Metabolic Modeling for Cadaveric Organ Resuscitation

在美国，慢性肝病和肝硬化每年导致约30,000人死亡，其中4,000人直接归因于缺乏可用于移植的供肝。如果通过使心脏死亡（DCD）后获得的供体可移植等边缘病例扩大供体器官库，这些数字可能会大幅减少。据估计，每年约有6000个尸体肝脏因缺血心源性死亡而仅轻微受损，可以复苏用于移植。我们的实验室和其他实验室的证据表明，机器灌注是一种非常有前途的方法，可以恢复尸体器官，否则这些器官会被供体排斥。然而，这种机器灌注装置的临床实现需要复杂的算法，以确保对系统的严格控制，最大限度地提高器官的活力，并在灌注结束时准确评估肝脏是否准备好移植。为这种器官活力最大化任务设计的算法存在显着差距，这阻碍了这些技术的临床翻译和该领域的垂直进步。我们的长期目标是开发新的工程策略，以实现边缘供体器官的有效移植，并减少因器官短缺而导致的死亡。本研究的目的是开发一种动态的在线方法来评估灌注过程中的肝脏活力，并利用它来优化肝脏代谢，以增强缺血后的恢复。这里要检验的中心假设是灌注期间肝脏活力与机器灌注期间肝脏代谢功能相关。本文描述的工作有望产生一个动态的在线肝脏活力评分，可用于评估移植手术前供体器官的状况，最终减少移植边缘供体器官时的猜测。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速复杂器官保存模式的发展，减少因肝功能衰竭而导致的死亡，从而改善医疗保健。

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.