New Solutions Islet Recovery Preservation of Pancreas

新解决方案 胰岛恢复 保存胰腺

• 批准号: 7154824
• 负责人: MICHAEL John TAYLOR
• 金额: $ 16.2万
• 依托单位: CELL AND TISSUE SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7154824
• 关键词: animal tissue; cytoprotection; diabetes mellitus therapy; high throughput technology; histology; human tissue; insulin dependent diabetes mellitus; ischemia; laboratory mouse; nonhuman therapy evaluation; pancreas; pancreatic islet transplantation; pancreatic islets; perfusion; technology /technique development; temperature; tissue /organ preservation

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) has been designed and constructed in a previous study that demonstrated the feasibility of 24h perfusion preservation at 2-7 degrees C using a porcine model. This exceeds the 16h documented to be the present clinical limits of safe, static cold storage of donor pancreata. Here we propose a complimentary study to address the second important factor for further development of this technology, namely the design and optimization of the perfusate to maximize the yield and viability of isolated islets after hypothermic machine perfusion preservation. More specifically, in the Phase I study a new proprietary solution (Unisol) will be compared with current standard organ preservation solutions (KPS1 and UW Viaspan) for 24h preservation of fresh porcine pancreata. The safety and efficacy of this new technology will be further investigated during a Phase II study in which the design of the solution used to perfuse the pancreas in the PTR will be optimized in four specific aims. The first step will be to use a system of high throughput assays to select cytoprotective additives to be incorporated into the base perfusates. The second step will entail a comparison of pancreas perfusates with the addition of the cytoprotective cocktail for machine preservation of fresh pancreata with no warm ischemia. 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 using the optimized perfusate 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. Project Narrative: Insulin-dependent diabetes is one of the major health problems worldwide and there is now a great deal of interest in developing an option for a potential cure by transplantation of islet cells isolated from a donor pancreas. A critical component of this approach is the availability of sufficient high quality islets to reverse diabetes in the patient. This research is focused on the development of new technologies (a perfusion machine and protective solutions) for improving the quality of pancreas preservation to yield larger numbers of high functioning islet cells.

描述（由申请人提供）：由于使用“ Edmonton方案”获得的结果，兰格汉斯胰岛的胰岛胰岛移植引起了人们的关注。但是，目前，供体胰腺胰腺分离和移植的采购仍处于起步阶段。由于在运输到胰岛隔离和移植中心期间，大多数偏远供体站点的胰腺未能得到采购。灌注/保存技术已被证明对肾脏移植中的缺血性损伤产生了重大影响。该提案旨在将这种方法应用于可行胰岛进行移植的保存和采购。该提案的主要目的是使用最先进的灌注技术和新的保存解决方案来检验以下假设：机器灌注可以提高缺血性胰腺制备的胰岛的产量和生存能力。为此，在先前的研究中设计和构建了原型胰腺转运蛋白（PTR），该研究证明了使用猪模型在2-7摄氏度下24H灌注保存的可行性。这超过了16小时的记录是供体胰腺安全，静态冷藏的当前临床限制。在这里，我们提出了一项免费研究，以解决该技术进一步开发的第二个重要因素，即灌注液的设计和优化，以最大程度地提高隔离胰岛的产量和生存能力。更具体地说，在第一阶段研究中，将将一种新的专有溶液（UNISOL）与当前标准器官保存溶液（KPS1和UW Viaspan）进行比较，以24小时保存新鲜的猪胰腺。在II期研究中将进一步研究这项新技术的安全性和功效，在该研究中，用于在PTR中灌注胰腺的解决方案的设计将在四个特定目标中进行优化。第一步是使用高吞吐量测定系统来选择将细胞保护添加剂掺入基础灌注液中。第二步将需要比较胰腺灌注液与添加细胞保护鸡尾酒以机器保存新鲜胰腺，没有温暖的缺血。然后，将使用优化的灌注液在猪胰岛分离参数上进行冷灌注时间（24和48h）与温暖的缺血时间（最长60分钟）之间的相互作用，以定义潜在的临床范围和技术限制。最后，将采用不适合移植的人类胰腺来临时验证该技术。预计胰腺转运蛋白和胰腺灌注方案的可用性将允许大多数（如果不是全部）使用适合在美国移植的胰腺，此外，PTR可以允许胰岛隔离银行业务用于长期存储。银行业务将使时间可以更好地匹配捐助者与接收者，现成的可用性，并在移植前实现质量保证/控制程序。该研究计划得到了与有兴趣验证该灌注技术未来使用的三个主要临床中心合作的支持。 项目叙述：胰岛素依赖性糖尿病是全球主要的健康问题之一，现在通过从供体胰腺中分离出的胰岛细胞来开发潜在治愈的选择有很大的兴趣。这种方法的一个关键组成部分是有足够的高质量胰岛可逆转患者的糖尿病。这项研究的重点是开发新技术（一种灌注机和保护溶液），以提高胰腺保存质量，以产生大量高功能的胰岛细胞。