Local delivery of fingolimod from three-dimensional scaffolds impacts islet graft efficacy and microenvironment in a murine diabetic model.

The local delivery of immunosuppressive agents could significantly promote the success of islet transplantation for the treatment of Type 1 diabetes. Fingolimod, a clinically-approved sphingosine-1-phosphate receptor agonist, has been found to dampen allograft islet rejection in rodent models when delivered systemically. Herein, we engineered a platform for the local delivery of fingolimod by incorporating it within a macroporous polydimethylsiloxane (PDMS) scaffold specifically designed for islet transplantation. In vitro drug release studies quantifying kinetics confirmed sustained release within targeted dose levels for >7 days. Fingolimod-PDMS scaffolds containing syngeneic islets were subsequently transplanted into diabetic mice for examination of the effect of local fingolimod release on engraftment. Surprisingly, either delayed or abrogated efficacy was observed when scaffolds contained a dosage of fingolimod >0.5% w/w; despite drug release rates estimated at ~80-fold less than published systemic delivery reports where no detrimental effects were noted. Histological analysis of explants indicated a dose-dependent modulation of cellular migration and phenotype at the graft site, with high doses impairing host infiltration and engraftment while lower doses promoted leucocyte migration. Mechanistic in vivo and in vitro studies observed unique host and islet responses to local fingolimod delivery, with impairment of murine islet viability and function. Overall, this study confirmed the ability to modulate local delivery of fingolimod in a sustained-release manner using a three-dimensional PDMS scaffold; however, the observed detrimental impacts at the site of islet transplantation do not support further investigation of local delivery at the graft site in murine models.