PDF(Pubmed)
Abstract：
UNASSIGNED: Successful diabetes reversal using pancreatic islet transplantation by various groups illustrates the significant achievements made in cell-based diabetes therapy. While clinically, intraportal islet delivery is almost exclusively used, it is not without obstacles, including instant blood-mediated inflammatory reaction (IBMIR), relative hypoxia, and loss of function over time, therefore hindering long-term success. Here we demonstrate the perihepatic surface of non-human primates (NHPs) as a potential islet delivery site maximizing favorable characteristics, including proximity to a dense vascular network for adequate oxygenation while avoiding IBMIR exposure, maintenance of portal insulin delivery, and relative ease of accessibility through minimally invasive surgery or percutaneous means. In addition, we demonstrate a targeted mapping technique of the perihepatic surface, allowing for the testing of multiple experimental conditions, including a semi-synthetic hydrogel as a possible three-dimensional framework to improve islet viability.
UNASSIGNED: Perihepatic allo-islet cell transplants were performed in immunosuppressed cynomolgus macaques using a targeted mapping technique to test multiple conditions for biocompatibility. Transplant conditions included islets or carriers (including hydrogel, autologous plasma, and media) alone or in various combinations. Necropsy was performed at day 30, and histopathology was performed to assess biocompatibility, immune response, and islet viability. Subsequently, single-injection perihepatic allo-islet transplant was performed in immunosuppressed diabetic cynomolgus macaques. Metabolic assessments were measured frequently (i.e., blood glucose, insulin, C-peptide) until final graft retrieval for histopathology.
UNASSIGNED: Targeted mapping biocompatibility studies demonstrated mild inflammatory changes with islet-plasma constructs; however, significant inflammatory cell infiltration and fibrosis were seen surrounding sites with the hydrogel carrier affecting islet viability. In diabetic NHPs, perihepatic islet transplant using an autologous plasma carrier demonstrated prolonged function up to 6 months with improvements in blood glucose, exogenous insulin requirements, and HbA1c. Histopathology of these islets was associated with mild peri-islet mononuclear cell infiltration without evidence of rejection.
UNASSIGNED: The perihepatic surface serves as a viable site for islet cell transplantation demonstrating sustained islet function through 6 months. The targeted mapping approach allows for the testing of multiple conditions simultaneously to evaluate immune response to biomaterials at this site. Compared to traditional intraportal injection, the perihepatic site is a minimally invasive approach that allows the possibility for graft recovery and avoids IBMIR.
UNASSIGNED: Perihepatic allo-islet cell transplants were performed in immunosuppressed cynomolgus macaques using a targeted mapping technique to test multiple conditions for biocompatibility. Transplant conditions included islets or carriers (including hydrogel, autologous plasma, and media) alone or in various combinations. Necropsy was performed at day 30, and histopathology was performed to assess biocompatibility, immune response, and islet viability. Subsequently, single-injection perihepatic allo-islet transplant was performed in immunosuppressed diabetic cynomolgus macaques. Metabolic assessments were measured frequently (i.e., blood glucose, insulin, C-peptide) until final graft retrieval for histopathology.
UNASSIGNED: Targeted mapping biocompatibility studies demonstrated mild inflammatory changes with islet-plasma constructs; however, significant inflammatory cell infiltration and fibrosis were seen surrounding sites with the hydrogel carrier affecting islet viability. In diabetic NHPs, perihepatic islet transplant using an autologous plasma carrier demonstrated prolonged function up to 6 months with improvements in blood glucose, exogenous insulin requirements, and HbA1c. Histopathology of these islets was associated with mild peri-islet mononuclear cell infiltration without evidence of rejection.
UNASSIGNED: The perihepatic surface serves as a viable site for islet cell transplantation demonstrating sustained islet function through 6 months. The targeted mapping approach allows for the testing of multiple conditions simultaneously to evaluate immune response to biomaterials at this site. Compared to traditional intraportal injection, the perihepatic site is a minimally invasive approach that allows the possibility for graft recovery and avoids IBMIR.
摘要：
■各组使用胰岛移植成功逆转糖尿病，说明了基于细胞的糖尿病治疗取得的重大成就。在临床上,几乎只使用门内胰岛递送，它不是没有障碍，包括即时血液介导的炎症反应（IBMIR），相对缺氧,随着时间的推移和功能的丧失，因此阻碍了长期的成功。在这里，我们证明了非人灵长类动物（NHP）的肝周表面作为一个潜在的胰岛传递部位最大化有利的特征，包括接近密集的血管网络以获得足够的氧合，同时避免IBMIR暴露，维持门静脉胰岛素输送，以及通过微创手术或经皮手段相对容易进入。此外,我们展示了肝周表面的靶向标测技术，允许测试多个实验条件，包括半合成水凝胶作为可能的三维框架，以提高胰岛活力。
■使用靶向定位技术在免疫抑制的食蟹猴中进行肝周同种异体胰岛细胞移植，以测试多种条件的生物相容性。移植条件包括胰岛或载体（包括水凝胶，自体血浆,和介质)单独或以各种组合。在第30天进行尸检，并进行组织病理学以评估生物相容性。免疫反应，和胰岛活力。随后，在免疫抑制的糖尿病食蟹猴中进行单次注射肝周同种异体胰岛移植。代谢评估经常测量(即，血糖，胰岛素，C-肽）直到最终的移植物恢复用于组织病理学。
■靶向定位生物相容性研究表明，胰岛-血浆结构有轻度炎症变化；然而，在水凝胶载体影响胰岛活力的情况下，周围部位可见明显的炎症细胞浸润和纤维化。在糖尿病性NHP中，使用自体血浆载体的肝周胰岛移植显示了长达6个月的延长功能，并改善了血糖，外源性胰岛素需求，和HbA1c。这些胰岛的组织病理学与轻度胰岛周围单核细胞浸润有关，没有排斥的证据。
■肝周表面作为胰岛细胞移植的可行部位，显示出持续6个月的胰岛功能。有针对性的作图方法允许同时测试多种条件，以评估该部位对生物材料的免疫反应。与传统的门内注射相比，肝周部位是一种微创方法，可以恢复移植物并避免IBMIR。
■使用靶向定位技术在免疫抑制的食蟹猴中进行肝周同种异体胰岛细胞移植，以测试多种条件的生物相容性。移植条件包括胰岛或载体（包括水凝胶，自体血浆,和介质)单独或以各种组合。在第30天进行尸检，并进行组织病理学以评估生物相容性。免疫反应，和胰岛活力。随后，在免疫抑制的糖尿病食蟹猴中进行单次注射肝周同种异体胰岛移植。代谢评估经常测量(即，血糖，胰岛素，C-肽）直到最终的移植物恢复用于组织病理学。
■靶向定位生物相容性研究表明，胰岛-血浆结构有轻度炎症变化；然而，在水凝胶载体影响胰岛活力的情况下，周围部位可见明显的炎症细胞浸润和纤维化。在糖尿病性NHP中，使用自体血浆载体的肝周胰岛移植显示了长达6个月的延长功能，并改善了血糖，外源性胰岛素需求，和HbA1c。这些胰岛的组织病理学与轻度胰岛周围单核细胞浸润有关，没有排斥的证据。
■肝周表面作为胰岛细胞移植的可行部位，显示出持续6个月的胰岛功能。有针对性的作图方法允许同时测试多种条件，以评估该部位对生物材料的免疫反应。与传统的门内注射相比，肝周部位是一种微创方法，可以恢复移植物并避免IBMIR。
