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(申请人提供)：全世界已达成共识，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，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的临床护理标准，对供体胰岛的需求将会升级。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将胰岛与来源胰腺分离的技术的效率。不幸的是，胰岛在长时间的缺血后极易受到不可逆转的损伤，而身体胰腺的冷缺血对胰岛产量不利，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，但最好的技术仍然受到一些冷缺血损伤的影响。缺氧仍然被认为是一个关键因素，为了减少缺血时的氧债，人们采取的一种策略是使用全氟碳化合物(PFC)，试图增加对冷缺血器官的氧气输送。然而，器官被淹没在水/PFC界面的两层方法只在小动物模型中被证明是成功的。作为另一种方法，支持这一提议的假设是，PFC需要被灌流到器官中，以向缺氧的冷缺血细胞提供有效的氧气输送。这项拟议研究的总体目标是将三种可能影响捐献器官质量的技术结合起来，特别是胰腺。它们是：i)低温机器灌流(HMP)；ii)低温血液置换(HBS)；以及iii)全氟化合物氧合(PFC)。我们的假设是，带有PFC增强HBS的HMP将提供更好的胰腺低温保存，这一假设将使用两个特定目标进行测试：第一个目标是建立Unisol-PFC的血流动力学，其中Unisol是一种专有HBS。使用已建立的猪模型，我们的HMP和Unisol HBS基线技术将被用于在Unisol中制备PFC乳剂(Unisol-PFC)，促进有效灌流所需的灌流参数将使用LifePort(R)灌注机确定。第二个目的是评估PFC灌流对胰岛灌流后分离质量的影响。使用已建立的分叶灌流模型，目标将是比较用Unisol-PFC灌流和单独灌流Unisol的猪胰叶分离的胰岛的产量和质量。这种方法的预期结果是，实施PFC增强灌流将提供可持续的氧气储存库，以满足延长冷缺血保存期间器官明显减少的需求。反过来，这将为高能磷酸盐再生提供手段，并避免公认的无氧糖酵解的后果，即器官在缺氧和缺血期间被迫切换到无氧糖酵解。虽然这些研究是专门针对胰岛移植的临床需要而设计的，但潜在的技术发展将很容易适用于所有可移植的器官。 公共卫生相关性：胰岛素依赖型糖尿病是世界范围内的主要健康问题之一，通过移植从供体胰腺分离的胰岛细胞来开发潜在的治疗方法受到了极大的兴趣。这一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。目前在移植前保存器官的方法，或在分离胰岛之前保存胰腺的方法，依赖于低温保存方式，在这种方式下，器官仍然承受着一些缺氧的损伤。这项研究的重点是开发一种新的替代技术，通过使用新的惰性携氧溶液的灌流技术来维持向器官的氧气输送。