San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Medical University of Vienna, Vienna, Austria.
Biomaterials. 2019 Apr;199:40-51. doi: 10.1016/j.biomaterials.2019.01.035. Epub 2019 Jan 24.
Islet transplantation is superior to extrinsic insulin supplementation in the treating severe Type 1 diabetes. However, its efficiency and longevity are limited by substantial islet loss post-transplantation due to lack of engraftment and vascular supply. To overcome these limitations, we developed a novel approach to bio-fabricate functional, vascularized islet organs (VIOs) ex vivo. We endothelialized acellular lung matrixes to provide a biocompatible multicompartment scaffold with an intact hierarchical vascular tree as a backbone for islet engraftment. Over seven days of culture, islets anatomically and functionally integrated into the surrounding bio-engineered vasculature, generating a functional perfusable endocrine organ. When exposed to supra-physiologic arterial glucose levels in vivo and ex vivo, mature VIOs responded with a physiologic insulin release from the vein and provided more efficient reduction of hyperglycemia compared to intraportally transplanted fresh islets. In long-term transplants in diabetic mice, subcutaneously implanted VIOs achieved normoglycemia significantly faster and more efficiently compared to islets that were transplanted in deviceless fashion. We conclude that ex vivo bio-fabrication of VIOs enables islet engraftment and vascularization before transplantation, and thereby helps to overcome limited islet survival and function observed in conventional islet transplantation. Given recent progress in stem cells, this technology may enable assembly of functional personalized endocrine organs.
胰岛移植在治疗严重 1 型糖尿病方面优于外源性胰岛素补充。然而，由于缺乏植入和血管供应，移植后大量胰岛丢失，其效率和寿命受到限制。为了克服这些限制，我们开发了一种新的方法，即在体外生物制造功能性、血管化胰岛器官 (VIO)。我们将细胞外肺基质内皮化，为胰岛植入提供一个具有完整分级血管树的生物相容性多腔支架作为骨干。在 7 天的培养过程中，胰岛在解剖学和功能上与周围的生物工程血管整合，形成具有功能的可灌注内分泌器官。当在体内和体外暴露于超生理动脉葡萄糖水平时，成熟的 VIO 从静脉释放出生理性胰岛素，并与门静脉内移植的新鲜胰岛相比，更有效地降低高血糖。在糖尿病小鼠的长期移植中，与非设备移植的胰岛相比，皮下植入的 VIO 更快、更有效地实现了正常血糖水平。我们得出结论，体外生物制造 VIO 可在移植前实现胰岛的植入和血管化，从而有助于克服传统胰岛移植中观察到的有限的胰岛存活和功能。鉴于最近在干细胞方面的进展，这项技术可能能够组装具有功能的个性化内分泌器官。
