Weaver Jessica D, Song Yun, Yang Ethan Y, Ricordi Camillo, Pileggi Antonello, Buchwald Peter, Stabler Cherie L
1 Department of Biomedical Engineering, University of Miami , Miami, Florida.
2 Diabetes Research Institute, University of Miami , Miami, Florida.
Tissue Eng Part A. 2015 Aug;21(15-16):2250-61. doi: 10.1089/ten.tea.2014.0487. Epub 2015 Jul 10.
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.
炎症对细胞和组织的植入有显著损害，特别是对于胰岛移植而言，对炎症环境的低耐受性会导致大量移植物丢失。使用抗炎药进行局部治疗，如糖皮质激素，具有靶向给药的优势，可将全身给药相关的广泛副作用降至最低。聚二甲基硅氧烷（PDMS）是一种灵活的平台，能够持续递送疏水性药物。在此，我们评估了负载抗炎糖皮质激素地塞米松（Dex）的PDMS构建体在局部减轻胰岛移植炎症方面的能力。以棒状或盘状几何形状制备的Dex-PDMS构建体在治疗相关水平上表现出延长的持续释放。在体外，Dex-PDMS构建体抑制内毒素诱导的人单核细胞和巨噬细胞活化，但不损害胰岛的活力或功能。在小鼠模型中，与接种胰岛的支架共同移植的Dex-PDMS棒在早期和晚期植入过程中均表现出对宿主炎症反应的抑制，且未显著改变胰岛移植效力。这些掺杂糖皮质激素的PDMS构建体的简便特性允许优化靶向剂量递送，在细胞和组织移植中具有广泛的适用性。
