University of Arizona, Department of Surgery, Institute of Cellular Transplantation, Tucson, AZ 85721, USA.
University of Arizona, Department of Surgery, Institute of Cellular Transplantation, Tucson, AZ 85721, USA.
Adv Drug Deliv Rev. 2019 Jan 15;139:139-156. doi: 10.1016/j.addr.2019.05.002. Epub 2019 May 8.
Human allogeneic islet transplantation (ITx) is emerging as a promising treatment option for qualified patients with type 1 diabetes. However, widespread clinical application of allogeneic ITx is hindered by two critical barriers: the need for systemic immunosuppression and the limited supply of human islet tissue. Biocompatible, retrievable immunoisolation devices containing glucose-responsive insulin-secreting tissue may address both critical barriers by enabling the more effective and efficient use of allogeneic islets without immunosuppression in the near-term, and ultimately the use of a cell source with a virtually unlimited supply, such as human stem cell-derived β-cells or xenogeneic (porcine) islets with minimal or no immunosuppression. However, even though encapsulation methods have been developed and immunoprotection has been successfully tested in small and large animal models and to a limited extent in proof-of-concept clinical studies, the effective use of encapsulation approaches to convincingly and consistently treat diabetes in humans has yet to be demonstrated. There is increasing consensus that inadequate oxygen supply is a major factor limiting their clinical translation and routine implementation. Poor oxygenation negatively affects cell viability and β-cell function, and the problem is exacerbated with the high-density seeding required for reasonably-sized clinical encapsulation devices. Approaches for enhanced oxygen delivery to encapsulated tissues in implantable devices are therefore being actively developed and tested. This review summarizes fundamental aspects of islet microarchitecture and β-cell physiology as well as encapsulation approaches highlighting the need for adequate oxygenation; it also evaluates existing and emerging approaches for enhanced oxygen delivery to encapsulation devices, particularly with the advent of β-cell sources from stem cells that may enable the large-scale application of this approach.
同种异体胰岛移植 (ITx) 作为一种有前途的治疗方法，正在为合格的 1 型糖尿病患者出现。然而，同种异体 ITx 的广泛临床应用受到两个关键障碍的阻碍：需要全身免疫抑制和人类胰岛组织的有限供应。含有葡萄糖反应性胰岛素分泌组织的生物相容性、可回收的免疫隔离装置可以通过在近期内实现更有效和高效地使用同种异体胰岛而无需免疫抑制，以及最终使用具有几乎无限供应的细胞来源，例如人类干细胞衍生的β细胞或具有最小或无需免疫抑制的异种（猪）胰岛，来解决这两个关键障碍。然而，尽管已经开发了封装方法并在小动物和大动物模型中成功测试了免疫保护作用，并且在概念验证临床研究中也进行了有限的测试，但尚未证明封装方法在治疗人类糖尿病方面的有效性和一致性。越来越多的共识认为，供氧不足是限制其临床转化和常规应用的一个主要因素。缺氧会对细胞活力和β细胞功能产生负面影响，而对于临床封装设备所需的高密度播种，这个问题会更加严重。因此，正在积极开发和测试用于可植入设备中封装组织的增强氧气输送方法。这篇综述总结了胰岛微结构和β细胞生理学以及封装方法的基本方面，强调了充足供氧的必要性；它还评估了现有的和新兴的增强氧气输送到封装设备的方法，特别是随着干细胞来源的β细胞的出现，这可能使这种方法得到大规模应用。
