Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets

Abstract

<p id="d4200813e164">In this study we show that pancreatic islets embedded in modules coated with endothelial cells and injected under the skin return streptozotocin-induced diabetic SCID/beige mice to normoglycemia. The transplanted islets became revascularized and directly integrated with host’s vasculature, a feature not seen previously in the subcutaneous space. These implants were also retrievable, an important clinical consideration. The success here means that islet transplantation can move away from inhospitable sites such as the peritoneal cavity or the liver. </p><p class="first" id="d4200813e167">The transplantation of pancreatic islets, following the Edmonton Protocol, is a promising treatment for type I diabetics. However, the need for multiple donors to achieve insulin independence reflects the large loss of islets that occurs when islets are infused into the portal vein. Finding a less hostile transplantation site that is both minimally invasive and able to support a large transplant volume is necessary to advance this approach. Although the s.c. site satisfies both these criteria, the site is poorly vascularized, precluding its utility. To address this problem, we demonstrate that modular tissue engineering results in an s.c. vascularized bed that enables the transplantation of pancreatic islets. In streptozotocin-induced diabetic SCID/beige mice, the injection of 750 rat islet equivalents embedded in endothelialized collagen modules was sufficient to restore and maintain normoglycemia for 21 days; the same number of free islets was unable to affect glucose levels. Furthermore, using CLARITY, we showed that embedded islets became revascularized and integrated with the host’s vasculature, a feature not seen in other s.c. studies. Collagen-embedded islets drove a small (albeit not significant) shift toward a proangiogenic CD206 ⁺MHCII ⁻(M2-like) macrophage response, which was a feature of module-associated vascularization. While these results open the potential for using s.c. islet delivery as a treatment option for type I diabetes, the more immediate benefit may be for the exploration of revascularized islet biology. </p>