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Oligomeric collagen as an encapsulation material for islet/β-cell replacement: effect of islet source, dose, implant site, and administration format.

ABSTRACT: Replacement of islets/β-cells that provide long-lasting glucose-sensing and insulin-releasing functions has the potential to restore extended glycemic control in individuals with type 1 diabetes. Unfortunately, persistent challenges preclude such therapies from widespread clinical use, including cumbersome administration via portal vein infusion, significant loss of functional islet mass upon administration, limited functional longevity, and requirement for systemic immunosuppression. Previously, fibril-forming type I collagen (oligomer) was shown to support subcutaneous injection and in situ encapsulation of syngeneic islets within diabetic mice, with rapid (<24 h) reversal of hyperglycemia and maintenance of euglycemia for beyond 90 days. Here, we further evaluated this macroencapsulation strategy, defining effects of islet source (allogeneic and xenogeneic) and dose (500 and 800 islets), injection microenvironment (subcutaneous and intraperitoneal), and macrocapsule format (injectable and preformed implantable) on islet functional longevity and recipient immune response. We found that xenogeneic rat islets functioned similarly to or better than allogeneic mouse islets, with only modest improvements in longevity noted with dosage. Additionally, subcutaneous injection led to more consistent encapsulation outcomes along with improved islet health and longevity, compared with intraperitoneal administration, whereas no significant differences were observed between subcutaneous injectable and preformed implantable formats. Collectively, these results document the benefits of incorporating natural collagen for islet/β-cell replacement therapies.

SUBMITTER: Stephens CH

PROVIDER: S-EPMC7473915 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immunoisolation of pancreatic islets is a technology in which islets are encapsulated in semipermeable but immunoprotective polymeric membranes. The technology allows for successful transplantation of insulin-producing cells in the absence of immunosuppression. Different approaches of immunoisolation are currently under development. These approaches involve intravascular devices that are connected to the bloodstream and extravascular devices that can be distinguished in micro- and macrocapsules and are usually implanted in the peritoneal cavity or under the skin. The technology has been subject of intense fundamental research in the past decade. It has co-evolved with novel replenishable cell sources for cure of diseases such as Type 1 Diabetes Mellitus that need to be protected for the host immune system. Although the devices have shown significant success in animal models and even in human safety studies most technologies still suffer from undesired tissue responses in the host. Here we review the past and current approaches to modulate and reduce tissue responses against extravascular cell-containing micro- and macrocapsules with a focus on rational choices for polymer (combinations). Choices for polymers but also choices for crosslinking agents that induce more stable and biocompatible capsules are discussed. Combining beneficial properties of molecules in diblock polymers or application of these molecules or other anti-biofouling molecules have been reviewed. Emerging are also the principles of polymer brushes that prevent protein and cell-adhesion. Recently also immunomodulating biomaterials that bind to specific immune receptors have entered the field. Several natural and synthetic polymers and even combinations of these polymers have demonstrated significant improvement in outcomes of encapsulated grafts. Adequate polymeric surface properties have been shown to be essential but how the surface should be composed to avoid host responses remains to be identified. Current insight is that optimal biocompatible devices can be created which raises optimism that immunoisolating devices can be created that allows for long term survival of encapsulated replenishable insulin-producing cell sources for treatment of Type 1 Diabetes Mellitus.

Project description:Wound infections are a significant clinical problem affecting millions of people worldwide. Topically applied antibacterial formulations with longer residence time and controlled antimicrobial release would offer significant benefits for improved prevention and treatment of infected wounds. In this study, we developed collagen mimetic peptide (CMP) tethered vancomycin (Van)-containing liposomes (Lipo) (CMP-Van-Lipo) hybridized to collagen-based hydrogels ('co-gels,' e.g., collagen/fibrin combination hydrogels) for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in vitro and in vivo. Tethering CMP-Van-Lipo nanostructures to co-gels enabled sustained Van release and enhanced in vitro antibacterial effects against MRSA as compared to Van loaded co-gels or Van-Lipo loaded co-gels following multiple fresh bacterial inoculations over a period of 48 h. These results were successfully translated in vivo wherein MRSA infected wounds were effectively treated with CMP-Van-Lipo loaded co-gels for up to 9 days, whereas the activity of Van loaded co-gels and Van-Lipo loaded co-gels were limited to <2 days. Moreover, CMP-Van-Lipo retained in vivo antibacterial activity even after re-inoculation with bacteria; however, Van loaded co-gels and Van-Lipo loaded co-gels allowed significant bacterial growth demonstrating their limited efficacy. Altogether, these results provide proof-of-concept that CMP-Van-Lipo loaded co-gels can be effective topical formulations for preventive treatment of MRSA wound infections. STATEMENT OF SIGNIFICANCE: Current topical antimicrobial formulations (e.g., creams, gels, and ointments) do not control release, leaving antimicrobial concentrations either too high or too low at different time points, and provoking the development of antibacterial resistance and recurrence of wound infections. Here, collagen mimetic peptides (CMPs) were used to stably hybridize vancomycin-containing liposomal nanocarriers (CMP-Van-Lipo) within collagen-fibrin co-gels via triple-helical integration with collagen, enabling control over Van release for prolonged time periods and minimizing the adverse effects of the Lipo formulations on fibroblast cell viability in the wound bed. The CMP-Van-Lipo loaded co-gel's higher antibacterial effects in vitro were successfully translated in vivo for treatment of MRSA-infected mouse wounds, and thus the co-gels can be a potentially translatable treatment for improved clinical wound management.

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Oligomeric collagen as an encapsulation material for islet/β-cell replacement: effect of islet source, dose, implant site, and administration format.

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