Bocca N, Pileggi A, Molano R D, Marzorati S, Wu W, Bodor N, Ricordi C, Buchwald P
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
Pharmazie. 2008 Mar;63(3):226-32.
Transplantation of pancreatic islets into subcutaneous, neovascularized devices is one of the possibilities explored as part of our search for a cure of diabetes. We have recently reported that syngeneic transplantation in a subcutaneous prevascularized device can restore euglycemia and sustain long-term function in rats and that explanted grafts showed preserved islets and intense vascular networks. Because all of the transplanted tissue is localized within the device, if such a bioartificial pancreas approach is used, localized immunosuppression might provide sufficient protection against rejection to achieve long-term function, while also avoiding the serious systemic side effects and the susceptibility for opportunistic infections that are commonly associated with systemic immunosuppressive therapies as only much smaller and localized doses are needed. Soft steroids are obvious candidates because soft drugs are specifically designed to produce targeted local activity, but no systemic side effects due to prompt metabolic (preferably extrahepatic, e.g., hydrolytic) inactivation. However, local concentrations that are effective for immunosuppression, but non-toxic to insulin-producing beta-cells have to be found, and nontrivial difficulties related to long-term local deliverability have to be addressed. Here, we report preliminary results obtained using in vitro studies with human islets used to establish a tentative therapeutic concentration range together with fully scaled three-dimensional finite element method (FEM)-based Comsol multiphysics computational models that were used to explore various possibilities to achieve and maintain these concentration levels within the device.
将胰岛移植到皮下新生血管化装置中是我们探索治疗糖尿病方法的一种途径。我们最近报道，在皮下预血管化装置中进行同基因移植可以恢复大鼠的血糖正常水平并维持长期功能，并且移植的胰岛显示出胰岛保存良好且血管网络密集。由于所有移植组织都局限于装置内，如果采用这种生物人工胰腺方法，局部免疫抑制可能提供足够的保护以防止排斥反应，从而实现长期功能，同时还能避免严重的全身副作用以及与全身免疫抑制疗法相关的机会性感染易感性，因为仅需要小得多的局部剂量。软类固醇显然是合适的选择，因为软药物专门设计用于产生靶向局部活性，但由于迅速的代谢（最好是肝外代谢，例如水解）失活而不会产生全身副作用。然而，必须找到对免疫抑制有效但对产生胰岛素的β细胞无毒的局部浓度，并且必须解决与长期局部给药相关的重大困难。在此，我们报告了使用体外研究获得的初步结果，该研究使用人类胰岛来确定初步的治疗浓度范围，同时还使用了基于全尺寸三维有限元方法（FEM）的Comsol多物理场计算模型，以探索在装置内实现和维持这些浓度水平的各种可能性。
