Liver transplantation is the only cure for end stage liver decease. This is limited by the known organ shortage. The usage of marginal grafts, e.g. older, fatty and DCD livers as well as splitting livers are approaches to address this problem, but couldn’t solve it finally. Therefore living liver donation plays a role in exceeding the donor pool.
A problem in this field is the ethical discussion how much risks for a living donor can be accepted in order to save the life of the potential recipient. Therefore living liver donation in pediatric transplantation is by far more established than in adults. On one hand there is no ethical doubt for parents to donate for their children, on the other hand the needed graft size is significant smaller than for adult transplantation. The latter makes living liver donation for pediatric transplantation more safe than for adults as only approximately 20 % of the liver, the left lateral segment (LLS), needs to be removed, while this is for adult transplantation up to 70 %.
Independent from that the liver – remnant in the donor as well as graft in the recipient – will regenerate. After removal of 70 % of a healthy donor liver this liver will grow back to the functional volume in approximately 6 weeks.
The idea of the proposed research project is to induce liver regeneration in an ex vivo perfusion setting. This would allow growing LLS after living donation in order to serve for adult liver transplant recipients. Requirement is to establish a long-term perfusion system, which allows keeping a liver graft functional intact for days.
A long term Ex Vivo Liver Perfusion model should first be developed in a small animal model, followed by a large animal model before translated into a human model. One of the keys is to determine the ideal perfusion temperature. Keeping in mind that organ assessment, respectively functional monitoring is only possible with in the physiological temperature where enzymes are still working and that on the other side ATP depletion is one of the problems, which has to be avoided, a sub-normothermic temperature seems to be best. The optimum remains to be investigated. Another critical key is the composition of the perfusate to keep the liver under long-term perfusion alive. Last, but not least it is the core of the study to determine mediators and / or conditions to support liver regeneration in an ex vivo setting.
This guides the steps in this research project. The small animal model will serve to develop a long term Ex Vivo Live Perfusion system. The questions, which need to be addressed, are the composition of the perfusion solution. A special focus will be on the question whether or not a cell free (no erythrocytes) solution is possible. Without erythrocytes the classical oxygen carrier is lacking, which is a disadvantage regarding the ATP depletion, but reduces the risk of clotting and immunological response. The determination of the optimal temperature plays a major role in this question, as decreasing the temperature will reduce oxygen consumption. Consecutive an acellular perfusate might be possible.
Once the small animal model is successful developed it has to be transferred in a larger animal model before being translated into human livers.
The PhD student will primarily work on the establishment of the small animal model, which will be a rat model. This contains technical developments in the field of Ex Vivo Liver Perfusion as well as the determination of the composition of the perfusate and its ideal temperature. For this he will learn micro-technical techniques in order to perform liver retrievals. In a later stage we also have to prove graft survival in long term ex vivo liver perfusion in a liver transplant model.
The small animal model will also serve to investigate methods to induce liver regeneration in an ex vivo liver perfusion setting.
Contact: Markus Boehnert, ErasmusMC: firstname.lastname@example.org