Porous Scaffolds Support Extrahepatic Human Islet Transplantation, Engraftment, and Function in Mice

Abstract

Islet transplantation as a therapy or cure for type 1 diabetes has significant promise but has been limited by islet mass requirements and long-term graft failure. The intrahepatic and intravascular site may be responsible for significant loss of transplanted islets. Nonencapsulating biomaterial scaffolds provide a strategy for architecturally defining and modulating extrahepatic sites beyond the endogenous milieu to enhance islet survival and function. We utilized scaffolds to transplant human islets into the intraperitoneal fat of immunodeficient mice. A smaller human islet mass than previously reported reversed murine diabetes and restored glycemic control at human blood glucose levels. Graft function was highly dependent on the islet number transplanted and directly correlated to islet viability, as determined by the ATP-to-DNA ratio. Islets engrafted and revascularized in host tissue, and glucose tolerance testing indicated performance equivalent to healthy mice. Addition of extracellular matrix, specifically collagen IV, to scaffold surfaces improved graft function compared to serum-supplemented media. Porous scaffolds can facilitate efficient human islet transplantation and provide a platform for modulating the islet microenvironment, in ways not possible with current clinical strategies, to enhance islet engraftment and function.

A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids

“…Given that we recovered human tissues that were largely devoid of lung epithelium, we hypothesized that transplantation of HLOs would be enhanced if provided a structural niche, which has been demonstrated to improve engraftment, vascularization and to support the survival of transplanted pancreatic beta cells (Gibly et al, 2013; Blomeier et al, 2006; Hlavaty et al, 2014; Graham et al, 2013; Kheradmand et al, 2011; Gibly et al, 2011). Microporous PLG scaffolds provide a rigid environment for the tissue to adhere to along with a porous (250–425 µm diameter) honeycomb-like structure to enable tissue growth and infiltration of vasculature (Figure 1A).…”

“…Thus, while all of these highly vascular sites have been utilized for engraftment in other contexts (Finkbeiner et al, 2015b; Watson et al., 2014; Pepper et al, 2013; Bartholomeus et al, 2013; Smink et al, 2013), HLOs did not thrive in these environments. We turned to microporous poly(lactide-co-glycolide) (PLG) scaffolds in order to create an alternative niche for the HLOs during transplantation since PLG scaffolds have led to improved survival and function of pancreatic beta cells following transplantation (Gibly et al, 2013; Blomeier et al, 2006; Hlavaty et al, 2014; Graham et al, 2013; Kheradmand et al, 2011). …”

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.…”

Immune Response Associated with Islet Xenotransplantation in Small and Large Animal Models

“…Similarly, scaffolding involves transplanting islets on a porous, biodegradable material. This offers some of the protection of encapsulation with evidence for longer term function and survival of islet xenografts compared to encapsulation [41].…”