Barkai Uriel, Rotem Avi, de Vos Paul
Uriel Barkai, Avi Rotem, Beta-O2 Technologies, Rosh HaAyin 4809900, Israel.
World J Transplant. 2016 Mar 24;6(1):69-90. doi: 10.5500/wjt.v6.i1.69.
At present, proven clinical treatments but no cures are available for diabetes, a global epidemic with a huge economic burden. Transplantation of islets of Langerhans by their infusion into vascularized organs is an experimental clinical protocol, the first approach to attain cure. However, it is associated with lifelong use of immunosuppressants. To overcome the need for immunosuppression, islets are encapsulated and separated from the host immune system by a permselective membrane. The lead material for this application is alginate which was tested in many animal models and a few clinical trials. This review discusses all aspects related to the function of transplanted encapsulated islets such as the basic requirements from a permselective membrane (e.g., allowable hydrodynamic radii, implications of the thickness of the membrane and relative electrical charge). Another aspect involves adequate oxygen supply, which is essential for survival/performance of transplanted islets, especially when using large retrievable macro-capsules implanted in poorly oxygenated sites like the subcutis. Notably, islets can survive under low oxygen tension and are physiologically active at > 40 Torr. Surprisingly, when densely crowded, islets are fully functional under hyperoxic pressure of up to 500 Torr (> 300% of atmospheric oxygen tension). The review also addresses an additional category of requirements for optimal performance of transplanted islets, named auxiliary technologies. These include control of inflammation, apoptosis, angiogenesis, and the intra-capsular environment. The review highlights that curing diabetes with a functional bio-artificial pancreas requires optimizing all of these aspects, and that significant advances have already been made in many of them.
目前，糖尿病作为一种造成巨大经济负担的全球性流行病，虽有经过验证的临床治疗方法，但尚无治愈手段。将胰岛输注到血管化器官中进行移植是一种实验性临床方案，也是实现治愈的首要方法。然而，这与终身使用免疫抑制剂有关。为了克服免疫抑制的需求，胰岛被封装起来，并通过一种具有选择透过性的膜与宿主免疫系统隔离开。用于此应用的主要材料是藻酸盐，它已在许多动物模型和一些临床试验中进行了测试。本综述讨论了与移植的封装胰岛功能相关的所有方面，例如对具有选择透过性的膜的基本要求（例如，允许的流体动力学半径、膜厚度的影响以及相对电荷）。另一个方面涉及充足的氧气供应，这对于移植胰岛的存活/功能至关重要，特别是当使用植入皮下等低氧部位的大型可回收大胶囊时。值得注意的是，胰岛能够在低氧张力下存活，并且在大于40托时具有生理活性。令人惊讶的是，当胰岛密集聚集时，在高达500托的高氧压力下（>大气氧张力的300%）仍能完全发挥功能。该综述还阐述了移植胰岛最佳性能的另一类要求，即辅助技术。这些包括炎症控制、细胞凋亡、血管生成以及囊内环境。该综述强调，用功能性生物人工胰腺治愈糖尿病需要优化所有这些方面，并且其中许多方面已经取得了重大进展。
