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

可移植肝脏短缺肝移植是挽救肝功能衰竭患者生命的一种治疗方法。可悲的是，由于器官短缺，等候名单上15%的病人要么死亡，要么身体不适，无法进行移植。尽管如此，五分之二的潜在死亡捐赠者的肝脏被拒绝移植。许多器官数量下降是因为捐献者的器官在保存过程中太容易变质。更好的保存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，当肝脏被植入病人体内时，这些有害物质被释放出来。与冰储存相比，体温下的机器灌注有许多好处。这台机器为肝脏提供营养和氧气，使其能够正常新陈代谢。这使得器官可以在保存过程中恢复，从而减少移植时的损伤和更多的可移植肝脏。目前的肝脏灌注装置许可使用时间长达24小时。延长灌注至7天在实验室似乎是可行的，但仍处于早期发育阶段。移植中延长灌注的好处延长灌注可以改善移植结果，增加器官利用率。额外的可用时间将有助于改进受体准备，计划白天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，使受损器官复苏。延长灌注在肝衰竭中的应用除了移植，延长灌注在治疗急性和急性伴慢性肝衰竭方面也有希望。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，这意味着如果这些病人能得到暂时的支持，许多人会康复。虽然肾功能衰竭患者可以通过透析治疗，但由于肝脏的复杂作用，肝功能衰竭的等效治疗已被证明是难以捉摸的。然而，在机器灌注过程中，肝脏保留了许多这些功能。如果肝脏能够成功灌注足够长的时间以允许肝脏再生，那么不可移植的肝脏就可以用来支持肝功能衰竭患者恢复，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)评估基于延长肝脏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)加入一个专门的过滤器，去除灌注血液中的有害物质，纠正盐水平。2)在灌注血液中加入一种溶液，使衰老的红细胞恢复活力。3)提供鱼油为基础的脂肪与肝脏的营养。为了确定机器灌注的肝脏是否能够取代衰竭的肝脏，我将对肝脏进行与肝功能衰竭类似的挑战。最后，我们将比较两种连接方法：一种是血液直接在“病人”（在这种情况下，是第二个机器灌注的肝脏）和支持系统之间交换，另一种是专门的过滤器防止细胞在两个循环之间混合。未来计划长期灌注将与器官评估和保存期间的基因治疗工作相结合，以加速它们的发育。肝支持实验将在猪身上进行研究，以确定该系统在实践中是否有效。

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.