Pancreas perfusion with PFC-Unisol

使用 PFC-Unisol 进行胰腺灌注

• 批准号: 8199010
• 负责人: MICHAEL John TAYLOR
• 金额: $ 31.2万
• 依托单位: CELL AND TISSUE SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8199010
• 关键词: Adopted; Adoption; Animal Model; Animals; Beds; Biological Preservation; Blood; Blood Substitutes; Brain Hypoxia-Ischemia; Cells; Clinical; Clinical Trials; Consensus; Cryopreservation; Development; Diabetes Mellitus; Diffuse; Diffusion; Emulsions; Family suidae; Fibrinogen; Fluorocarbons; Glucose; Goals; Health; Hour; Human; Hypoxia; In Vitro; Individual; Injury; Insulin; Insulin-Dependent Diabetes Mellitus; Ischemia; Islets of Langerhans Transplantation; Kidney; Length; Literature; Lobe; Methods; Modality; Modeling; Natural regeneration; Organ; Organ Donor; Organ Preservation; Outcome; Oxygen; Pancreas; Patients; Penetration; Perfusion; Regional Perfusion; Reporting; Research; Solutions; Source; Techniques; Technology; Testing; Time; Tissues; Transplantation; University of Wisconsin-lactobionate solution; Xenograft procedure; anaerobic glycolysis; aqueous; base; clinical practice; deprivation; design; improved; inorganic phosphate; interest; islet; meetings; natural hypothermia; novel strategies; oxygen debt; pressure; response; standard of care; technology development

DESCRIPTION (provided by applicant): There is a worldwide consensus that islet transplantation may be considered a viable option for the treatment of insulin-dependent diabetes mellitus, and clinical trials are underway at many centers around the world. As this approach for curing diabetes transitions into a routine clinical standard of care so the demand for donor islets will escalate. Moreover, the potential for xenotransplantation to relieve the demand on an inadequate supply of human pancreases will also be dependent upon the efficiency of techniques for isolating islets from the source pancreases. Unfortunately, islets are highly vulnerable to irreversible damage after prolonged ischemia, and cold ischemia of the cadaveric pancreas is detrimental to islet yield such that new approaches are needed for improved methods of pancreas preservation to increase the yields of high quality islets. Hypothermia has proved to be the bed-rock of the most widely used methods of organ preservation but the best techniques are still subject to some cold ischemic injury. Oxygen deprivation is still regarded as a key factor and one strategy adopted to try to reduce the oxygen debt during ischemia has been to use perfluorocarbons (PFC) in an attempt to augment oxygen delivery to the cold ischemic organ. However, the Two-Layer Method, in which the organ is submerged at the aqueous/PFC interface, has only proved successful in small animal models. As an alternative approach the hypothesis underpinning this proposal is that PFCs will need to be perfused into the organ to provide effective oxygen delivery to the hypoxic cold ischemic cells. The general aim of the proposed research is to combine three technologies that could impact the quality of donor organs, and notably pancreases. These are: i) hypothermic machine perfusion (HMP); ii) hypothermic blood substitution (HBS); and iii) oxygenation with perfluorochemicals (PFC). Our hypothesis that HMP with PFC-augmented HBS will provide superior hypothermic preservation of pancreases will be tested using two specific aims: The first aim will be to establish perfusion dynamics with Unisol-PFC, where Unisol is a proprietary HBS. Using an established porcine model, our baseline technology of HMP with Unisol HBS will be adapted to prepare an emulsion of PFC in Unisol (Unisol-PFC) and the perfusion parameters necessary to facilitate efficient perfusion will be determined using a LifePort(R) perfusion machine. The second aim will be to evaluate the efficacy of PFC-perfusion on the quality of post-perfusion isolation of islets. Using an established model of split-lobe perfusion the goal will be to compare the yield and quality of islets isolated from porcine pancreas lobes perfused with Unisol-PFC compared with Unisol alone. The anticipated outcome of this approach is that the implementation of PFC-augmented perfusion will provide a sustainable reservoir of O2 to meet the markedly reduced demands of the organ during extended cold ischemic storage. In turn, this will provide the means for high energy phosphate regeneration and avert the well recognized consequences of anaerobic glycolysis that the organ is forced to switch to during hypoxia and ischemia. While these studies are specifically designed to focus on the clinical need in islet transplantation, the underlying technology developments will be readily applicable to all transplantable organs. PUBLIC HEALTH RELEVANCE: Insulin-dependent diabetes is one of the major health problems worldwide and there is a great deal of interest in developing 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. Current methods of storing organs prior to transplantation, or storing the pancreas prior to islet isolation, rely on hypothermic preservation modalities in which the organ still endures some injury from oxygen deprivation. This research is focused on the development of a new alternative technique to sustain oxygen delivery to the organ using perfusion technology with new inert oxygen-carrying solutions.

描述（由申请人提供）：世界范围内一致认为胰岛移植可能被认为是治疗胰岛素依赖型糖尿病的可行选择，并且世界各地的许多中心正在进行临床试验。随着这种治疗糖尿病的方法转变为常规临床护理标准，对供体胰岛的需求将会增加。此外，异种移植缓解人类胰腺供应不足的需求的潜力也将取决于从来源胰腺中分离胰岛的技术的效率。不幸的是，胰岛在长期缺血后极易受到不可逆的损伤，并且尸体胰腺的冷缺血不利于胰岛产量，因此需要新的方法来改进胰腺保存方法以提高高质量胰岛的产量。低温已被证明是最广泛使用的器官保存方法的基础，但最好的技术仍然会受到一些冷缺血性损伤。缺氧仍然被认为是一个关键因素，为减少缺血期间的氧债而采用的一种策略是使用全氟化碳（PFC）来尝试增加向冷缺血器官的氧气输送。然而，将器官浸入水/PFC界面的两层法仅在小动物模型中被证明是成功的。作为替代方法，支持该提议的假设是，需要将 PFC 灌注到器官中，以向缺氧的冷缺血细胞提供有效的氧气输送。拟议研究的总体目标是将三种可能影响捐赠器官质量的技术结合起来，特别是胰腺。它们是： i) 低温机器灌注 (HMP)； ii) 低温血液替代（HBS）； iii) 用全氟化合物 (PFC) 进行氧化。我们的假设是，带有 PFC 增强 HBS 的 HMP 将提供卓越的胰腺低温保存功能，我们将使用两个具体目标进行测试：第一个目标是使用 Unisol-PFC 建立灌注动力学，其中 Unisol 是一种专有的 HBS。使用已建立的猪模型，我们的 HMP 与 Unisol HBS 基线技术将适用于在 Unisol 中制备 PFC 乳液 (Unisol-PFC)，并且将使用 LifePort(R) 灌注机确定促进高效灌注所需的灌注参数。第二个目标是评估 PFC 灌注对胰岛灌注后分离质量的功效。使用已建立的裂叶灌注模型，目标是比较从用 Unisol-PFC 灌注的猪胰叶中分离出的胰岛与单独使用 Unisol 的胰岛的产量和质量。这种方法的预期结果是，PFC增强灌注的实施将提供可持续的氧气储存库，以满足器官在长期冷缺血储存期间显着减少的需求。反过来，这将为高能磷酸盐再生提供手段，并避免器官在缺氧和缺血期间被迫转向无氧糖酵解的众所周知的后果。虽然这些研究是专门针对胰岛移植的临床需求而设计的，但基础技术的发展将很容易适用于所有可移植器官。 公共健康相关性：胰岛素依赖型糖尿病是世界范围内的主要健康问题之一，人们对通过移植从供体胰腺中分离的胰岛细胞来开发潜在的治疗方法非常感兴趣。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。目前在移植前储存器官或在胰岛分离前储存胰腺的方法依赖于低温保存方式，在这种方式中，器官仍会因缺氧而遭受一些损伤。这项研究的重点是开发一种新的替代技术，利用灌注技术和新的惰性携氧溶液来维持向器官的氧气输送。