非生物型人工肝技术的优化与生物型人工肝研究进展

周莉; 杨颜榕; 陈煜

doi:10.12449/JCH240204

非生物型人工肝技术的优化与生物型人工肝研究进展

DOI: 10.12449/JCH240204

首都医科大学附属北京佑安医院肝病中心四科（疑难肝病及人工肝中心），肝衰竭与人工肝治疗研究北京市重点实验室，北京 100069

基金项目:

国家重点研发计划项目 (2022YFC2304400);

北京市医院管理中心“登峰”人才培养计划 (DFL20221501);

高层次公共卫生技术人才培养计划 (2022-2-012);

北京市科技新星计划 (20220484201)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：周莉、杨颜榕负责查阅和分析资料，撰写论文；陈煜负责选题，拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
陈煜， chybeyond1071@ccmu.edu.cn （ORICD： 0000-0003-1906-7486）

计量
- 文章访问数: 366
- HTML全文浏览量: 231
- PDF下载量: 94
- 被引次数: 0
出版历程
- 收稿日期: 2023-11-13
- 录用日期: 2023-12-15
- 出版日期: 2024-02-19

Optimization of non-bioartificial liver technology and research advances in biological artificial liver

Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research，Forth Department of Liver Disease Center/Difficult and Complicated Liver Diseases and Artificial Liver Center，Beijing YouAn Hospital，Capital Medial University，Beijing 100069，China

Research funding:

National Key Research and Development Program of China (2022YFC2304400);

Beijing Hospitals Authority’s Ascent Plan (DFL20221501);

Construction Project of High-level Technology Talents in Public Health (2022-2-012);

Beijing Nova Program (20220484201)

More Information

Corresponding author: CHEN Yu， chybeyond1071@ccmu.edu.cn （ORICD： 0000-0003-1906-7486）

摘要

摘要: 肝衰竭是临床常见综合征，进展快速，预后不良。目前其内科治疗方法仍有限，人工肝治疗是一种有效的治疗方法。非生物型人工肝技术在临床上广泛应用，其具体的启动时机、模式的选择、参数的设置需要临床医生根据疾病的病理生理机制及动态演变过程，结合患者具体情况决定。与非生物型人工肝相比，生物型人工肝能更好地模拟肝细胞的生物学功能，目前其核心技术已取得实质性的进展，相关临床研究也在积极进行，在未来有广阔的发展前景。本文就非生物型人工肝技术的优化及生物型人工肝相关进展进行总结与探讨，以期为人工肝技术的临床应用与研究提供参考。
- 肝，人工 /
- 肝功能衰竭 /
- 治疗学
Abstract: Liver failure is a common clinical syndrome with rapid progression and poor prognosis. Currently， there are still limited internal medical treatment methods for liver failure， and artificial liver support therapy is an effective treatment method. Non-bioartificial liver technology is widely used in clinical practice， and clinicians should determine the starting time， mode， and specific parameters of treatment according to the pathophysiological mechanism and dynamic evolution process of the disease， as well as the specific conditions of patients. Compared with non-bioartificial liver， biological artificial liver can better simulate the biological function of liver cells. At present， substantial progress has been made in its core technology， and related clinical studies are being conducted actively， suggesting a vast potential for future development. This article summarizes and discusses the optimization of non-bioartificial liver technology and the advances in biological artificial liver， in order to provide a reference for the clinical application and research of artificial liver technology.
- Liver， Artificial /
- Liver Failure /
- Therapeutics

HTML全文

参考文献(43)

[1]	Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association; Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Guideline for diagnosis and treatment of liver failure(2018)[J]. J Clin Hepatol, 2019, 35( 1): 38- 44. DOI: 10.3969/j.issn.1001-5256.2019.01.007. 中华医学会感染病学分会肝衰竭与人工肝学组, 中华医学会肝病学分会重型肝病与人工肝学组. 肝衰竭诊治指南(2018年版)[J]. 临床肝胆病杂志, 2019, 35( 1): 38- 44. DOI: 10.3969/j.issn.1001-5256.2019.01.007.
[2]	Chinese College of Transplant Doctors, Liver Transplantation Group, Chinese Society of Organ Transplantation, Chinese Medical Association. Chinese clinical practice guidelines on liver transplantation for hepatocellular carcinoma(2021 edition)[J]. Chin J Dig Surg, 2022, 21( 4): 433- 443. DOI: 10.3760/cma.j.cn115610-20220316-00135. 中国医师协会器官移植医师分会, 中华医学会器官移植学分会肝移植学组. 中国肝癌肝移植临床实践指南(2021版)[J]. 中华消化外科杂志, 2022, 21( 4): 433- 443. DOI: 10.3760/cma.j.cn115610-20220316-00135.
[3]	WU ZT, PENG Q, GAO Y, et al. Advances in bioartificial liver system[J]. Chin J Cell Biol, 2019, 41( 4): 594- 600. DOI: 10.11844/cjcb.2019.04.0006. 武之涛, 彭青, 高毅, 等. 生物人工肝的研究进展[J]. 中国细胞生物学学报, 2019, 41( 4): 594- 600. DOI: 10.11844/cjcb.2019.04.0006.
[4]	ZHOU L, CHEN Y. Model selection and curative effect judgment criteria for artificial liver in the treatment of liver failure[J]. Chin J Hepatol, 2022, 30( 2): 127- 130. DOI: 10.3760/cma.j.cn501113-20220108-00008. 周莉, 陈煜. 人工肝治疗肝衰竭模式选择及其疗效判断标准[J]. 中华肝脏病杂志, 2022, 30( 2): 127- 130. DOI: 10.3760/cma.j.cn501113-20220108-00008.
[5]	Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Expert consensus on clinical application of artificial liver and blood purification(2022 edition)[J]. J Clin Hepatol, 2022, 38( 4): 767- 775. DOI: 10.3969/j.issn.1001-5256.2022.04.007. 中华医学会肝病学分会重型肝病与人工肝学组. 人工肝血液净化技术临床应用专家共识(2022年版)[J]. 临床肝胆病杂志, 2022, 38( 4): 767- 775. DOI: 10.3969/j.issn.1001-5256.2022.04.007.
[6]	LI G, ZHANG P, ZHU Y. Artificial liver support systems for hepatitis B virus-associated acute-on-chronic liver failure: A meta-analysis of the clinical literature[J]. J Viral Hepat, 2023, 30( 2): 90- 100. DOI: 10.1111/jvh.13767.
[7]	WANG L, XU WX, ZHU S, et al. Double plasma molecular adsorption system with sequential low-dose plasma exchange in patients with hepatitis B virus-related acute-on-chronic liver failure: A prospective study[J]. J Clin Transl Hepatol, 2023, 11( 4): 908- 917. DOI: 10.14218/JCTH.2022.00254.
[8]	XU W, ZHU S, YANG L, et al. Safety and efficacy of double plasma molecular adsorption system with sequential low-volume plasma exchange in intermediate-stage hepatitis B virus-related acute-on-chronic liver failure[J]. J Med Virol, 2023, 95( 3): e28650. DOI: 10.1002/jmv.28650.
[9]	SWAROOP S, ARORA U, BISWAS S, et al. Therapeutic plasma-exchange improves short-term, but not long-term, outcomes in patients with acute-on-chronic liver failure: A propensity score-matched analysis[J]. J Clin Apher, 2023, 38( 4): 376- 389. DOI: 10.1002/jca.22033.
[10]	CHEN YY, LI H, XU BY, et al. Plasma exchange-based non-bioartificial liver support system improves the short-term outcomes of patients with hepatitis B virus-associated acute-on-chronic liver failure: A multicenter prospective cohort study[J]. Front Med(Lausanne), 2021, 8: 779744. DOI: 10.3389/fmed.2021.779744.
[11]	WU HH, LUO CL. Short-term efficacy analysis of artificial liver therapy in patients with hepatitis B virus-related acute-on-chronic liver failure with different models for end-stage liver disease score[J]. China Pract Med, 2023, 18( 13): 7- 11. DOI: 10.14163/j.cnki.11-5547/r.2023.13.002. 吴慧慧, 罗长柳. 人工肝治疗不同终末期肝病模型评分的乙型肝炎病毒相关性慢加急性肝衰竭患者的短期疗效分析[J]. 中国实用医药, 2023, 18( 13): 7- 11. DOI: 10.14163/j.cnki.11-5547/r.2023.13.002.
[12]	CHEN Y. Highlight of a new clinical classification of acute-on-chronic liver failure[J]. J Pract Hepatol, 2020, 23( 4): 457- 458. DOI: 10.3969/j.issn.1672-5069.2020.04.001. 陈煜. 再论慢加急性肝衰竭新的临床分型及临床意义[J]. 实用肝脏病杂志, 2020, 23( 4): 457- 458. DOI: 10.3969/j.issn.1672-5069.2020.04.001.
[13]	LIN JH, CHEN LX, LAN LQ, et al. Association between the initial time of artificial liver plasma dialysis filtration intervention and the in-hospital prognosis in patients with hepatitis B-related chronic onset acute liver failure[J]. Chin J Blood Purif, 2023, 22( 3): 221- 226. DOI: 10.3969/j.issn.1671-4091.2023.03.014. 林建辉, 陈丽霞, 蓝丽琴, 等. 人工肝血浆透析滤过干预启动时间与乙型肝炎相关性慢加急性肝衰竭患者院内预后之间的关联[J]. 中国血液净化, 2023, 22( 3): 221- 226. DOI: 10.3969/j.issn.1671-4091.2023.03.014.
[14]	AN XY, HU LX, LI M, et al. A study on treatment timing selection and short-term efficacy prediction with changes in cytokine levels before and after non-biological artificial liver treatment in acute-on-chronic liver failure[J]. Chin J Hepatol, 2022, 30( 11): 1218- 1224. DOI: 10.3760/cma.j.cn501113-20220524-00278. 安薪宇, 胡灵溪, 李妹, 等. 非生物型人工肝治疗前后细胞因子水平变化对慢加急性肝衰竭治疗时机选择及其短期疗效的预测[J]. 中华肝脏病杂志, 2022, 30( 11): 1218- 1224. DOI: 10.3760/cma.j.cn501113-20220524-00278.
[15]	MAIWALL R, BAJPAI M, CHOUDHURY AK, et al. Therapeutic plasma-exchange improves systemic inflammation and survival in acute-on-chronic liver failure: A propensity-score matched study from AARC[J]. Liver Int, 2021, 41( 5): 1083- 1096. DOI: 10.1111/liv.14806.
[16]	OCSKAY K, KANJO A, GEDE N, et al. Uncertainty in the impact of liver support systems in acute-on-chronic liver failure: A systematic review and network meta-analysis[J]. Ann Intensive Care, 2021, 11( 1): 10. DOI: 10.1186/s13613-020-00795-0.
[17]	LARSEN FS, SCHMIDT LE, BERNSMEIER C, et al. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial[J]. J Hepatol, 2016, 64( 1): 69- 78. DOI: 10.1016/j.jhep.2015.08.018.
[18]	YANG ZY, ZHANG ZW, CHENG QY, et al. Plasma perfusion combined with plasma exchange in chronic hepatitis B-related acute-on-chronic liver failure patients[J]. Hepatol Int, 2020, 14( 4): 491- 502. DOI: 10.1007/s12072-020-10053-x.
[19]	LI S, CHEN Y. Coping with shortage of plasma-The new therapeutic pattern of non-bioartificial liver[J]. J Clin Hepatol, 2017, 33( 9): 1687- 1692. DOI: 10.3969/j.issn.1001-5256.2017.09.012. 李爽, 陈煜. 血浆紧缺情况下非生物型人工肝治疗新模式的探讨[J]. 临床肝胆病杂志, 2017, 33( 9): 1687- 1692. DOI: 10.3969/j.issn.1001-5256. 2017.09.012.
[20]	LI S, ZHOU L, LIU J, et al. Clinical observation of plasma exchange replacement of partial plasma with hydroxyethyl starch in the treatment of patients with liver failure[J]. Chin J Gastroenterol Hepatol, 2019, 28( 7): 735- 739. DOI: 10.3969/j.issn.1006-5709.2019.07.004. 李爽, 周莉, 刘静, 等. 血浆置换应用羟乙基淀粉替代部分血浆治疗肝衰竭的临床观察[J]. 胃肠病学和肝病学杂志, 2019, 28( 7): 735- 739. DOI: 10.3969/j.issn.1006-5709.2019.07.004.
[21]	FUJIWARA K, ABE R, YASUI S, et al. High recovery rate of consciousness by high-volume filtrate hemodiafiltration for fulminant hepatitis[J]. Hepatol Res, 2019, 49( 2): 224- 231. DOI: 10.1111/hepr.13255.
[22]	TAKIKAWA Y, KAKISAKA K, SUZUKI Y, et al. Multicenter study on the consciousness-regaining effect of a newly developed artificial liver support system in acute liver failure: An on-line continuous hemodiafiltration system[J]. Hepatol Res, 2021, 51( 2): 216- 226. DOI: 10.1111/hepr.13557.
[23]	KOMURA T, TANIGUCHI T, SAKAI Y, et al. Efficacy of continuous plasma diafiltration therapy in critical patients with acute liver failure[J]. J Gastroenterol Hepatol, 2014, 29( 4): 782- 786. DOI: 10.1111/jgh.12440.
[24]	YANG XS, ZHOU L, LI L, et al. Influence of duration of plasma diafiltration on therapeutic outcome of liver failure[J]. J Clin Hepatol, 2018, 34( 5): 1052- 1054. DOI: 10.3969/j.issn.1001-5256.2018.05.025. 杨仙珊, 周莉, 李璐, 等. 血浆透析滤过治疗时间对肝衰竭治疗效果的影响[J]. 临床肝胆病杂志, 2018, 34( 5): 1052- 1054. DOI: 10.3969/j.issn.1001-5256.2018.05.025.
[25]	WAN YM, LI YH, XU ZY, et al. Therapeutic plasma exchange versus double plasma molecular absorption system in hepatitis B virus-infected acute-on-chronic liver failure treated by entercavir: A prospective study[J]. J Clin Apher, 2017, 32( 6): 453- 461. DOI: 10.1002/jca.21535.
[26]	YAO J, LI S, ZHOU L, et al. Therapeutic effect of double plasma molecular adsorption system and sequential half-dose plasma exchange in patients with HBV-related acute-on-chronic liver failure[J]. J Clin Apher, 2019, 34( 4): 392- 398. DOI: 10.1002/jca.21690.
[27]	WU B, DU LY, MA YJ, et al. Effects of different combinations of artificial liver support system on efficacy and inflammatory indexes of patients with hepatitis B virus-related acute-on-chronic liver failure in early and middle stages[J/CD]. Chin J Liver Dis(Electronic Version), 2021, 13( 1): 32- 38. DOI: 10.3969/j.issn.1674-7380.2021.01.006. 吴蓓, 杜凌遥, 马元吉, 等. 不同组合人工肝支持系统治疗乙型肝炎病毒相关早、中期慢加急性肝衰竭患者的疗效及对炎症指标的影响[J/CD]. 中国肝脏病杂志(电子版), 2021, 13( 1): 32- 38. DOI: 10.3969/j.issn.1674-7380.2021.01.006.
[28]	SALIBA F, BAÑARES R, LARSEN FS, et al. Artificial liver support in patients with liver failure: A modified DELPHI consensus of international experts[J]. Intensive Care Med, 2022, 48( 10): 1352- 1367. DOI: 10.1007/s00134-022-06802-1.
[29]	MONET C, DE JONG A, AARAB Y, et al. Adverse events, short- and long-term outcomes of extra corporeal liver therapy in the intensive care unit: 16 years experience with MARS^® in a single center[J]. Crit Care, 2022, 26( 1): 282. DOI: 10.1186/s13054-022-04165-z.
[30]	AGARWAL B, CAÑIZARES RB, SALIBA F, et al. Randomized, controlled clinical trial of the DIALIVE liver dialysis device versus standard of care in patients with acute-on- chronic liver failure[J]. J Hepatol, 2023, 79( 1): 79- 92. DOI: 10.1016/j.jhep.2023.03.013.
[31]	POPESCU M, DAVID C, MARCU A, et al. Artificial liver support with CytoSorb and MARS in liver failure: A retrospective propensity matched analysis[J]. J Clin Med, 2023, 12( 6): 2258. DOI: 10.3390/jcm12062258.
[32]	MA YJ, CHEN F, XU Y, et al. Safety and efficacy of regional citrate anticoagulation during plasma adsorption plus plasma exchange therapy for patients with acute-on-chronic liver failure: A pilot study[J]. Blood Purif, 2019, 48( 3): 223- 232. DOI: 10.1159/000500408.
[33]	WANG M, MA YJ, DU LY, et al. Association between longer duration of citrate accumulation and 90-day mortality of acute-on-chronic liver failure[J]. Crit Care, 2021, 25( 1): 387. DOI: 10.1186/s13054-021-03819-8.
[34]	PENG B, LU JQ, GUO HB, et al. Regional citrate anticoagulation for replacement therapy in patients with liver failure: A systematic review and meta-analysis[J]. Front Nutr, 2023, 10: 1031796. DOI: 10.3389/fnut.2023.1031796.
[35]	WANG XY, ZHOU L, DONG JL, et al. Anticoagulant efficacy and safety comparison of nafmostat mesylate and heparin during double plasma molecular absorption system treatment in patients with liver failure[J]. J Pract Hepatol, 2023, 26( 6): 843- 846. DOI: 10.3969/j.issn.1672-5069.2023.06.019. 王新月, 周莉, 董金玲, 等. 双重血浆分子吸附系统治疗肝衰竭患者应用甲磺酸萘莫司他与肝素抗凝有效性与安全性比较研究[J]. 实用肝脏病杂志, 2023, 26( 6): 843- 846. DOI: 10.3969/j.issn.1672-5069.2023.06.019.
[36]	ZHANG K, ZHANG L, LIU W, et al. In vitro expansion of primary human hepatocytes with efficient liver repopulation capacity[J]. Cell Stem Cell, 2018, 23( 6): 806- 819. DOI: 10.1016/j.stem.2018.10.018.
[37]	WANG J, REN H, LIU Y, et al. Bioinspired artificial liver system with hiPSC-derived hepatocytes for acute liver failure treatment[J]. Adv Healthc Mater, 2021, 10( 23): e2101580. DOI: 10.1002/adhm.202101580.
[38]	TUERXUN K, HE J, IBRAHIM I, et al. Bioartificial livers: a review of their design and manufacture[J]. Biofabrication, 2022, 14( 3): 1- 24. DOI: 10.1088/1758-5090/ac6e86.
[39]	DUAN Z, XIN S, ZHANG J, et al. Comparison of extracorporeal cellular therapy(ELAD^®) vs standard of care in a randomized controlled clinical trial in treating Chinese subjects with acute-on-chronic liver failure[J]. Hepat Med, 2018, 10: 139- 152. DOI: 10.2147/HMER.S180246.
[40]	THOMPSON J, JONES N, AL-KHAFAJI A, et al. Extracorporeal cellular therapy(ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial[J]. Liver Transpl, 2018, 24( 3): 380- 393. DOI: 10.1002/lt.24986.
[41]	LI WJ, ZHU XJ, YUAN TJ, et al. An extracorporeal bioartificial liver embedded with 3D-layered human liver progenitor-like cells relieves acute liver failure in pigs[J]. Sci Transl Med, 2020, 12( 551): eaba5146. DOI: 10.1126/scitranslmed.aba5146.
[42]	SHI XL, GAO YM, YAN YP, et al. Improved survival of porcine acute liver failure by a bioartificial liver device implanted with induced human functional hepatocytes[J]. Cell Res, 2016, 26( 2): 206- 216. DOI: 10.1038/cr.2016.6.
[43]	WANG Y, ZHENG Q, SUN Z, et al. Reversal of liver failure using a bioartificial liver device implanted with clinical-grade human-induced hepatocytes[J]. Cell Stem Cell, 2023, 30( 5): 617- 631. DOI: 10.1016/j.stem.2023.03.013.