Type 1 Diabetes (T1D) is a chronic pro-inflammatory autoimmune disease consisting of islet-infiltrating leukocytes involved in pancreatic β-cell lysis. One promising treatment for T1D is islet transplantation; however, clinical application is constrained due to limited islet availability, adverse effects of immunosuppressants, and declining graft survival. Islet encapsulation may provide an immunoprotective barrier to preserve islet function and prevent immune-mediated rejection after transplantation. We previously demonstrated that a novel cytoprotective nanothin multilayer coating for islet encapsulation consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly(N-vinylpyrrolidone) (PVPON), was efficacious in dampening in vitro immune responses involved in transplant rejection and preserving in vitro islet function. However, the ability of (PVPON/TA) to maintain islet function in vivo and reverse diabetes has not been tested. Recent evidence has demonstrated that modulation of redox status can affect pro-inflammatory immune responses. Therefore, we hypothesized that transplanted (PVPON/TA)-encapsulated islets can restore euglycemia to diabetic mice and provide an immunoprotective barrier. Our results demonstrate that (PVPON/TA) nanothin coatings can significantly decrease in vitro chemokine synthesis and diabetogenic T cell migration. Importantly, (PVPON/TA)-encapsulated islets restored euglycemia after transplantation into diabetic mice. Our results demonstrate that (PVPON/TA)-encapsulated islets may suppress immune responses and enhance islet allograft acceptance in patients with T1D.

Local modulation of oxidative stress is crucial for a variety of biochemical events including cellular differentiation, apoptosis, and defense against pathogens. Currently employed natural and synthetic antioxidants exhibit a lack of biocompatibility, bioavailability, and chemical stability, resulting in limited capability to scavenge reactive oxygen species (ROS). To mediate these drawbacks, we have developed a synergistic manganoporphyrin-polyphenol polymeric nanothin coating and hollow microcapsules with efficient antioxidant activity and controllable ROS modulation. These materials are produced by multilayer assembly of a natural polyphenolic antioxidant, tannic acid (TA), with a synthesized copolymer of polyvinylpyrrolidone containing a manganoporphyrin modality (MnP-PVPON) which mimics the enzymatic antioxidant superoxide dismutase. The redox activity of the copolymer is demonstrated to dramatically increase the antioxidant response of MnP-PVPON/TA capsules versus unmodified PVPON/TA capsules through reduction of a radical cationic dye and to significantly suppress the proliferation of superoxide via cytochrome C competition. Inclusion of MnP-PVPON as an outer layer enhances radical-scavenging activity as compared to localization of the layer in the middle or inner part of the capsule shell. In addition, we demonstrate that TA is crucial for the synergistic radical-scavenging activity of the MnP-PVPON/TA system which exhibits a combined superoxide dismutase-like ability and catalase-like activity in response to the free radical superoxide challenge. The MnP-PVPON/TA capsules exhibit a negligible, 8% loss of shell thickness upon free radical treatment, while PVPON/TA capsules lose 39% of their shell thickness due to the noncatalytic free-radical-scavenging of TA, as demonstrated by small angle neutron scattering (SANS). Finally, we have found the manganoporphyrin-polyphenol capsules to be nontoxic to splenocytes from NOD mice after 48 h incubation. Our study illustrates the strong potential of combining catalytic activity of manganoporphyrins with natural polyphenolic antioxidants to design efficient free-radical-scavenging materials that may eventually be used in antioxidant therapies and as free radical dissipating protective carriers of biomolecules for biomedical or industrial applications.

Type 1 diabetes (T1D) is an autoimmune disease resulting in pancreatic b-cell lysis via reactive oxygen species (ROS), pro-inflammatory cytokines, and islet-infiltrating leukocytes. One promising treatment for T1D is islet transplantation, but its clinical application is constrained due to islet availability, adverse effects of immunosuppressants on islet function, and declining graft survival. Islet encapsulation may provide an immunoprotective barrier to aid in preserving function and curbing immune-mediated rejection post transplantation. We previously demonstrated that a cytoprotective nanothin multilayer coating consisting of tannic acid (TA), an immunomodulatory antioxidant, and poly (N-vinylpyrrolidone) (PVPON), curtailed immune responses involved in transplant rejection. We hypothesized that (PVPON/TA) coating may hinder the synthesis of redox-sensitive chemokines that recruit immune cells to sites of islet engraftment and blunt ROS-dependent cues necessary for M1 macrophage differentiation. (PVPON/TA) coatings elicited a 7-fold decrease in M1 macrophage-derived pro-inflammatory chemokines CCL5 and CXCL10, blunted M1 macrophage activation markers, and curbed diabetogenic CD4 T cell migration approximately 2-fold. Importantly, murine islet encapsulation with (PVPON/TA) material restored euglycemia in immunodeficient-diabetic mice post transplantation. Our studies demonstrate that (PVPON/TA) multilayer coatings represent a promising immunomodulatory biomaterial for islet transplantation. Future studies will evaluate the efficiency of PVPON/TA coated islets in curbing hyperglycemia by allotransplantation into diabetic rodent models.

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