Pancreas Transporter Development and Validation

胰腺转运蛋白的开发和验证

基本信息

批准号：
7123761
负责人：
MICHAEL John TAYLOR
金额：
$ 48.95万
依托单位：
CELL AND TISSUE SYSTEMS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7123761
关键词：
athymic mouse biomedical equipment development clinical biomedical equipment clinical research cold temperature human tissue pancreatic islet transplantation pancreatic islets perfusion swine tissue /organ preservation

项目摘要

DESCRIPTION (provided by applicant): Transplantation of islets of Langerhans for the clinical treatment of Type I diabetes has had a resurgence of interest due to results obtained using the "Edmonton protocol". However, at this time, procurement of donor pancreases for islet isolation and transplantation is in its infancy. Most pancreases at more remote donor sites are not procured due to justified concerns about post-mortem ischemia during transport to the islet isolation and transplant center. Perfusion/preservation technology has been shown to have a major impact in circumventing ischemic injury in kidney transplantation. This proposal seeks to apply this approach to the preservation and procurement of viable islets for transplantation. The primary objective of this proposal is to use state-of-the-art perfusion technology and new preservation solutions to test the hypothesis that machine perfusion can improve the yield and viability of islets prepared from ischemic pancreases. To this end, a prototype pancreas transporter (PTR) was designed and constructed in the Phase I study. The feasibility of 24h perfusion preservation at 2-7¿C was demonstrated using a porcine model that exceeds the 16h documented to be the present clinical limits of safe, static cold storage of donor pancreatic. Islet yield and function was demonstrated to be equivalent to that obtained from fresh control pancreases. The safety and efficacy of this new technology will be further investigated during this Phase II study with three specific aims. The first step will be to implement design modifications to the PTR ensuing from the Phase I feasibility study. The second step will entail a comparison of the yield and function indices for islets isolated from pancreata perfused for 24h on the PTR with indices obtained from control, 24h conventionally stored pancreata. Then the interaction between cold perfusion time (24 and 48h) and warm ischemia time (up to 60 min) on porcine islet isolation parameters will be evaluated for the definition of the potential clinical scope and technology limits. Finally, human pancreases that are unsuitable for transplantation will be employed for pre-clinical validation of this technology. It is anticipated that the availability of a pancreas transporter and pancreas perfusion protocols will permit utilization of most, if not all, pancreases suitable for transplantation in the U.S. Furthermore, the PTR may permit islet isolation banking for long-term storage. Banking would allow time for better HLA matching of donors to recipients, off-the-shelf availability, and enable quality assurance/control procedures to be conducted prior to transplantation. This research program is supported by collaboration with three major clinical centers interested in validation of this perfusion technology for their future use.

描述（由申请人提供）：由于使用“埃德蒙顿方案”获得的结果，用于临床治疗 I 型糖尿病的朗格汉斯胰岛移植重新引起了人们的兴趣，然而，此时，采购供体胰腺用于胰岛分离。由于对运输至胰岛分离和移植过程中死后缺血的合理担忧，大多数较偏远供体部位的胰腺都未获得。灌注/保存技术已被证明对避免肾移植中的缺血性损伤具有重大影响。该提案旨在将这种方法应用于保存和获取用于移植的活胰岛。最先进的灌注技术和新的保存解决方案，以测试机器灌注可以提高缺血性胰腺制备的胰岛的产量和活力的假设。为此，设计了一个原型胰腺转运蛋白（PTR）。在 I 期研究中构建了 2-7° 24 小时灌注保存的可行性。 C 使用猪模型进行了证明，该模型超过了目前记录的供体胰腺安全、静态冷藏的 16 小时的临床极限，其胰岛产量和功能与从新鲜对照胰腺获得的安全性和功效相当。这项新技术将在第二阶段研究中得到进一步研究，有三个具体目标：第一步是对第一阶段可行性研究后的 PTR 进行设计修改，第二步将进行产量和功能指数的比较。为了从胰腺中分离的胰岛在 PTR 上灌注 24 小时，并从对照、常规保存的胰腺 24 小时获得指数，然后将猪胰岛分离参数上的冷灌注时间（24 和 48 小时）与热缺血时间（最多 60 分钟）之间的相互作用表示为。最后，评估潜在临床范围和技术限制的定义，不适合移植的人类胰腺将用于该技术的临床前验证。预计胰腺转运蛋白和胰腺灌注方案的可用性将允许在美国使用大多数（如果不是全部）适合移植的胰腺。此外，PTR 可能允许胰岛隔离储存以进行长期储存。为了更好地匹配供体与受体的 HLA，提供现成的可用性，并在移植前进行质量保证/控制程序。该研究项目得到了与对此验证感兴趣的三个主要临床中心的合作支持。灌注技术以供将来使用。