Metabolic Modeling for Cadaveric Organ Resuscitation

描述(申请人提供)：在美国，慢性肝病和肝硬变每年导致约30,000人死亡，其中4,000人直接因缺乏可供移植的供体肝脏而死亡。如果通过使边缘病例(如心脏死亡(DCD)后获得的捐赠者)可移植来扩大捐赠者器官库，这些数字可能会大幅减少。据估计，每年约有6,000个身体肝脏因心脏缺血后死亡而受到轻微损害，可以复苏进行移植。来自我们实验室和其他实验室的证据表明，机器灌流是恢复身体器官的一种非常有前途的方法，否则这些器官将被排斥在捐赠者池中。然而，临床上实现这样的机器灌流设备需要复杂的算法来确保对系统的严格控制，最大限度地提高器官的生存能力，并在灌流结束时准确评估肝脏是否准备好进行移植。针对这种器官活性最大化任务设计的算法存在很大差距，这阻碍了这些技术的临床翻译和该领域的垂直发展。我们的长期目标是开发新的工程策略，使边缘供体器官能够有效地移植，并减少由于器官短缺而导致的死亡。这项研究的目的是开发一种动态的、在线的方法来评估肝脏在灌流过程中的生存能力，并利用它来优化肝脏的代谢，以促进缺血的恢复。这里要检验的中心假设是，灌流过程中的肝脏活力与机器灌流过程中的肝脏代谢功能相关。本文描述的工作有望产生动态的、在线的肝脏存活评分，该评分可用于在移植手术前评估供体器官的状况，最终减少边缘供体器官移植所涉及的猜测。这项工作的结果也将对工程科学产生积极的影响，为这些复杂的、动态的器官保存系统的过程设计和控制的集成奠定基础。这项工作还有望通过加快开发复杂的器官保存模式和减少因肝功能衰竭而导致的死亡来改善医疗保健。

DESCRIPTION (provided by applicant): ABSTRACT Chronic liver disease and cirrhosis causes about 30,000 deaths annually in the US, 4,000 of which are directly due to lack of a donor liver available for transplant. These numbers could be reduced dramatically should the donor organ pool be expanded by rendering marginal cases, such as Donors obtained after Cardiac Death (DCD), transplantable. It is estimated that about 6,000 cadaveric livers/yr are only marginally damaged by ischemia post-cardiac death and could be resuscitated for transplantation. There is evidence from our lab and others that machine perfusion is a very promising approach for recovering cadaveric organs that would be otherwise rejected from the donor pool. However, clinical realization of such a machine perfusion device requires sophisticated algorithms that ensure tight control of the system, maximize the viability of the organ and accurately assess if the liver is ready for transplantation at the end of perfusion. There is a significant gap of algorithms designed for such an organ viability maximization task, which prevents clinical translation of these technologies and vertical advancement of the field. Our long-term goal is to develop novel engineering strategies to enable efficient transplantation of marginal donor organs and reduce deaths due to organ shortage. The objective of the proposed study is to develop a dynamic, online method to assess liver viability during perfusion and employ it to optimize liver metabolism to enhance recovery from ischemia. The central hypothesis to be tested here is that the liver viability during perfusion is correlated to liver metabolic function during machine perfusion. The work described here is expected to generate a dynamic, on-line liver viability score which can be used to assess the condition of the donor organs prior to transplantation surgery, ultimately reducing the guesswork involved in transplantation of marginal donor organs. The results of this work will also have a positive impact on engineering science by establishing the basis for integration of process design & control of these complex, dynamic organ preservation systems. The work is also expected to lead to improvements in healthcare by accelerating development of sophisticated organ preservation modalities and reducing deaths due to liver failure.