Macroporous Three-Dimensional PDMS Scaffolds for Extrahepatic Islet Transplantation

Abstract

Clinical islet transplantation has demonstrated success in treating type 1 diabetes. A current limitation is the intrahepatic portal vein transplant site, which is prone to mechanical stress and inflammation. Transplantation of pancreatic islets into alternative sites is preferable, but challenging, as it may require a three-dimensional vehicle to confer mechanical protection and to confine islets to a well-defined, retrievable space where islet neovascularization can occur. We have fabricated biostable, macroporous scaffolds from poly(dimethylsiloxane) (PDMS) and investigated islet retention and distribution, metabolic function, and glucose-dependent insulin secretion within these materials. Islets from multiple sources, including rodents, non-human primates, and humans, were tested in vitro. We observed high islet retention and distribution within PDMS scaffolds, with retention of small islets (< 100 µm) improved through the post-loading addition of fibrin gel. Islets loaded within PDMS scaffolds exhibited viability and function comparable to standard culture conditions when incubated under normal oxygen tensions, but displayed improved viability compared to standard two-dimensional culture controls under low oxygen tensions. In vivo efficacy of scaffolds to support islet grafts was evaluated after transplantation in the omental pouch of chemically-induced diabetic syngeneic rats, which promptly achieved normoglycemia. Collectively, these results are promising in that they indicate the potential for transplanting islets into a clinically relevant, extrahepatic site that provides spatial distribution of islets, as well as intra-device vascularization.

Proangiogenic Hydrogels Within Macroporous Scaffolds Enhance Islet Engraftment in an Extrahepatic Site

“…Recent approaches, however, have sought to generate an integrated islet graft site through the use of macroporous scaffolds. [13][14][15] This approach seeks to create intimacy between the islets and the surrounding environment, while also providing a platform for modulation and control of the local transplant site. Our laboratory has demonstrated, in rat and nonhuman primate models, that the use of a poly(dimethylsiloxane) (PDMS) macroporous scaffold within an alternative transplant site can be highly effective in restoring normoglycemia.…”

Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone

“…In addition, the frequent changes in blood glucose levels and high glucose concentrations are known to be deleterious to the islets. Therefore, many studies have pursued alternative sites with a more adequate microenvironment for pancreatic islet transplantation, such as organs (renal subcapsule, omentum, peritoneum, subcutaneous site, muscle) (14-16), various vascular sites (celiac artery, vein, spleen, lung) (17,18), immunoprivileged sites (testis, thymus) (19,20), or devices and capsules (21)(22)(23)(24)(25). These may optimize engraftment, survival, and function as well as decrease immunogenicity and promote proliferation and regeneration.…”

Encapsulation technologies in beta cell replacement therapies for Type 1 diabetes

“…In 2014, Pagliuca et al, and Rezania et al both reported successful validation of a seven-stage protocol to generate insulin-secreting cells that were able to reverse hyperglycemia in diabetic mice within months after transplantation [163,164]. These recent developments represent significant breakthroughs in developing a cure for T1D using hESC transplantation.…”

“…Pancreatic stem cells [160,161], hESCs [162][163][164], induced pluripotent stem cells (iPSCs) [165][166][167][168][169], mesenchymal [170][171][172][173][174] and adipose-derived stem cells (ADSCs) [175,176] have all been used to derive islet-like cell clusters or insulin-producing cells (IPCs) that are viable, express markers similar to terminally differentiated β-cells (Insulin, GLUT2) and are able to respond to a glucose challenge. These cells have all demonstrated good function after encapsulation within bioencapsulation devices and several in vivo studies have also been conducted.…”