islet encapsulation may eliminate the need for lifelong immunosuppression in islet transplantation for type 1 diabetes increasing the applicability of islet transplantation to the more than three million adults and children with type 1 diabetes in the US. So far, traditional encapsulation procedures have not been effective in patients because of transport limitations of traditional capsules. Our novel encapsulation strategy - conformal coating - addresses all transport limitations and it is compatible with most devices for extrahepatic ITX and the unlimited source of insulin-secreting cells derived from stem cells. !
|Buchwald, Peter; Tamayo-Garcia, Alejandro; Manzoli, Vita et al. (2018) Glucose-stimulated insulin release: Parallel perifusion studies of free and hydrogel encapsulated human pancreatic islets. Biotechnol Bioeng 115:232-245|
|Manzoli, Vita; Villa, Chiara; Bayer, Allison L et al. (2018) Immunoisolation of murine islet allografts in vascularized sites through conformal coating with polyethylene glycol. Am J Transplant 18:590-603|
|Tomei, Alice A (2018) Engineering Confined and Prevascularized Sites for Islet Transplantation. Transplantation 102:1793-1794|