J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.
Diabetes Research Institute, University of Miami, Miami, FL, USA.
J Tissue Eng Regen Med. 2018 Feb;12(2):393-404. doi: 10.1002/term.2464. Epub 2017 Aug 1.
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.
局部递送免疫抑制剂可以显著提高胰岛移植治疗 1 型糖尿病的成功率。芬戈莫德是一种临床批准的鞘氨醇-1-磷酸受体激动剂，当全身给药时，已被发现可抑制啮齿动物同种异体胰岛移植物排斥反应。在此，我们通过将其包裹在专门设计用于胰岛移植的多孔聚二甲基硅氧烷 (PDMS) 支架中，构建了一种用于局部递芬戈莫德的平台。体外药物释放研究定量动力学证实，在 >7 天的时间内，药物以目标剂量水平持续释放。随后，将含有同基因胰岛的芬戈莫德-PDMS 支架移植到糖尿病小鼠体内，以检查局部释放芬戈莫德对移植的影响。令人惊讶的是，当支架中含有 >0.5%w/w 的芬戈莫德剂量时，观察到效果延迟或消除；尽管药物释放率估计比发表的系统给药报告低约 80 倍，但在这些报告中没有观察到不利影响。对移植物的组织学分析表明，细胞迁移和表型在移植物部位呈剂量依赖性调节，高剂量会损害宿主浸润和移植，而低剂量会促进白细胞迁移。体内和体外的机制研究观察到局部递芬戈莫德给药引起的独特宿主和胰岛反应，损害了小鼠胰岛的活力和功能。总体而言，这项研究证实了使用三维 PDMS 支架以持续释放方式调节局部递芬戈莫德的能力；然而，在胰岛移植部位观察到的有害影响不支持进一步在小鼠模型中研究移植物部位的局部递送。
