The cure for Type 1 diabetes mellitus (T1DM) is likely to require an effective strategy for suppressing or evading the immune system. When considering curative treatments, it is almost inevitable to consider novel ways of inducing tolerogenicity to insulin-producing β cells. While the main mechanism of achieving tolerogenicity is restoring regulatory T cell (CD4+CD25+Fox3+) to effector T-cell (CD4+Fox3-) homeostasis, the means of achieving this are multifarious. The advent of a glucocorticoid-free immunosuppressive regimen was an early indication of how immunotherapeutics affect β-cell function. As newer biologics are developed, suppressing the immune system continues to become more specific and dynamic. An ever-evolving field of immunology has shifted the paradigm of how T1DM is understood, and the repurposing of T-cell-based biotechnology has the potential to change the way that it is treated. Regulatory T cells can be bioengineered to express T-cell receptors with affinity for peptide–human leukocyte antigen complexes that are frequently encountered in T1DM. Exosomes with embedded T-cell receptors can be isolated from regulatory T cells for use as an off-the-shelf therapy.

Background. Islet transplantation is a promising treatment for type 1 diabetes. It has the potential to improve glycemic control, particularly in patients suffering from hypoglycemic unawareness and glycemic instability. As most islet grafts do not function permanently, efforts are needed to create an accessible and replaceable site, for islet grafts or for insulin-producing cells obtained from replenishable sources. To this end, we designed and tested an artificial, polymeric subcutaneous transplantation site that allows repeated transplantation of islets. Methods. In this study, we developed and compared scaffolds made of poly(D,L,-lactide-co-ε-caprolactone) (PDLLCL) and polycaprolactone (PCL). Efficacy was first tested in mice‚ and then, as a proof of principle for application in a large animal model, the scaffolds were tested in pigs, as their skin structure is similar to that of humans. Results. In mice, islet transplantation in a PCL scaffold expedited return to normoglycemia in comparison to PDLLCL (7.7 ± 3.7 versus 16.8 ± 6.5 d), but it took longer than the kidney capsule control group. PCL also supported porcine functional islet survival in vitro. Subcutaneous implantation of PDLLCL and PCL scaffolds in pigs revealed that PCL scaffolds were more stable and was associated with less infiltration by immune cells than PDLLCL scaffolds. Prevascularized PCL scaffolds were therefore used to demonstrate the functional survival of allogenic islets under the skin of pigs. Conclusions. To conclude, a novel PCL scaffold shows efficacy as a readily accessible and replaceable, subcutaneous transplantation site for islets in mice and demonstrated islet survival after a month in pigs.

Subcutaneous polymer scaffolds have shown potential for creating an optimal transplantation site in cellular replacement therapy, e.g., when transplanting insulin-producing cells to cure type 1 diabetes. Imperative for these scaffolds is a high degree of vascularization to guarantee long-term functional cellular survival. In this study, the effect of the nitric oxide (NO) donor S-nitroso-N-acetyl-dl-penicillamine (SNAP) on the vascularization degree of a subcutaneous poly(d,l-lactide-co-ε-caprolactone) (PDLLCL) scaffold was investigated. To this end, scaffolds were implanted under the skin of C57BL/6 mice. Each mouse received a control scaffold and a scaffold containing SNAP. At day 7, 14, and 28, the oxygen percentage within the scaffolds was measured and at day 28, the vascularization degree was determined with lectin infusion and gene expression analysis. We measured lower oxygen percentages within the scaffolds containing the NO-donor up to day 14 compared to the control scaffolds, but no differences were found at day 28. Although blood vessels in the scaffolds were well perfused, no differences between the groups were found in the lectin staining and gene expression of vascular markers, such as CD31, CD105, and VEGFa. To conclude, in this biomaterial setting, addition of a NO-donor did not improve the vascularization degree of the subcutaneous scaffold.