Controlled Release of Dexamethasone from Organosilicone Constructs for Local Modulation of Inflammation in Islet Transplantation.

Abstract

Inflammation is a significant detriment to the engraftment of cells and tissues, particularly for islet transplantation, where a low tolerance for the inflammatory milieu results in significant graft loss. Local treatment with anti-inflammatories, such as glucocorticoids, provides the benefits of site-targeted delivery with minimization of the broad side effects associated with systemic delivery. Polydimethylsiloxane (PDMS) is a flexible platform that is capable of providing sustained delivery of hydrophobic drugs. Here, we evaluated the capacity of PDMS constructs loaded with the anti-inflammatory glucocorticoid dexamethasone (Dex) to locally mitigate inflammation in islet grafts. Dex-PDMS constructs, fabricated in rod or disk geometries, demonstrated prolonged and sustained release at therapeutically relevant levels. In vitro, Dex-PDMS constructs inhibited endotoxin-induced human monocyte and macrophage activation, but they did not impair islet viability or function. Dex-PDMS rods, co-transplanted with islet-seeded scaffolds in a murine model, demonstrated suppression of host inflammatory responses during early- and late-phase engraftment, without significantly altering islet graft potency. The facile nature of these glucocorticoid-doped PDMS constructs allows for the optimization of targeted dose delivery with wide applicability in cell and tissue transplantation.