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Manuscript NO: 47378
Manuscript Type: SYSTEMATIC REVIEWS
Bioartificial liver support systems for acute liver failure: A systematic review and meta-analysis of the clinical and preclinical literature
He YT et al. Bioartificial liver for acute liver failure
Yu-Ting He, Ya-Na Qi, Bing-Qi Zhang, Jian-Bo Li, Ji Bao
Yu-Ting He, Bing-Qi Zhang, Ji Bao, Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Ya-Na Qi, Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Jian-Bo Li, Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
ORCID number: Yu-Ting He (0000-0003-4107-2118); Ya-Na Qi (0000-0003-4287-7348); Bing-Qi Zhang (0000-0001-5146-8592); Jian-Bo Li (0000-0001-8430-392X); Ji Bao (0000-0001-8413-3270).
Author contributions: He YT and Qi YN contributed equally to the work and are co-first authors. He YT and Bao J designed the research; He YT, Qi YN, and Zhang BQ contributed to literature selection and data extraction; He YT, Qi YN, Bao J, and Li JB contributed to analysis and interpretation of the data; He YT and Qi YN drafted the original manuscript; Bao J and Li JB revised the article; All authors have read the final article and approved the publication of the manuscript.
Conflict-of-interest statement: The authors have no conflict of interests to disclose.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.
Open-Access: This is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: HYPERLINK "http://creativecommons.org/licenses/by-nc/4.0/" http://creativecommons.org/licenses/by-nc/4.0/
Manuscriptsource: Invitedmanuscript
Corresponding author: Ji Bao, PhD, Associate Professor, Laboratory of Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Wuhou District, Chengdu 610041, Sichuan Province, China. HYPERLINK "mailto:baoji@scu.edu.cn" baoji@scu.edu.cn
Telephone: +86-18980606618
Fax: +86-28-85164033
Received: March 20, 2019
Peer-review started: March 20, 2019
First decision: March 27, 2019
Revised: May 3, 2019
Accepted: May 31, 2019
Article in press:
Published online:
Abstract
BACKGROUND
Acute liver failure (ALF) has a high mortality varying from 80% to 85% with rapid progress in multi-organ system failure. Bioartificial liver (BAL) support systems have the potential to provide temporary support to bridge patients with ALF to liver transplantation or spontaneous recovery. In the past decades, several BAL support systems have been conducted in clinicaltrials. More recently, concerns have been raised on the renovation of high-quality cell sources and configuration of BAL support systems to provide more benefits to ALF models in preclinical experiments.
AIM
To investigate the characteristics of studies about BAL support systems for ALF, and to evaluate their effects on mortality.
METHODS
Eligible clinical trials and preclinical experiments on large animals were identified on Cochrane Library, PubMed, and EMbase up to March 6, 2019. Two reviewers independently extracted the necessary information, including key BAL indicators, survival and indicating outcomes, and adverse events during treatment. Descriptive analysis was used to identify the characteristics of the included studies, and a meta-analysis including only randomized controlled trial (RCT) studies was done to calculate the overall effect of BAL on mortality among humans and large animals, respectively.
RESULTS
Of the 30 selected studies, 18 were clinical trials and 12 were preclinical experiments. The meta-analysis result suggested that BAL might reduce mortality in ALF in large animals, probably due to the recent improvement of BAL, including the type, cell source, cell mass, and bioreactor, but seemed ineffective for humans [BAL vs control: relative risk (95% confidence interval), 0.27 (0.12-0.62) for animals and 0.72 (0.48-1.08) for humans]. Liver and renal functions, hematologic and coagulative parameters, encephalopathy index, and neurological indicators seemed to improve after BAL, with neither meaningful adverse events nor porcine endogenous retrovirus infection.
CONCLUSION
BAL may reduce the mortality of ALF by bridging the gap between preclinical experiments and clinical trials. Clinical trials using improved BAL must be designed scientifically and conducted in the future to provide evidence for transformation.
Key words: Bioartificial liver; Acute liver failure; Preclinical experiment; Clinical trial; Meta-analysis
The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
Core tip: This systematic review and meta-analysis included a large number of studies about clinical trials and preclinical experiments of bioartificial liver (BAL) support systems for treating patients and large animal models with acute liver failure. We summarized the characteristics of studies, BAL, and outcomes in all the studies and compared the pooled effect by meta-analysis including only randomized controlled trial studies regarding mortality after BAL among humans and large animals, respectively.
He YT, Qi YN, Zhang BQ, Li JB, Bao J. Bioartificial liver support systems for acute liver failure: A systematic review and meta-analysis of the clinical and preclinical literature. World J Gastroenterol 2019; In press
INTRODUCTION
Acute liver failure (ALF) is characterized by an acute episode of liver dysfunction in individuals without underlying chronic liver diseases, sometimes causing a rapid onset of encephalopathy and coagulopathy followed by multiorgan system failure. Patients with ALF have a high mortality ranging from 80% to 85%, approaching 90% among those with severe fulminant hepatic failure (FHF)[ HYPERLINK \l "_ENREF_1" \o "Bernuau, 1986 #36" 1]. The most effective treatment method for patients with ALF is liver transplantation, as it has increased the 5-year survival rate by 75%[2]. Although some patients might recover spontaneously, many would die during waiting for a compatible donor because of aggressive deterioration of liver function or development of cerebral edema, intracranial hypertension, and even irreversible brain damage. Thus, a liver support system must be developed to maintain a viable status of these patients prior to the transplantation.
During the past decades, several artificial devices for removing toxins from patients blood through filtration and adsorption have improved clinical status in some cases. However, a meta-analysis of six randomized controlled trials (RCTs) concluded that artificial liver support systems might not reduce the mortality in ALF ADDIN EN.CITE Kjaergard200341414117Kjaergard, Lise L,Jianping, LiuBodil, Als NielsenChristian, GluudArtificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic reviewJamaJama217-22228922003[ HYPERLINK \l "_ENREF_3" \o "Kjaergard, 2003 #41" 3]. Moreover, the newly developed bioartificial liver (BAL) support systems that incorporate a hepatoma cell line or primary hepatocytes into a bioreactor when processing blood or plasma proved meaningful for prolonging the survival time of ALF animals in preclinical trials. Several types have been applied for the treatment of patients with ALF in phase I studies or controlled clinical trials, and improved neurological status and liver and renal functions, thus bridging to transplantation or spontaneous recovery ADDIN EN.CITE ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_4" \o "Pless, 2010 #53" 4-7]. However, the survival outcome and adverse effects of such alternative methods are controversial ADDIN EN.CITE Kjaergard200341414117Kjaergard, Lise L,Jianping, LiuBodil, Als NielsenChristian, GluudArtificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic reviewJamaJama217-22228922003Stutchfield201133333317Stutchfield, B M,Simpson, K. ,.Wigmore, S J,Systematic review and meta-analysis of survival following extracorporeal liver supportBritish Journal of SurgeryBritish Journal of Surgery623-6319852011[ HYPERLINK \l "_ENREF_3" \o "Kjaergard, 2003 #41" 3, HYPERLINK \l "_ENREF_8" \o "Stutchfield, 2011 #33" 8].
In addition, the BAL has various types with different cell sources, cell mass, and culture methods, as well as architectural design such as the bioreactor, scaffold, and separation, which might be associated with the effect and safety of the BAL in treating ALF ADDIN EN.CITE Maarten Paul200454545417Maarten Paul, Van De KerkhoveRuurdtje, HoekstraChamuleau, Robert A F M,Gulik, Thomas M, VanClinical application of bioartificial liver support systemsAnnals of SurgeryAnnals of Surgery21624022004[ HYPERLINK \l "_ENREF_9" \o "Maarten Paul, 2004 #54" 9]. Furthermore, the BAL has been modified and renovated in preclinical experiments on large animals but has not been used in clinical trials ADDIN EN.CITE ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "Li, 2018 #57" 10-12], which caused a significant gap between clinical and preclinical studies.
One objective of our study was to investigate the characteristics of studies about BAL for ALF in both clinical trials and recent preclinical experiments on large animals. In particular, we looked at key indicators of the BAL, survival outcome, and adverse events regarding the treatment. Another objective was to evaluate the pooled effect of the BAL on mortality by conducting a meta-analysis of randomized controlled studies stratified among patients with ALF and large animals.
MATERIALS AND METHODS
This study was constructed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The protocol has been registered in PROSPERO, an international prospective register of systematic reviews (Registration number: CRD42019133215).
Inclusion and exclusion criteria
We included studies about any of the BAL for ALF, including all clinical trials, case reports, and RCTs in patients with ALF and preclinical experiments in large animals (monkeys, pigs, and dogs) published in the past 10 years. The language was limited to English.
The exclusion criteria were as follows: (1) not focusing on the outcome of BAL, or the ALF group could not be separated from the other study populations such as patients with acute-on-chronic liver failure; (2) duplicates of previous publications; (3) based on incomplete data; and (4) reviews, meta-analyses, comments, guidelines, letters, editorial articles, and project or conference summaries. If more than one study by the same author using the same data was published, either the study with the largest sample size or the most recently published study was included.
Literature search and selection
By using a searching strategy and filter that combined keywords or subjects about BAL and ALF, which had been pre-tested and improved repeatedly, we searched the Cochrane Library, PubMed, and EMbase to identify eligible articles till March 6, 2019 according to the inclusion and exclusion criteria, by setting the following key elements (Patients: ALF; Intervention: BAL; Comparison: None; Outcome: including but not limited to mortality, bridging time, liver and renal function; keywords used for literature search are shown in Supplementary material). Literature about preclinical experiments in large animals was limited to papers published in the past 10 years. The references used in the eligible articles were also reviewed to examine other potential sources.
Teams of paired reviewers who were trained and knowledgeable about the study screened the literature independently. We screened the title and keywords first and excluded unqualified studies according to the predefined criteria. Then, we read the abstracts and full texts carefully to further exclude unqualified literature. The decision to exclude studies was determined by two reviewers. Inconsistent results were resolved either by discussion or decided by a third reviewer. Finally, the remaining studies were enrolled to be reviewed and analyzed. The flow chart of the study selection is shown in Figure 1.
Data extraction
We extracted the following information from each eligible article: (1) basic information of the included studies, including the publication year, title of the article, journal along with impact factor in 2018, country of the first author, study setting, study type (clinical trial, case report, or preclinical experiment), and data sources (full text and abstract); (2) detailed information of clinical trials in humans, including the type of BAL [e.g., HepatAssist, extracorporeal liver assist device (ELAD), academic medical center (AMC)-BAL, modular extracorporeal liver support (MELS), novel bioartificial liver support system (BLSS), radial-flow bioreactor (RFB)-BAL, and hybrid bioartificial liver (HBAL)], whether hybrid or not, cell sources (e.g., porcine hepatocytes, C3A cells, or primary human hepatocytes), cell mass, sample size, ALF subtype [fulminant hepatic failure (FHF) or primary nonfunction (PNF)], age and sex of subjects, disease etiology [e.g., PNF, viral, indeterminate, autoimmune, Acetaminophen (AO), and ischemic], BAL treatment time, outcomes (i.e., bridging time, orthotopic liver transplantation, death events, and recovery), follow-up time, stable or unstable hemodynamics, effects on liver and renal functions, hematologic and coagulative parameters, encephalopathy index, neurological status, adverse events during treatment (e.g., transitory hypotension), and porcine endogenous r e t r o v i r u s ( P E R V ) t e s t r e s u l t ; ( 3 ) d a t a o f p r e c l i n i c a l e x p e r i m e n t o n l a r g e a n i m a l s , i n c l u d i n g a n i m a l s p e c i e s ( e . g . , p i g , c a n i n e , a n d m o n k e y ) , n u m b e r o f a n i m a l s , s e x ( f e m a l e a n d m a l e ) , w e i g h t ( k g ) , i n d u c e r o f a c u t e l i v e r f a i l u r e ( e . g . , D - g a l a c t o s a m i n e , h e p a t i c a r t e r y l i g a t i o n , s u r g i c a l l i g a t i o n o f a l l b l o o d f l o w t o t h e l i v e r , - a m a n i t i n , a n d l i p o p o l y s a c c h a r i d e ) , t y p e o f B A L ( e . g . , F B B A L , H B A L , H B A L S S , S R B A L , h i H e p - B A L , a n d U C L B A L ) , c e l l s o u r c e s ( e . g . , a l g i n a t e - c h i t o s a n e n c a p s u l a t e d p r i m a r y p o r c i n e h e p a t o c y t e s , c o - c u l t u r e d p i g h e p a t o c y t e s , b o n e m a r r o w m e s e n c h y m a l s t e m c e l l s , h u m a n h e p a t i c C L - 1 c e l l s g r o w n i n m i c r o g r a v i t y c u l t u r e , H i H e p s , a n d t h r e e - d i m e n s i o n a l H e p G 2 - c e l l s p h e r o i d s ) , c e l l m a s s , b i o r e a c t o r ( e . g . , c h o a n o i d f l u i d i z e d b e d b i o r e a c t o r , m u l t i - l a y e r a t - p l a t e b i o r e a c t o r a n i o n i c r e s i n a d s o r p t i o n c o l u m n , f l u i d i z e d - b e d b i o r e a c t o r , p e r f u s i o n b i o r e a c t o r , s p h e r o i d r e s e r v o i r , a n d p a c k e d - b e d b i o r e a c t o r ) , t r e a t m e n t t i m e , s u r v i v a l t i m e o r r a t e a t a s p e c i f i c t i m e p o i n t , o t h e r e f f e c t s s u c h a s a m m o n i a l e v e l , a n d P E R V test result.
For data extraction and scoring, paired reviewers conducted the survey independently on the basis of the literature database and recorded the necessary information. The results of the paired reviewers were cross-checked, and disagreements were resolved by discussion or decided by a third reviewer.
Statistical analysis
We conducted description analyses of the study characteristics of clinical trials and preclinical experiments on large animals by using the absolute numbers and percentages of the qualitative variables, and mean [standard deviation (SD)] or median (percentile) of the quantitative data. The bias risk of the included RCT studies was assessed according to the Cochrane assessment method for RCTs, while risk of non-RCT studies was assessed according to the Newcastle-Ottawa Quality Assessment Scale for cohort studies.
By selecting clinical RCTs and preclinical RCT experiments with survival outcome (death event) recorded at a specific time, we combined the effect of selected studies on the relative ratio (RR) scale by performing a meta-analysis with a random effect model and assigning weights according to the estimated variance. The heterogeneity of the included studies was also tested, with Q-test significance (P < 0.05) or I2 > 50% indicating that heterogeneity existed between studies. The overall RR and 95% confidence interval (CI) were calculated. We also conducted sensitivity analyses to examine the impact of using alternative effect measures (odds ratio vs relative ratio), pooling methods [Peto vs Mantel-Hanszel (M-H)], and statistical models (fixed- vs random-effects). Beggs funnel plot was also used to evaluate the publication bias.
All the statistical analyses were performed with SPSS 23.0 (IBM Corp. Armonk, NY, United States) and Review Manager 5.3 (RevMan, the Cochrane Collaboration, Oxford, England).
RESULTS
We identified 215 studies preliminarily, and then excluded 67 unrelated or ineligible articles, 34 articles about artificial liver support system, 14 articles about in vitro function evaluation, 1 duplicate article, 4 articles with unavailable data, and 65 reviews. We finally included 30 articles in the analyses, of which 18 were human clinical trials ADDIN EN.CITE ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Demetriou, 2004 #20" 6, HYPERLINK \l "_ENREF_7" \o "Ellis, 1996 #45" 7, HYPERLINK \l "_ENREF_13" \o "Rozga, 1994 #4" 13-28] (only 2 were RCT studies ADDIN EN.CITE ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Demetriou, 2004 #20" 6, HYPERLINK \l "_ENREF_7" \o "Ellis, 1996 #45" 7]) and 12 were preclinical experiments in large animals ADDIN EN.CITE ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_5" \o "Guoliang, 2011 #21" 5, HYPERLINK \l "_ENREF_10" \o "Li, 2018 #57" 10-12, HYPERLINK \l "_ENREF_29" \o "Shi, 2012 #56" 29-36].
Among the 30 articles, 94.4% (17/18) were clinical trials published before 2005, with only 1 phase = 1 \* ROMANI clinical trial published in 2018 (only abstract available). Studies about preclinical experiments in large animals in the recent 10 years accounted for 40% of the articles (12/30). The median (P25-P75) impact factor (IF) of the journals was 4.04 (2.60-9.20), with 8 articles having an IF < 3 and 5 having an IF > 10. Approximately two-thirds of the studies were conducted by authors in the United States (11/30) and China (8/30). One RCT study was done in England and published in Hepatology in 1996 ADDIN EN.CITE Ellis199645454517Ellis, A. J.Hughes, R. D.Wendon, J. A.Dunne, J.Langley, P. G.Kelly, J. H.Gislason, G. T.Sussman, N. L.Williams, R.Pilot-controlled trial of the extracorporeal liver assist device in acute liver failureHepatologyHepatology1446-14512461996[7] while the other one was performed in 11 United States and 9 European sites by United States researchers and published in Annals of Surgery in 2004 ADDIN EN.CITE Demetriou200420202017Demetriou, Achilles A,Brown, Robert S,Busuttil, Ronald W,Jeffrey, FairMcguire, Brendan M,Philip, RosenthalJan Schulte, Am EschJan, LerutNyberg, Scott L,Mauro, SalizzoniProspective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failureAnnals of SurgeryAnnals of Surgery667-702395HumansLiver Failure, AcuteBilirubinProportional Hazards ModelsSurvival AnalysisProspective StudiesAdolescentAdultAgedMiddle Aged2004[ HYPERLINK \l "_ENREF_6" \o "Demetriou, 2004 #20" 6]. More than one-third (12/30) of the studies were about hybrid support systems (e.g., HBAL, MELS, HBALSS, and HepatAssist), distributed in 9 clinical trial studies and 3 preclinical experimental studies. The available data that we analyzed were mostly from full texts (29/30), and 1 abstract of clinical trial was also included considering the limited number of eligible studies in humans and the availability of valuable information in the abstract (as shown in Supplemental Table 1).
Characteristics of the BAL, subjects, outcomes, and adverse events in the clinical trials
From the 18 clinical trials, 332 patients with ALF were included, with 295 cases of FHF subtypes and 37 cases of PNF subtypes. The mean age was 35.4 years, and females accounted for 69.4% of the patients according to the reported data. Most of the disease etiologies were indeterminate (103 cases), viruses (45 cases), and AO (33 cases). The types of BAL included HepatAssist (6 cases), ELAD (3 cases), AMC-BAL (2 cases), MELS (2 cases), BLSS (1 case), RFB-BAL (1 case), HBAL (1 case), Lifeliver (1 case), and BAL (1 case), and in one case the BAL type was unclear; of these 9 were hybrids and 8 were non-hybrids. Most of the cells were sourced from porcine hepatocytes (14/18), followed by C3A cells (3/18) and primary human hepatocytes (1/18). The mean cell mass was approximately 9 ( 109 (Table 1).
The mean treatment time was around 25 h. Among the 317 reported patients, 201 received orthotopic liver transplant (OLT) and 57 recovered without OLT. The mean survival rate in the OLT group was 93%, with the follow-up period ranging from 7 d to 62 mo. Hemodynamics were stable in all patients. These results show that BAL improved liver and renal functions in all the patients, except 3 with PNF ADDIN EN.CITE ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Demetriou, 2004 #20" 6, HYPERLINK \l "_ENREF_14" \o "Watanabe, 1997 #5" 14, HYPERLINK \l "_ENREF_15" \o "Chen, 2010 #6" 15], in terms of the different biochemical parameters, with decreased ammonia, bilirubin, and transaminase levels in 12, 12, and 10 studies, respectively. Other meaningful indicators were reduced, including lactate ALB, BUN, and creatinine levels. By examining prothrombin time (PT), international normalized ratio, or other parameters, 9 studies found improvements in hematological and coagulative status. Ten of 12 reported studies showed an improvement in encephalopathy index. Thirteen of 16 reported studies showed improvements in neurological indicators, showing decreased intracranial pressure (ICP) and increased cerebral perfusion pressure, Glasgow coma score, and comprehensive level of consciousness score. In 3 studies on ALF subtypes, the encephalopathy index and neurological indicators showed improvements in patients with FHF but not in patients with PNF ADDIN EN.CITE ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Demetriou, 2004 #20" 6, HYPERLINK \l "_ENREF_14" \o "Watanabe, 1997 #5" 14, HYPERLINK \l "_ENREF_15" \o "Chen, 2010 #6" 15]. However, one case report of a patient with PNF showed improvement in the neurological status with a change in coma stage from IV to I after BAL treatment[ HYPERLINK \l "_ENREF_22" \o "Sauer, 2003 #13" 22] (Table 2).
During BAL treatment, 9 studies reported adverse events such as transient hypotension, decreased body temperature, tachycardia, pyrexia, and hypoglycemia, which had no clinical significance and resolved in all. PERV test results in 8 reported studies were all negative (Table 2).
Characteristics of the BAL, animal, and outcomes in the preclinical experiments with large animals
Of 12 studies that performed preclinical experiments with pigs (8 studies, 160 animals), monkeys (2 studies, 45 animals), and canines (2 studies, 40 animals), the proportions of male and female animals were 45.3% (111/245) and 30.2% (74/245), respectively. Inducers included D-galactosamine in 7 studies (145 animals) ADDIN EN.CITE ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_5" \o "Guoliang, 2011 # 2 1 " 5 , H Y P E R L I N K \ l " _ E N R E F _ 1 2 " \ o " S h i , 2 0 1 6 # 3 " 1 2 , H Y P E R L I N K \ l " _ E N R E F _ 2 9 " \ o " S h i , 2 0 1 2 # 5 6 " 2 9 - 3 3 ] , s u r g i c a l o p e r a t i o n i n 3 s t u d i e s ( 5 3 a n i m a l s ) A D D I N E N . C I T E A D D I N E N . C I T E . D A T A [ H Y P E R L I N K \ l " _ E N R E F _ 1 1 " \ o " S e l d e n , 2 0 1 3 # 2 2 " 1 1 , HYPERLINK \l "_ENREF_34" \o "Selden, 2017 #27" 34, HYPERLINK \l "_ENREF_35" \o "Lee, 2017 #28" 35], 85% hepatectomy in 1 study (18 animals) ADDIN EN.CITE Chen201958585817Chen, H. S.Joo, D. J.Shaheen, M.Li, Y.Wang, Y.Yang, J.Nicolas, C. T.Predmore, K.Amiot, B.Michalak, G.Mounajjed, T.Fidler, J.Kremers, W. K.Nyberg, S. L.William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN.
Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.
West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Radiology, Mayo Clinic, Rochester, MN.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
Department of Biostatistics, Mayo Clinic, Rochester, MN.Randomized Trial of Spheroid Reservoir Bioartificial Liver in Porcine Model of Posthepatectomy Liver FailureHepatologyHepatology (Baltimore, Md.)Hepatology329-3426912018/07/202019Jan0270-91393002250210.1002/hep.30184Nlm<