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.

An engineered macroencapsulation membrane releasing FTY720 to precondition pancreatic islet transplantation

“…Investigated membranes include hydrogels (predominately alginate) and synthetic polymers such as polytetrafluoroethylene and polycaprolactone . Common sites for macroencapsulated and scaffold‐supported islets include intraperitoneal/omentum and subcutaneous spaces . Encapsulation‐based transplantation has not yet performed well enough to warrant replacing the intraportal technique for clinical allogenic islet transplant, but is under clinical investigation with stem cell‐derived transplants .…”

Co-localized immune protection using dexamethasone-eluting micelles in a murine islet allograft model

“…Notwithstanding, glucocorticoids dampen inflammatory responses by suppressing selected proinflammatory pathways, such as macrophage activation and secretion of IL‐1β . Whereas higher percentages of localized Dex had deleterious effects on islet engraftment, low percentages yielded improved graft function . Furthermore, very low dose of Dex facilitates several adaptations that lead to an enhanced insulin secretory capacity .…”

“…13 Whereas higher percentages of localized Dex had deleterious effects on islet engraftment, low percentages yielded improved graft function. 13,34 Furthermore, very low dose of Dex facilitates several adaptations that lead to an enhanced insulin secretory capacity. 35 Moreover, incorporating Dex within alginate matrices resulted in reduced fibrotic overgrowth and improved islet xenografts.…”

Tissue‐engineering approaches in pancreatic islet transplantation

“…However, their use is limited by the hydrophobic nature of these materials (which reduces their biocompatibility) and the release of proinflammatory acidic by‐products during their degradation (Gunatillake & Adhikari, ). Synthetic scaffolds have been used alone in several in vitro and in vivo islet and islet‐like transplantation approaches in animals, mainly at extrahepatic sites, both as micro‐ (Abalovich et al, ; Jang, Lee, Park, & Byun, ; Rengifo, Giraldo, Labrada, & Stabler, ; Teramura & Iwata, ; Wilson, Cui, & Chaikof, ) and macro‐encapsulation devices (Blomeier et al, ; Dufour et al, ; Frei, Li, Jiang, Buchwald, & Stabler, ; Gibly, Zhang, Lowe, & Shea, ; Hill et al, ; Jiang et al, ; Juang, Bonner‐Weir, Ogawa, Vacanti, & Weir, ; G. Mao, Chen, Bai, Song, & Wang, ; Pedraza et al, ; Rios et al, ; Salvay et al, ; C. Song et al, ; Weaver et al, ). Most of these studies have reported an improvement in islet engraftment and a decreased immune response.…”

“…Mao, Chen, Bai, Song, & Wang, 2009;Pedraza et al, 2013;Rios et al, 2016;Salvay et al, 2008;C. Song et al, 2009;Weaver et al, 2015). Most of these studies have reported an improvement in islet engraftment and a decreased immune response.…”