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

Shortage of transplantable livers
Liver 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 transplantation
Prolonged 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 failure
Beyond 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 research
1) 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 Plans
Prolonged 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.

Background
Liver preservation by normothermic machine perfusion (LNMP) increases organ utilisation for transplant. Although current devices are licensed for 24-hour perfusion, 7-day perfusion appears experimentally feasible.
Beyond its utility in transplantation, prolonged NMP may enable a perfused liver to provide temporary extra-corporeal liver support through connection to patients with acute and acute-on-chronic liver failure (ALF). As NMP-preserved livers retain a range of liver functions, this system may reduce mortality where others have failed.

Aims
P1: Optimisation of LNMP to support 7-day perfusion.
P2: Assessment of capacity of prolonged LNMP to provide Biological Liver Support (BLS).
P3: Determination of optimal interface between patient and BLS circulations.

Methodology
A porcine model of Donation by Circulatory Death will be used to procure livers for NMP.
P1: 3 interventions will be tested for their potential to prolong LNMP:
a) Incorporation of high molecular weight cut-off dialysis.
b) Red blood cell (RBC) rejuvenation therapy.
c) Omega-3 polyunsaturated fatty acid-enriched nutrition.
P2: The capacity of an NMP-liver to reproduce liver function will be quantified through assessment of lactate, ammonia, ICG clearance and factor V synthesis. The ability of an NMP-liver to remove the damage-associated molecular patterns released by a failing liver will be measured in an ex situ model of the BLS set-up. A healthy NMP-liver ('BLS') will be connected to a second NMP-liver, induced to fail through paracetamol overdose ('patient').
P3: The same model will assess the effect of whole-blood versus plasma-only exchange between the 'patient' and 'BLS' circulations on RBC mixing, immune response and functional capacity.

Future Plans
Prolonged LNMP will improve transplant logistics, viability testing and pre-implantation therapeutic delivery. Parts 2 and 3 will provide proof-of-principle for an efficacy study in a porcine ALF model.