MICA: Optimisation of prolonged normothermic liver machine perfusion and assessment of its feasibility to provide extra-corporeal liver support

MICA：长时间常温肝脏机器灌注的优化及其提供体外肝脏支持的可行性评估

• 批准号: MR/X001458/1
• 负责人: Alexander Sagar
• 金额: $ 31.92万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX001458%2F1
• 关键词: MICA; Optimisation; prolonged; normothermic; liver

Shortage of transplantable liversLiver transplantation is a life-saving treatment for patients with liver failure. Sadly, 15% of patients on the waiting list either die, or become too unwell for a transplant, due to an organ shortage. Despite this, 2 out of 5 potential deceased donor livers are declined for transplant. Many of these declines are because the donors possess characteristics that make their organs too susceptible to deterioration during preservation. Improved preservation will increase the number of transplantable livers. How are livers preserved?The traditional method is on ice. During this period, the organ metabolises without oxygen, generating harmful substances that are released when the liver is implanted into the patient. Machine perfusion at body-temperature has a number of benefits over ice storage. The machine provides the liver with nutrients and oxygen to enable normal metabolism. This allows the organ to recover during preservation, resulting in less injury on implantation and more transplantable livers.Current liver perfusion devices are licensed up to 24 hours. Prolonged perfusion up to 7 days seems possible in the laboratory, but remains at the early development stage. The benefits of prolonged perfusion in transplantationProlonged perfusion will improve transplant outcomes and increase organ utilisation. The additional time available will enable improved recipient preparation, planned day-time surgery and wider organ-sharing. It will facilitate more detailed assessment of organ quality to minimise discarding of viable livers, and delivery of treatments to resuscitate injured organs. Use of prolonged perfusion in liver failureBeyond transplantation, prolonged perfusion holds promise as a treatment for acute and acute-on-chronic liver failure. These are severe forms of liver injury and many of these patients do not survive. However, the liver possesses the ability to regenerate, meaning that if these patients can be supported temporarily, many will recover. Whereas patients with kidney failure can be supported with dialysis, an equivalent for liver failure has proven elusive due to the complex roles of the liver. However, livers retain many of these functions during machine perfusion. If a liver can be successfully perfused for enough time to allow liver regeneration, a non-transplantable liver could be used to support patients with liver failure to recovery, or to survive long enough to receive a suitable organ. Aims of the research1) Improve machine perfusion of the liver at body temperature to enable prolonged perfusion to 7 days. 2) Assess whether a liver support system, based on prolonged machine perfusion of a liver, is capable of replacing the function of a failing liver.3) Determine the best method to connect a patient to the liver support system. How will these be achieved?I will test three interventions targeted at prolonging machine perfusion:1) Incorporation of a specialist filter to remove harmful substances from the perfusion blood and correct the salt levels.2) Addition of a solution to the perfusion blood to rejuvenate old red blood cells.3) Provision of fish-oil based fats with the nutrition for the liver. To determine whether a machine-perfused-liver is capable of replacing a failing liver, I will subject the liver to challenges that mirror those that occur in liver failure. Finally, we will compare two connection methods: one in which blood is directly exchanged between the "patient" (in this case, a second machine-perfused liver) and the support system, and a second in which specialist filters prevent cells mixing between the two circulations. Future PlansProlonged perfusion will be combined with work exploring organ assessment and gene therapies during preservation to accelerate their development. The liver support experiments will lead to a study in pigs to determine whether the system is effective in practice.

可移植肝脏的短缺肝移植是肝功能衰竭患者的一种挽救生命的治疗方法。不幸的是，由于器官短缺，等待名单上的15%的患者要么死亡，要么身体不适，无法接受移植。尽管如此，五分之二的潜在死亡供体肝脏被拒绝移植。其中许多下降是因为捐赠者具有使他们的器官在保存过程中太容易变质的特征。改进保存方法将增加可移植肝脏的数量。肝脏是如何保存的？传统的方法是在冰上。在此期间，器官在没有氧气的情况下代谢，产生有害物质，这些物质在肝脏植入患者体内时释放出来。在体温下的机器灌注比冰储存有许多好处。这台机器为肝脏提供营养和氧气，使其能够正常代谢。这使得器官在保存过程中可以恢复，从而减少植入时的损伤，并提供更多可移植的肝脏。目前的肝脏灌注设备许可时间长达24小时。在实验室中延长灌注至7天似乎是可能的，但仍处于早期开发阶段。移植中延长灌注的益处延长灌注将改善移植结果并提高器官利用率。额外的可用时间将有助于改善受体准备，计划日间手术和更广泛的器官共享。这将有助于更详细地评估器官质量，以尽量减少丢弃有活力的肝脏，并提供治疗以复苏受损器官。延长灌注在肝衰竭中的应用除了移植，延长灌注有望成为急性和慢性加急性肝衰竭的治疗方法。这些都是严重的肝损伤形式，其中许多患者无法存活。然而，肝脏具有再生能力，这意味着如果这些患者可以暂时得到支持，许多人将恢复。虽然肾衰竭患者可以通过透析来支持，但由于肝脏的复杂作用，肝衰竭的等效物已被证明是难以捉摸的。然而，肝脏在机器灌注期间保留了许多这些功能。如果肝脏可以成功灌注足够的时间以允许肝脏再生，则不可移植的肝脏可以用于支持肝功能衰竭的患者恢复，或者存活足够长的时间以接受合适的器官。研究目的1）改善在体温下肝脏的机器灌注，使灌注时间延长至7天。2)评估基于肝脏长时间机器灌注的肝脏支持系统是否能够替代衰竭肝脏的功能。3）确定将患者连接到肝脏支持系统的最佳方法。如何实现这些目标？我将测试三种针对延长机器灌注的干预措施：1）引入专业过滤器以去除灌注血液中的有害物质并纠正盐水平。2）向灌注血液中添加溶液以恢复旧的红细胞。3）提供鱼油脂肪和肝脏营养。为了确定机器灌注的肝脏是否能够替代衰竭的肝脏，我将使肝脏接受反映肝衰竭中发生的挑战。最后，我们将比较两种连接方法：一种是在“患者”（在这种情况下，第二台机器灌注的肝脏）和支持系统之间直接交换血液，第二种是专业过滤器防止两个循环之间的细胞混合。 未来计划延长灌注将与探索保存期间的器官评估和基因治疗相结合，以加速其发展。肝脏支持实验将导致对猪的研究，以确定该系统在实践中是否有效。