Reversal of diabetes in mice with a bioengineered islet implant incorporating a type I collagen hydrogel and sustained release of vascular endothelial growth factor.
Reversal of diabetes in mice with a bioengineered islet implant incorporating a type I collagen hydrogel and sustained release of vascular endothelial growth factor.
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DOI：
10.3727/096368912x636786
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发表时间：
2012
影响因子：
3.3
通讯作者：
Gebe JA
中科院分区：
文献类型：
--
作者：
Vernon RB;Preisinger A;Gooden MD;D'Amico LA;Yue BB;Bollyky PL;Kuhr CS;Hefty TR;Nepom GT;Gebe JA
我们已经开发了一种生物工程植入物（BI），以评估在小鼠胰岛移植模型中促进移植物存活和功能的策略。BI的尺寸适合植入肠系膜褶皱内，由注入I型胶原水凝胶的圆盘形聚乙烯醇海绵组成，其中含有分散的供体胰岛。为了促进胰岛血管化，BI包含一种球形藻酸盐水凝胶，用于持续释放血管内皮生长因子（VEGF）。含有450-500个来自同基因（C57 B1/6）供体的胰岛和20 ng VEGF的BI在100%的小鼠（8/8）中逆转了链脲佐菌素（STZ）诱导的糖尿病，而含有等量胰岛但缺乏VEGF的BI仅在62.5%的小鼠（5/8）中逆转了STZ诱导的糖尿病。在这些“+VEGF”和“−VEGF”组之间，达到正常血糖的时间（植入后8-18天）没有统计学差异;然而，相对于−VEGF组，+VEGF组的一过性术后低血糖明显减少。值得注意的是，一旦BI开始完全调节血糖水平，这两组中达到血糖正常的小鼠都不需要外源性胰岛素治疗。此外，与未接受STZ的健康非糖尿病（对照）小鼠的反应相比，移植小鼠对葡萄糖挑战的反应接近正常。在未来的研究中，此处描述的BI将作为平台，用于评价在BI内局部递送的免疫调节化合物在自身免疫性（1型）糖尿病背景下预防或逆转糖尿病的能力。
We have developed a bioengineered implant (BI) to evaluate strategies to promote graft survival and function in models of islet transplantation in mice. The BI, sized for implantation within a fold of intestinal mesentery, consists of a disk-shaped, polyvinyl alcohol sponge infused with a type I collagen hydrogel that contains dispersed donor islets. To promote islet vascularization, the BI incorporates a spherical alginate hydrogel for sustained release of vascular endothelial growth factor (VEGF). BIs that contained 450–500 islets from syngeneic (C57Bl/6) donors and 20 ng of VEGF reversed streptozotocin (STZ)-induced diabetes in 100% of mice (8/8), whereas BIs that contained an equivalent number of islets, but which lacked VEGF, reversed STZ-induced diabetes in only 62.5% of mice (5/8). Between these “+VEGF” and “−VEGF” groups, the time to achieve normoglycemia (8–18 days after implantation) did not differ statistically; however, transitory, postoperative hypoglycemia was markedly reduced in the +VEGF group relative to the −VEGF group. Notably, none of the mice that achieved normoglycemia in these two groups required exogenous insulin therapy once the BIs began to fully regulate levels of blood glucose. Moreover, the transplanted mice responded to glucose challenge in a near-normal manner, as compared to the responses of healthy, nondiabetic (control) mice that had not received STZ. In future studies, the BIs described here will serve as platforms to evaluate the capability of immunomodulatory compounds, delivered locally within the BI, to prevent or reverse diabetes in the setting of autoimmune (type 1) diabetes.