组合型人工肝的研究进展

黄玥; 彭虹; 罗新华

doi:10.12449/JCH240203

组合型人工肝的研究进展

DOI: 10.12449/JCH240203

贵州省人民医院感染科，贵阳 550000

基金项目:

贵州省科学技术基金 (ZK［2021］Key 013)

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：黄玥负责查找文献，撰写文稿；彭虹负责审阅文稿；罗新华负责审阅文稿及最后定稿。

详细信息

通信作者:
罗新华， luoxinhua1972@126.com （ORCID： 0000-0001-8285-3063）

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出版历程
- 收稿日期: 2023-10-30
- 录用日期: 2023-11-29
- 出版日期: 2024-02-19

Research advances in combined artificial liver

Department of Infectious Diseases，Guizhou Provincial People’s Hospital，Guizhou 550000，China

Research funding:

Guizhou Science and Technology Foundation (ZK［2021］Key 013)

More Information

Corresponding author: LUO Xinhua， luoxinhua1972@126.com （ORCID： 0000-0001-8285-3063）

摘要

摘要: 目前体外人工肝支持系统在各种原因导致的肝衰竭、肝移植前后无功能时期、严重胆汁性淤积等疾病中取得良好治疗效果。其中非生物型人工肝（NBAL）通过各种模式互补组合广泛应用于临床，主要以改善机体凝血因子和白蛋白等物质的血浆置换模式联合其余增强清除体内有毒物质谱的模式。以肝细胞的合成、转化功能为设计理念的生物型人工肝（BAL）近年也取得飞速发展。肝衰竭患者先经NBAL解毒后，再予以BAL合成、转化体内活性物质，能更接近人体肝脏正常生理功能。根据患者病情个体化组合NBAL模式，再结合疗效稳定的BAL是未来重症肝病患者体外支持治疗方向。
- 组合型非生物人工肝 /
- 组合型生物人工肝 /
- 治疗学
Abstract: At present， in vitro artificial liver support system has achieved a good therapeutic effect in the diseases such as liver failure due to various causes， non-function state before and after liver transplantation， and severe cholestasis. Non-bioartificial liver （NBAL） is widely used in clinical practice through various combinations of modes， mainly the plasma exchange mode for improving coagulation factors and albumin combined with other modes for enhancing the elimination of toxic substances in the body. Bioartificial liver （BAL）， based on the design concept of the synthesis and transformation of hepatocytes， has achieved rapid development in recent years. Patients with liver failure can almost obtain the normal physiological function of human liver after NBAL detoxification and BAL synthesis and transformation of active substances in the body. NBAL mode combined with BAL with a stable therapeutic effect according to the conditions of the patient is the direction of in vitro support treatment for patients with severe liver disease in the future.
- Combined Non-biological Artificial Liver /
- Combined Bioartificial Liver /
- Therapeutics

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表 1 组合型NBAL模型的优缺点^［2］

Table 1. Advantages and disadvantages of combined NBAL model

国内常见的NBAL组合模式	优点	缺点
DPMAS+PE	特异性高效吸附胆红素、清除毒素，补充凝血因子及白蛋白	无法改善肾功能，以血浆为置换液行PE时可能会加重肝性脑病
PE+HDF	毒素清除范围与程度增加，改善肾功能不全与肝性脑病，维持内环境稳定	血浆需求量较大，治疗时间相对较长
HDF+DPMAS	不需要用血浆，对胆红素、炎性介质、内毒素、中小分子水溶性毒素清除能力强	无法补充白蛋白、凝血因子等，治疗时间长
PDF+PP	减少血浆应用量，更有效地清除胆红素及其他大分子毒素，补充凝血因子及白蛋白	治疗时间长，重症患者的凝血监测与抗凝要求高
PE+PP+HDF	对大、中、小分子毒素都具有很好的清除能力，同时补充凝血因子	血浆需求量较大，治疗时间长，需给予合理的抗凝方案及监测
注：DPMAS，双重血浆分子吸附系统。

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表 2 国内外常见的BAL来源与研究进展

Table 2. Sources and research progress of common BAL

系统	细胞来源	反应器	来源	相关研究结果
国内
hiHep-BAL	转分化细胞hiHep	多层平板模型	（1） NCT05035108；（2） NCT03084198；（3）微知卓生物科技有限公司	动物肝切除模型和临床扩大肝切除患者研究中，改善肝功能，增加术后肝脏再生速度，提高存活率^［35-36］
RL1-BAL	未知	未知	NCT04195282	比较PE与RL1-BAL+PE治疗HBV-ACLF的效果与预后。目前尚无相关临床指标。具体详细情况未公布
HepAssis2-BAL	人源肝细胞HL2	中空纤维反应器	（1） ChiCTR2300075781；（2）武汉仝干医疗科技股份有限公司	相比NBAL组，BAL组的血浆用量显著减少，生化指标降低幅度两组相当，长期无肝移植存活率显著升高。（结果来源该公司官网 http：//www.whtogo.com/detail_254.html）
IHH-BAL	永生化细胞IHH	微囊悬液式	苏州瑞徕生物科技有限公司	临床试验进行中，未见相关结果展示
ZHJ-Ⅲ系统	永生化细胞HepGL	灌流式	（1） ChiCTR1800016021；（2）广州乾晖生物科技有限公司	临床前研究阶段，结果尚未公布
Aliver系统	转分化细胞HepLPC	气液交互式	上海赛立维生物科技有限公司	临床前研究阶段。Ali-Cell肝细胞的BAL可以对肝衰竭患者血浆进行代谢解毒，并合成活性物质减轻肝损伤促进肝脏再生修复^［37］
国外
LifeLiver系统	未知	未知	（1） NCT03882346；（2）韩国三星医疗HLB Cell Co.公司	目前注册的研究是关于在等待紧急肝移植的急性或ACLF患者中的安全性和有效性，未见相关结果展示
ELAD系统	人肝癌细胞株C3A细胞	中空纤维反应器	（1） NCT01875874；（2） NCT01829347；（3） Vital therapies公司	Ⅲ期临床试验中因初期疗效不佳，ELAD相关研究已提前终止，无明确结果^［38］
HepatAssist系统	猪源肝细胞	中空纤维反应器	Circe biomedical公司	该系统已进行相关临床研究，尽管研究证明没有猪逆转录病毒感染的安全性问题，但是临床疗效仍然存在争议，处于Ⅲ期临床阶段^［33］
BLSS系统	猪源肝细胞	中空纤维反应器	（1） Excorp Medical公司；（2）匹兹堡大学；（3） PubMed	与HepatAssist的区别是没有活性炭，目前在Ⅰ~Ⅱ期临床阶段^［42］
MELS系统	原代人肝细胞/猪源肝细胞	中空纤维反应器	（1）柏林堡大学；（2） PubMed	基于3D构建的人肝细胞反应器，进入Ⅱ期临床阶段，也有采用猪肝细胞反应器，初步研究排除猪逆转录病毒感染风险^［43］

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