Abstract Drug-induced liver injury (DILI) is an important part of drug safety evaluation. Existing evaluation methods mainly rely on in vitro two-dimensional cell culture models and animal models, which cannot simulate the human complex physiological environment and have limited predictive ability for drug metabolism and toxicity. Therefore, it is necessary to develop in vitro liver replacement models that can accurately reproduce normal functions of human liver and its responses to drug toxicity. Human liver-on-chips not only have more comprehensive physiological microstructures and functions than two-dimensional cell models, but also eliminate species differences between animals and humans, and more effectively simulate the physiological or pathological state of human liver. At present, the human liver-on-chip, as a novel in vitro anthropomorphic model for DILI detection, is still in the initial development stage and has not yet formed a unified standard or guideline. However, its enormous potential and application prospects have attracted widespread attention. This consensus is oriented to the evaluation of DILI, relying on the human liver-on-chip platform, combined with relevant domestic and foreign model construction schemes, toxicity detection indicators and drug lists, as well as research literatures and data, to form this expert consensus and provide relevant suggestions. The consensus is aiming to promote the development of human liver-on-chip technology and its application in the detection of DILI.
Compiling Expert Group for Expert Consensus on Technical Specification of Human Liver-on-Chip for EvaluatingDrug-Induced Liver Injury. Expert Consensus on Technical Specification of Human Liver-on-Chip for Evaluating Drug-Induced Liver Injury[J]. Chinese Journal of Biomedical Engineering, 2024, 43(5): 513-524.
[1] Ramachandran P, Matchett KP, Dobie R, et al. Single-cell technologies in hepatology: new insights into liver biology and disease pathogenesis[J]. Nat Rev Gastroenterol Hepatol, 2020, 17(8): 457-472. [2] Vulto P, Joore J. Adoption of organ-on-chip platforms by the pharmaceutical industry[J]. Nat Rev Drug Discov, 2021, 20(12): 961-962. [3] Marx U. Biology-inspired microphysiological systems to advance medicines for patient benefit and animal welfare[J]. ALTEX, 2020, 37(3): 365-394. [4] Chalasani NP, Maddur H, Russo MW, et al; Practice Parameters Committee of the American College of Gastroenterology. ACG clinical guideline: diagnosis and management of idiosyncratic drug-induced liver injury[J]. Am J Gastroenterol, 2021, 116(5): 878-898. [5] Björnsson ES. Epidemiology and risk factors for idiosyncratic drug-induced liver injury[J]. Semin Liver Dis, 2014, 34(2): 115-122. [6] Shen T, Liu Y, Shang J, et al. Incidence and etiology of drug-induced liver injury in mainland China[J]. Gastroenterology, 2019, 156(8): 2230-2241. [7] Lammert C, Bjornsson E, Niklasson A, et al. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events[J]. Hepatology, 2010, 51(2): 615-620. [8] Yu YC, Mao YM, Chen CW, et al. CSH guidelines for the diagnosis and treatment of drug-induced liver injury[J]. Hepatol Int, 2017, 11(3): 221-241. [9] Fontana RJ, Bjornsson ES, Reddy R, et al. The evolving profile of idiosyncratic drug-induced liver injury[J]. Clin Gastroenterol Hepatol, 2023, 21(8): 2088-2099. [10] 中国医药生物技术协会药物性肝损伤防治技术专业委员会, 中华医学会肝病学分会药物性肝病学组. 中国药物性肝损伤诊治指南(2023年版)[J]. 中华肝脏病杂志, 2023, 31(4): 355-384. [11] Fontana RJ, Liou I, Reuben A, et al. AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury[J]. Hepatology, 2023, 77(3): 1036-1065. [12] European Association for the Study of the Liver. EASL clinical practice guidelines: drug-induced liver injury[J]. J Hepatol, 2019, 70(6): 1222-1261. [13] Hayashi PH, Fontana RJ. Clinical features, diagnosis, and natural history of drug-induced liver injury[J]. Semin Liver Dis, 2014, 34(2): 134-144. [14] Robles-Diaz M, Lucena MI, Kaplowitz N, et al. Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury[J]. Gastroenterology, 2014, 147(1): 109-118. [15] Low LA, Mummery C, Berridge BR, et al. Organs-on-chips: into the next decade[J]. Nat Rev Drug Discov, 2021, 20(5): 345-361. [16] Vega JMH, Hong HJ, Loutherback K, et al. A microfluidic device for long-term maintenance of organotypic liver cultures[J]. Adv Mater Technol, 2023, 8(2): 2201121. [17] Ronaldson-Bouchard K, Vunjak-Novakovic G. Organs on-a-chip: a fast track for engineered human tissues in drug development[J]. Cell Stem Cell, 2018, 22(3): 310-324. [18] Giobbe GG, Michielin F, Luni C, et al. Functional differentiation of human pluripotent stem cells on a chip[J]. Nat Methods, 2015, 12(7): 637-640. [19] Dianat N, Dubois-Pot-Schneider H, Steichen C, et al. Generation of functional cholangiocyte -like cells from human pluripotent stem cells and HepaRG cells[J]. Hepatology, 2014, 60(2): 700-714. [20] Broutier L, Mastrogiovanni G, Verstegen MM, et al. Human primary liver cancer -derived organoid cultures for disease modeling and drug screening[J]. Nat Med, 2017, 23(12): 1424-1435. [21] Beckwitt CH, Clark AM, Wheeler S, et al. Liver 'organ on a chip'[J]. Exp Cell Res, 2018, 363(1): 15-25. [22] Zeilinger K, Freyer N, Damm G, et al. Cell sources for in vitro human liver cell culture models[J]. Exp Biol Med (Maywood), 2016, 241(15): 1684-1698. [23] Donato MT, Tolosa L. Stem-cell derived hepatocyte-like cells for the assessment of drug-induced liver injury[J]. Differentiation, 2019, 106: 15-22. [24] Donato MT, Jover R, Gómez-Lechón MJ. Hepatic cell lines for drug hepatotoxicity testing: limitations and strategies to upgrade their metabolic competence by gene engineering[J]. Curr Drug Metab, 2013, 14(9): 946-968. [25] Deng J, Wei W, Chen Z, et al. Engineered liver-on-a-chip platform to mimic liver functions and its biomedical applications: a review[J]. Micromachines (Basel), 2019, 10(10): 676. [26] Donato MT, Lahoz A, Castell JV, et al. Cell lines: a tool for in vitro drug metabolism studies[J]. Curr Drug Metab, 2008, 9(1): 1-11. [27] Takayama K, Inamura M, Kawabata K, et al. Efficient generation of functional hepatocytes from human embryonic stem cells and induced pluripotent stem cells by HNF4α transduction[J]. Mol Ther, 2012, 20(1): 127-137. [28] Gómez-Lechón MJ, Tolosa L, Conde I, et al. Competency of different cell models to predict human hepatotoxic drugs[J]. Expert Opin Drug Metab Toxicol, 2014, 10(11): 1553-1568. [29] Ware BR, Berger DR, Khetani SR. Prediction of drug-induced liver injury in micropatterned co-cultures containing iPSC-derived human hepatocytes[J]. Toxicol Sci, 2015, 145(2): 252-262. [30] Gough A, Soto-Gutierrez A, Vernetti L, et al. Human biomimetic liver microphysiology systems in drug development and precision medicine[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(4): 252-268. [31] Xu L, Hui AY, Albanis E, et al. Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis[J]. Gut, 2005, 54(1): 142-151. [32] Khazali AS, Clark AM, Wells A. A pathway to personalizing therapy for metastases using liver-on-a-chip platforms[J]. Stem Cell Rev Rep, 2017, 13(3): 364-380. [33] Kidambi S, Sheng L, Yarmush ML, et al. Patterned co-culture of primary hepatocytes and fibroblasts using polyelectrolyte multilayer templates[J]. Macromol Biosci, 2007, 7(3): 344-353. [34] Ma C, Zhao L, Zhou EM, et al. On-chip construction of liver lobule-like microtissue and its application for adverse drug reaction assay[J]. Anal Chem, 2016, 88(3): 1719-1727. [35] Ma LD, Wang YT, Wang JR, et al. Design and fabrication of a liver-on-a-chip platform for convenient, highly efficient, and safe in situ perfusion culture of 3D hepatic spheroids[J]. Lab Chip, 2018, 18(17): 2547-2562. [36] Cui X, Hartanto Y, Zhang H. Advances in multicellular spheroids formation[J]. J R Soc Interface, 2017, 14(127): 20160877. [37] Fang Y, Eglen RM. Three-dimensional cell cultures in drug discovery and development[J]. SLAS Discov, 2017, 22(5): 456-472. [38] Yu F, Choudhury D. Microfluidic bioprinting for organ-on-a-chip models[J]. Drug Discov Today, 2019, 24(6): 1248-1257. [39] Strauss AW, Bennett CD, Donohue AM, et al. Rat liver pre-proalbumin: complete amino acid sequence of the pre-piece. Analysis of the direct translation product of albumin messenger RNA[J]. J Biol Chem, 1977, 252(19): 6846-6855. [40] Judah JD, Quinn PS. Calcium ion-dependent vesicle fusion in the conversion of proalbumin to albumin[J]. Nature, 1978, 271(5643): 384-385. [41] Morris SM Jr. Regulation of enzymes of the urea cycle and arginine metabolism[J]. Annu Rev Nutr, 2002, 22: 87-105. [42] Rodríguez-Antona C, Donato MT, Boobis A, et al. Cytochrome P450 expression in human hepatocytes and hepatoma cell lines: molecular mechanisms that determine lower expression in cultured cells[J]. Xenobiotica, 2002, 32(6): 505-520. [43] Baudy AR, Otieno MA, Hewitt P, et al. Liver microphysiological systems development guidelines for safety risk assessment in the pharmaceutical industry[J]. Lab Chip, 2020, 20(2): 215-225. [44] Leung CM, de Haan P, Ronaldson-Bouchard K, et al. A guide to the organ-on-a-chip[J]. Nat Rev Methods Primers, 2022, 2(1): 1-29. [45] Ehrlich A, Duche D, Ouedraogo G, et al. Challenges and opportunities in the design of liver-on-chip microdevices[J]. Annu Rev Biomed Eng, 2019, 21: 219-239. [46] Hartung T. Toxicology for the twenty-first century[J]. Nature, 2009, 460: 208-212. [47] Li M, Izpisua Belmonte JC. Organoids - preclinical models of human disease[J]. N Engl J Med, 2019, 380(6): 569-579. [48] Riahi R, Shaegh SAM, Ghaderi M, et al. Automated microfluidic platform of bead-based electrochemical immunosensor integrated with bioreactor for continual monitoring of cell secreted biomarkers[J]. Sci Rep, 2016, 6(1): 24598. [49] Jang K, Otieno MA, Ronxhi J, et al. Reproducing human and cross-species drug toxicities using a liver-chip[J]. Scie Trans Med, 2019, 11(517): x5516. [50] Giobbe GG, Michielin F, Luni C, et al. Functional differentiation of human pluripotent stem cells on a chip[J]. Nat Methods, 2015, 12(7): 637-640. [51] Zhang Y, Gao H, Zhang Y, et al. Correlation between serum cytokines and clinicopathological features in patients with drug-induced liver injury[J]. Front Pharmacol, 2022, 13: 1070802. [52] Zhang CJ, Meyer SR, O'Meara MJ, et al. A human liver organoid screening platform for DILI risk prediction[J]. J Hepatol, 2023, 78(5): 998-1006. [53] Xu JJ, Henstock PV, Dunn MC, et al. Cellular imaging predictions of clinical drug-induced liver injury[J]. Toxicol Sci, 2008, 105(1): 97-105. [54] Li T, Tong W, Roberts R, et al. Deep learning on high-throughput transcriptomics to predict drug-induced liver injury[J]. Front Bioeng Biotechnol, 2020, 8: 562677. [55] Dragovic S, Vermeulen NP, Gerets HH, et al. Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man[J]. Arch Toxicol, 2016, 90(12): 2979-3003. [56] Deng X, Li M, Deng S, et al. Hybrid gene selection approach using XGBoost and multi-objective genetic algorithm for cancer classification[J]. Med Biol Eng Comput, 2022, 60(3): 663-681. [57] Ganaie MA, Tanveer M, Suganthan PN, et al. Oblique and rotation double random forest[J]. Neural Netw, 2022, 153: 496-517. [58] Wang H, Shao Y, Zhou S, et al. Support vector machine classifier via L0/1 soft-margin loss[J]. IEEE Trans Pattern Anal Mach Intell, 2022, 44(10): 7253-7265. [59] Ding C, Bao TY, Huang HL. Quantum-inspired support vector machine[J]. IEEE Trans Neural Netw Learn Syst, 2022, 33(12): 7210-7222. [60] Wang Y, Wang H, Deng P, et al. In situ differentiation and generation of functional liver organoids from human iPSCs in a 3D perfusable chip system[J]. Lab Chip, 2018, 18(23): 3606-3616. [61] Fu J, Qiu H, Tan CS. Microfluidic liver-on-a-chip for preclinical drug discovery[J]. Pharmaceutics, 2023, 15(4): 1300. [62] Tu C, Chao BS, Wu JC. Strategies for Improving the Maturity of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes[J]. Circ Res, 2018, 123(5): 512-514. [63] Ronaldson-Bouchard K, Teles D, Yeager K, et al. A multi-organ chip with matured tissue niches linked by vascular flow[J]. Nat Biomed Eng, 2022, 6(4): 351-371. [64] Zhao XF, Jiang YH, Liu CL, et al. Organoid technology and clinical applications in digestive system cancer[J]. Engineering, 2022, 9(2): 123-130. [65] Lohasz C, Loretan J, Sterker D, et al. A microphysiological cell-culturing system for pharmacokinetic drug exposure and high-resolution imaging of arrays of 3D microtissues[J]. Front Pharmacol, 2021, 12: 785851. [66] Buchanan BC, Yoon JY. Microscopic imaging methods for organ-on-a-chip platforms[J]. Micromachines (Basel), 2022, 13(2): 328. [67] Ewart L, Apostolou A, Briggs SA, et al. Performance assessment and economic analysis of a human liver-chip for predictive toxicology[J]. Commun Med (Lond), 2022, 2(1): 154. [68] Fernandez-Checa JC, Bagnaninchi P, Ye H, et al. Advanced preclinical models for evaluation of drug-induced liver injury-consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET][J]. J Hepatol, 2021, 75(4): 935-959.
