Abstract
Therapeutic approaches to combat type 1 diabetes (T1D) include donor pancreas transplantation, exogenous insulin administration and immunosuppressive therapies. However, these clinical applications are limited due to insufficient tissue compatible donors, side effects of exogenous insulin administration and/or increased onset of opportunistic infections attributable to induced global immunosuppression. An alternative approach to alleviate disease states is to utilize insulin-producing pancreatic islets seeded in a bioscaffold for implantation into diabetic recipients. The present studies now report that a newly developed cationic polymer biomaterial serves as an efficient bioscaffold for delivery of donor syngeneic pancreatic islet cells to reverse hyperglycemia in murine streptozotocin induced- or non-obese diabetic mouse models of T1D. Intraperitoneal implantation of pancreatic islets seeded within the copolymer bioscaffold supports long-term cell viability, response to extracellular signaling cues and ability to produce soluble factors into the microenvironment. Elevated insulin levels were measured in recipient diabetic mice upon implantation of the islet-seeded biomaterial coupled with reduced blood glucose levels, collectively resulting in increased survival and stabilization of metabolic indices. Importantly, the implanted islet-seeded biomaterial assembled into a solid organoid substructure that reorganized the extracellular matrix compartment and recruited endothelial progenitors for neovascularization. This allowed survival of the graft long-term in vivo and access to the blood for monitoring glucose levels. These results highlight the novelty, simplicity and effectiveness of this biomaterial for tissue regeneration and in vivo restoration of organ functions.
Highlights
Therapeutic approaches to combat type 1 diabetes (T1D) include donor pancreas transplantation, exogenous insulin administration and immunosuppressive therapies
For type 1 diabetes (T1D), this is due to autoimmune-mediated destruction of the pancreatic islet compartment leading to deregulation of glucose-responsive insulin production from beta cells[2,3,4]
Though subcutaneous exogenous insulin delivery is the standard route for regulating glucose levels in diabetics, it is associated with repetitive injection pain, lipodystrophy, noncompliance and peripheral hyperinsulinemia
Summary
Therapeutic approaches to combat type 1 diabetes (T1D) include donor pancreas transplantation, exogenous insulin administration and immunosuppressive therapies. Engineering of a microenvironment for the transplanted islets that provides both immune tolerance and efficient vascularization within the transplant microenvironment are ideal for long-term retention and adequate glucose responsive-insulin production[13,14] In these studies, building on previous approaches to islet implantation[6,15,16,17], an innovative new class of polysaccharide-polyamine copolymers is employed as a bioscaffold system to correct hyperglycemia in both streptozocin (STZ)-induced and autoimmune-driven non-obese diabetic (NOD) mice models[13,18]. The surface charge interactions allow the cellulosic material to associate and aggregate with the seeded beta cells ex vivo, further supporting cellular infiltration into the porous substructure These studies have found that intraperitoneal (i.p.) implanted donor-derived syngeneic islet seeded into the biomaterial reduced hyperglycemia levels and improved metabolic hormone balances in recipient diabetic mice. The islet-seeded copolymeric scaffold electrostatically assembled into a surrogate pancreas-like organoid that maintained the islet microenvironment, which included neovascularization within the transplant to prevent hypoxia and provide access to monitor blood glucose levels for reduction of hyperglycemia in recipients
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