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; 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）：有一个全球共识，即胰岛移植可能被认为是治疗胰岛素依赖性糖尿病的可行选择，并且在全球许多中心正在进行临床试验。由于这种方法将糖尿病过渡到常规的临床护理标准，因此对捐助胰岛的需求将升级。此外，异种移植的潜力减轻了对人类胰腺供应不足的需求，还将取决于将胰岛与源胰腺隔离的技术效率。不幸的是，胰岛在长时间的缺血后非常容易受到不可逆转的损害，而尸体胰腺的冷静脉症对胰岛产量有害，因此需要新的方法来改善胰腺保存方法以提高高质量胰岛的产量。体温过低已被证明是最广泛使用器官保存方法的床头，但最好的技术仍然受到一些冷缺血性损伤。氧气剥夺仍被视为关键因素，并且通过缺血期间使用一种试图减少氧债务的策略是使用全氟碳（PFC）试图将氧气递送到冷缺血器官中。然而，两层方法，其中器官在水性/PFC界面处浸没了，仅在小动物模型中才成功。作为另一种方法，该提议的基础是，将需要将PFC灌注到器官中，以便为低氧冷缺血细胞提供有效的氧气递送。拟议研究的总体目的是结合三种可能影响捐赠器官质量的技术，尤其是胰腺。这些是：i）低温机器灌注（HMP）； ii）低温鲜血替代（HBS）；和III）用全氟化学物（PFC）氧合。 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.使用已建立的猪模型，我们使用Unisol HBS的HMP基线技术将适应UNISOL（UNISOL-PFC）中PFC的乳液，并使用生命培养机（R）灌注机确定促进有效灌注所需的灌注参数。第二个目的是评估PFC-灌注对胰岛灌注后分离质量的疗效。使用既定的分裂灌注模型，目标是比较与单独使用UNISOL相比，用Unisol-PFC灌注的猪胰腺裂片的胰岛的产量和质量。这种方法的预期结果是，实施PFC隆重的灌注将为O2提供可持续的储层，以满足扩展的冷缺血性储存过程中器官的明显减少的需求。反过来，这将为高能量磷酸盐再生提供一种手段，并避免厌氧性糖酵解的良好认识的后果，即器官被迫在低氧和缺血期间切换到。尽管这些研究是专门针对胰岛移植中临床需求的专门设计的，但潜在的技术发展将很容易适用于所有可移植器官。 公共卫生相关性：胰岛素依赖性糖尿病是全球主要的健康问题之一，并且通过从供体胰腺中分离出的胰岛细胞来开发潜在的治愈方法引起了极大的兴趣。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。当前在移植之前存储器官的方法，或在胰岛分离之前存储胰腺，依赖于低温保存方式，其中器官仍然会因氧气剥夺而承受某些损伤。这项研究的重点是开发一种新的替代技术，使用新的含氧氧气解决方案使用灌注技术来维护氧气传递到器官。