New Solutions to Improve Islet Recovery after Machine Preservation of Pancreas

改善胰腺机器保存后胰岛恢复的新解决方案

• 批准号: 7328324
• 负责人: MICHAEL John TAYLOR
• 金额: $ 59.39万
• 依托单位: CELL AND TISSUE SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7328324
• 关键词: Accounting; Address; Adopted; Agreement; Allografting; Appendix; Attention; Award; Biological Assay; Biological Preservation; Biology; Buffers; Cells; Characteristics; Clinical; Collaborations; Companions; Condition; Cryopreservation; Cytoprotective Agent; Data; Development; Devices; Diabetes Mellitus; Drug Formulations; Evaluation; Family suidae; Funding; Gland; Goals; Grant; Harvest; Hospitals; Hour; Human; Immunosuppression; In Vitro; Insulin-Dependent Diabetes Mellitus; Ischemia; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Kidney; Legal patent; Letters; Medical center; Methods; Modeling; Modification; Monitor; National Institute of Diabetes and Digestive and Kidney Diseases; Numbers; Organ; Organ Preservation; Organ Preservation Solutions; Organ Procurements; Outcome; Pancreas; Perfusion; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Physiological; Procedures; Process; Protocols documentation; Range; Recovery; Relative (related person); Replacement Therapy; Research; Research Design; Research Institute; Resources; Review Committee; Safety; Scientist; Shipping; Ships; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Solutions; South Carolina; Specialist; Standards of Weights and Measures; Statistically Significant; System; Techniques; Technology; Testing; Therapeutic immunosuppression; Time; Tissues; Transplantation; United States Food and Drug Administration; University of Wisconsin-lactobionate solution; Validation; Viaspan; Warm Ischemia; Work; base; commercialization; concept; design; experience; high throughput screening; implantation; improved; interest; islet; kidney preservation; new technology; pre-clinical; programs; prototype; technology development; type I diabetic

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“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已重新引起人们的兴趣。然而，目前用于胰岛分离和移植的供体胰腺的采购还处于起步阶段。由于担心在运送到胰岛分离和移植中心过程中死后缺血，大多数较偏远供体部位的胰腺都没有获得。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采购用于移植的活胰岛。该提案的主要目标是使用最先进的灌注技术和新的保存解决方案来检验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，在之前的研究中设计并构建了原型胰腺转运蛋白（PTR），证明了使用猪模型在2-7℃下24小时灌注保存的可行性。这超过了目前记录的供体胰腺安全静态冷藏的 16 小时临床极限。在这里，我们提出一项补充研究，以解决该技术进一步发展的第二个重要因素，即灌注液的设计和优化，以最大限度地提高低温机器灌注保存后分离胰岛的产量和活力。更具体地说，在第一阶段研究中，将新的专有解决方案（Unisol）与当前标准器官保存解决方案（KPS1 和 UW Viaspan）进行比较，以保存新鲜猪胰腺 24 小时。这项新技术的安全性和有效性将在第二阶段研究中得到进一步研究，其中用于灌注 PTR 中胰腺的解决方案的设计将在四个具体目标上进行优化。第一步是使用高通量测定系统来选择要掺入基础灌注液中的细胞保护添加剂。第二步将需要对添加细胞保护混合物的胰腺灌注液进行比较，以机器保存新鲜胰腺而无需热缺血。然后，将使用优化的灌注液评估冷灌注时间（24 和 48 小时）和热缺血时间（最多 60 分钟）对猪胰岛隔离参数之间的相互作用，以确定潜在的临床范围和技术限制。最后，不适合移植的人类胰腺将被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利用大多数（如果不是全部）适合移植的胰腺。此外，PTR 可能允许胰岛隔离库进行长期储存。银行业务将允许有时间更好地进行供体与受体的 HLA 匹配、现成的可用性，并能够在移植前进行质量保证/控制程序。该研究计划得到了与三个主要临床中心的合作支持，这些中心对验证这种灌注技术的未来用途感兴趣。 项目叙述：胰岛素依赖型糖尿病是世界范围内的主要健康问题之一，现在人们对开发一种通过移植从供体胰腺中分离的胰岛细胞进行潜在治疗的选择非常感兴趣。该方法的一个关键组成部分是提供足够的高质量胰岛来逆转患者的糖尿病。这项研究的重点是开发新技术（灌注机和保护溶液），以提高胰腺保存的质量，以产生更多的高功能胰岛细胞。