Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, United States of America.
Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, Genoa 16163, Italy.
Biofabrication. 2021 Apr 7;13(3). doi: 10.1088/1758-5090/abdcac.
Islet transplantation is a promising approach to enable type 1 diabetic patients to attain glycemic control independent of insulin injections. However, up to 60% of islets are lost immediately following transplantation. To improve this outcome, islets can be transplanted within bioscaffolds, however, synthetic bioscaffolds induce an intense inflammatory reaction which can have detrimental effects on islet function and survival. In the present study, we first improved the biocompatibility of polydimethylsiloxane (PDMS) bioscaffolds by coating them with collagen. To reduce the inflammatory response to PDMS bioscaffolds, we then enriched the bioscaffolds with dexamethasone-loaded microplates (DEX-μScaffolds). These DEX-microplates have the ability to release DEX in a sustained manner over 7 weeks within a therapeutic range that does not affect the glucose responsiveness of the islets but which minimizes inflammation in the surrounding microenvironment. The bioscaffold showed excellent mechanical properties that enabled it to resist pore collapse thereby helping to facilitate islet seeding and its handling for implantation, and subsequent engraftment, within the epididymal fat pad (EFP). Following the transplantation of islets into the EFP of diabetic mice using DEX-μScaffolds there was a return in basal blood glucose to normal values by day 4, with normoglycemia maintained for 30 d. Furthermore, these animals demonstrated a normal dynamic response to glucose challenges with histological evidence showing reduced pro-inflammatory cytokines and fibrotic tissue surrounding DEX-μScaffolds at the transplantation site. In contrast, diabetic animals transplanted with either islets alone or islets in bioscaffolds without DEX microplates were not able to regain glycemic control during basal conditions with overall poor islet function. Taken together, our data show that coating PDMS bioscaffolds with collagen, and enriching them with DEX-microplates, significantly prolongs and enhances islet function and survival.
胰岛移植是一种有前途的方法，可以使 1 型糖尿病患者实现不依赖胰岛素注射的血糖控制。然而，多达 60%的胰岛在移植后立即丢失。为了改善这种结果，可以将胰岛移植到生物支架内，然而，合成生物支架会引起强烈的炎症反应，这可能对胰岛的功能和存活产生不利影响。在本研究中，我们首先通过涂覆胶原蛋白来改善聚二甲基硅氧烷（PDMS）生物支架的生物相容性。为了减少 PDMS 生物支架的炎症反应，我们随后用载有地塞米松的微板（DEX-μScaffolds）来丰富生物支架。这些 DEX 微板能够在治疗范围内持续释放 DEX 长达 7 周，而不会影响胰岛的葡萄糖反应性，但能最大限度地减少周围微环境中的炎症。生物支架具有优异的机械性能，能够抵抗孔塌陷，从而有助于促进胰岛的接种及其在附睾脂肪垫（EFP）内的植入和随后的植入。使用 DEX-μScaffolds 将胰岛移植到糖尿病小鼠的 EFP 后，第 4 天基础血糖恢复正常，30 天内维持正常血糖水平。此外，这些动物对葡萄糖刺激表现出正常的动态反应，组织学证据显示，DEX-μScaffolds 移植部位周围的促炎细胞因子和纤维组织减少。相比之下，单独移植胰岛或没有 DEX 微板的生物支架内移植胰岛的糖尿病动物在基础条件下无法恢复血糖控制，胰岛功能整体较差。总的来说，我们的数据表明，用胶原蛋白涂覆 PDMS 生物支架，并在其中添加 DEX 微板，可以显著延长和增强胰岛的功能和存活。
