SIMulation supported LIVer Assessment for donor organs (SimLivA) - Continuum-biomechanical modeling for staging of ischemia reperfusion injury during liver transplantation

背景：肝移植(LTX)是治疗急、慢性终末期肝病的唯一有效方法。人口结构变化和西方生活方式导致老年多发病潜在受者和捐赠者的比例上升。来自这类供者的肝移植，即所谓的边缘肝移植，通常会受到肝脏脂肪变性的影响，严重影响供体器官的质量。一个原因是组织结构的改变，导致灌注受损，进而影响肝脏新陈代谢和器官功能。在边缘移植的情况下，外科医生面临着接受或拒绝器官的临床决定，这分别显著增加了接受者的术后风险或增加了等待名单上的死亡风险。边缘移植的两个主要挑战是器官获取和移植之间的保存(冷缺血时间)和再灌注后的损伤(缺血再灌注损伤或IRI)。目标：我们共同设计的跨学科项目“模拟支持的供肝器官评估(SimLivA)”旨在数学模拟(脂肪变性的)边缘肝移植的机械变化和冷缺血对早期IRI的影响。我们解决了以下研究问题：(I)如何共同设计计算方法、实验研究、临床流程和技术工作流程？(Ii)如何改进预测IRI的多尺度连续生物力学模型？(Iii)如何获得对量化脂肪变性、缺血和再灌注损伤之间的关系至关重要的实验和临床数据？(Iv)如何评价模型的临床实用性？方法：为了达到这些目标，我们将扩展和修改我们的连续介质-生物力学多时相多尺度肝小叶PDE-ODE模型，以数值模拟依赖于脂肪变性程度和缺血时间的IRI。用于模型参数化和验证的实验和临床数据采集是在与建模密切合作的情况下设计的。将进行一项关于临床适用性的概念验证试验。我们的模型通过移植物的机械特性、肝窦灌流和受影响的分子通路之间的相互作用来结合肝脏的结构、灌流和功能，这可能有助于这些决策过程，并且是迫切需要的。这将是迈向硅内临床决策支持工具的第一步，通过硅内预测肝脏损伤和早期移植物功能，从而做出有利于或反对边缘器官的更好的决策。

Background: Liver transplantation (LTx) is the only curative treatment option for acute and chronic end-stage liver disease. Demographic change and western lifestyle result in an increasing rate of elderly multi-morbid potential recipients and donors. Liver grafts from such donors, so-called marginal liver grafts, are often affected by hepatic steatosis compromising the quality of the donor organ substantially. One reason is the alteration of the tissue structure, resulting in an impaired perfusion, which in turn affects hepatic metabolism and organ function. In case of a marginal graft, the surgeon is faced with the clinical decision to either accept or reject the organ, significantly increasing the postoperative risk for the recipient or increasing the risk of death on the waiting list, respectively. Two major challenges for marginal grafts are the storage between procurement of the organ and transplantation (cold ischemia time) and damage after reperfusion (ischemia reperfusion injury or IRI).Goal: Our co-designed interdisciplinary project “SIMulation supported LIVer Assessment for donor organs (SimLivA)” aims to mathematically model the impact of mechanical alterations of the (steatotic) marginal liver graft and cold ischemia on early IRI. We address the following research questions: (i) How to co-design computational methods, experimental studies, clinical processes, and technical workflows? (ii) How to improve the multiscale continuum-biomechanical model for prediction of IRI? (iii) How to obtain experimental and clinical data that are essential to quantify the relationship between steatosis, ischemia and reperfusion injury? (iv) How to evaluate the clinical usability of the model?Methods: To achieve these goals, we will extend and adapt our coupled continuum-biomechanical multiphase and multi-scale PDE-ODE model of the liver lobule to numerically simulate IRI in dependence of the degree of steatosis and ischemia duration. Experimental and clinical data acquisition for model parameterization and validation is designed in close collaboration with modeling. A proof-of-concept trial for clinical applicability will be performed. Our model couples structure, perfusion and function of the liver via the interplay between mechanical properties of the graft, hepatic sinusoidal perfusion and the affected molecular pathways, which might facilitate these decision processes and is urgently needed. This will be the first step towards an in-silico clinical decision support tool to reach a better decision pro or contra the marginal organ by in-silico predicting hepatic damage and early graft function.