Local release of dexamethasone from macroporous scaffolds accelerates islet transplant engraftment by promotion of anti-inflammatory M2 macrophages

Transplant-associated inflammatory responses generate an unfavorable microenvironment for tissue engraftment, particularly for cells susceptible to inflammatory stress, such as pancreatic islets. The localized delivery of anti-inflammatory agents, such as glucocorticoids, offers a promising approach to minimize the detrimental side effects associated with systemic delivery; however, the dosage must be carefully tailored to avoid deleterious responses, such as poor engraftment. Herein, we employed a polydimethylsiloxane (PDMS)-based three-dimensional scaffold platform for the local and controlled delivery of dexamethasone (Dex). Incorporation of 0.1% or 0.25% Dex within the scaffold was found to significantly accelerate islet engraftment in a diabetic mouse model, resulting in improved control of blood glucose levels during the early transplant period. Investigation into the mechanism of this impact found that local Dex delivery promotes macrophage polarization towards an anti-inflammatory (M2) phenotype and suppresses inflammatory pathways during the first week post-implantation. Alternatively, higher Dex loadings (0.5% and 1%) significantly delayed islet engraftment and function by impairing host cell migration into the implanted graft. Our results demonstrate the dose-dependent impact of local glucocorticoid delivery on the modulation of inflammatory responses at the implant site in vivo. Outcomes highlight the potential of this platform for generating favorable host responses that improve overall cellular transplant outcomes.