The Institute for BioNanotechnology in Medicine (IBNAM), Northwestern University, Chicago, IL; Department of Biomedical Engineering, Northwestern University, Evanston, IL.
Am J Transplant. 2014 Jul;14(7):1523-32. doi: 10.1111/ajt.12742. Epub 2014 Jun 6.
Islet transplantation represents a potential cure for type 1 diabetes, yet the clinical approach of intrahepatic delivery is limited by the microenvironment. Microporous scaffolds enable extrahepatic transplantation, and the microenvironment can be designed to enhance islet engraftment and function. We investigated localized trophic factor delivery in a xenogeneic human islet to mouse model of islet transplantation. Double emulsion microspheres containing exendin-4 (Ex4) or insulin-like growth factor-1 (IGF-1) were incorporated into a layered scaffold design consisting of porous outer layers for islet transplantation and a center layer for sustained factor release. Protein encapsulation and release were dependent on both the polymer concentration and the identity of the protein. Proteins retained bioactivity upon release from scaffolds in vitro. A minimal human islet mass transplanted on Ex4-releasing scaffolds demonstrated significant improvement and prolongation of graft function relative to blank scaffolds carrying no protein, and the release profile significantly impacted the duration over which the graft functioned. Ex4-releasing scaffolds enabled better glycemic control in animals subjected to an intraperitoneal glucose tolerance test. Scaffolds releasing IGF-1 lowered blood glucose levels, yet the reduction was insufficient to achieve euglycemia. Ex4-delivering scaffolds provide an extrahepatic transplantation site for modulating the islet microenvironment to enhance islet function posttransplant.
胰岛移植为 1 型糖尿病提供了一种潜在的治愈方法，但肝内递送的临床方法受到微环境的限制。微孔支架使肝外移植成为可能，并且可以设计微环境以增强胰岛移植和功能。我们研究了异种人胰岛在胰岛移植的小鼠模型中局部营养因子的递送。含有 Exendin-4 (Ex4) 或胰岛素样生长因子-1 (IGF-1) 的双乳液微球被纳入由多孔外层组成的分层支架设计中，用于胰岛移植和中心层用于持续释放因子。蛋白质的包封和释放既取决于聚合物浓度，也取决于蛋白质的特性。蛋白质在体外从支架中释放后保持生物活性。与不携带蛋白质的空白支架相比，在释放 Ex4 的支架上移植最小量的人胰岛可显著改善和延长移植物的功能，释放曲线显著影响移植物的功能持续时间。释放 Ex4 的支架使接受腹腔内葡萄糖耐量试验的动物能够更好地控制血糖。释放 IGF-1 的支架降低了血糖水平，但降低幅度不足以实现正常血糖水平。释放 Ex4 的支架为调节胰岛微环境提供了肝外移植部位，以增强移植后胰岛的功能。
