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To explore the efficacy and safety of a small-volume-plasma artificial liver support system (ALSS) in the treatment of acute-onchronic liver failure (ACLF). A retrospective analysis was performed. All ACLF patients received ALSS of plasma exchange & double plasma molecular absorb system (PE+DPMAS) treatment, and successfully completed this treatment. Patients were divided into small-volume and half-volume plasma groups. We compared the changes of the indicators on liver function, kidney function, blood coagulation function, and blood ammonia level before and after PE+DPMAS treatment; we compared the short-term and long-term curative effects between small-volume and half-volume plasma groups; and the factors influencing Week 4 and Week 12 mortality of ACLF patients were analyzed. The Week 4 improvement rates were 63.96 % and 66.86 % in the smallvolume and half-volume plasma groups, respectively. The Week 12 survival rates in the small-volume-plasma and half-volume plasma groups were 66.72 % and 64.61 %, respectively. We found several risk factors affecting Week 4 and Week 12 mortality. Kaplan-Meier survival curves suggested no significant difference in Week 4 and Week 12 survival rates between the small-volume and half-volume plasma groups (P=0.34). The small-volumeplasma PE+DPMAS treatment could effectively reduce bilirubin and bile acids, and this was an approach with high safety and few complications, similar to the half-volume-plasma PE+DPMAS treatment. The small-volume-plasma PE+DPMAS has the advantage of greatly reducing the need for intraoperative plasma, which is especially of importance in times of shortage of plasma. [ABSTRACT FROM AUTHOR]

This article concerns liver transplantation and its associated difficulties and risks, and also describes a more progressive method of saving people in need of a liver transplant—an artificial liver. An analysis of the BioUML software platform for modeling bioartificial liver systems is also presented. [ABSTRACT FROM AUTHOR]

The prognosis of Artificial liver support system (ALSS) for hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is hard to be expected, which results in multiple operations of ALSS and excessive consumption of plasma, increase in clinical cost. A total of 375 HBV-ACLF patients receiving ALSS treatment were randomly divided a train set and an independent test set. Logistic regression analysis was conducted and a decision tree was built based on 3-month survival as outcome. The ratio of total bilirubin before and after the first time of ALSS treatment was the most significant prognostic factor, we named it RPTB. Further, a decision tree based on the multivariate logistic regression model using CTP score and the RPTB was built, dividing patients into 3 main groups such as favorable prognosis group, moderate prognosis group and poor prognosis group. A clearly-presented and easily-understood decision tree was built with a good predictive value of prognosis in HBV-related ACLF patients after first-time ALSS treatment. It will help maximal the therapeutic value of ALSS treatment and may play an important role in organ allocation for liver transplantation in the future. [ABSTRACT FROM AUTHOR]

We aim to determine the impact of an artificial liver support system (ALSS) treatment before liver transplantation (LT), and identify the prognostic factors and evaluate the predictive values of the current commonly used ACLF prognostic models for short-term prognosis after LT. Data from 166 patients who underwent LT with acute-on-chronic liver failure (ACLF) were retrospectively collected from January 2011 to December 2018 from the First Affiliated Hospital of Zhejiang University School of Medicine. Patients were divided into two groups depending on whether they received ALSS treatment pre-LT. In the observation group, liver function tests and prognostic scores were significantly lower after ALSS treatment, and the waiting time for a donor liver was significantly longer than that of the control group. Both intraoperative blood loss and period of postoperative ICU care were significantly lower; however, there were no significant differences between groups in terms of total postoperative hospital stays. Postoperative 4-week and 12-week survival rates in the observation group were significantly higher than those of the control group. Similar trends were also observed at 48 and 96 weeks, however, without significant difference. Multivariate Cox regression analysis of the risk factors related to prognosis showed that preoperative ALSS treatment, neutrophil–lymphocyte ratio, and intraoperative blood loss were independent predicting factors for 4-week survival rate after transplantation. ALSS treatment combined with LT in patients with HBV-related ACLF improved short-term survival. ALSS treatment pre-LT is an independent protective factor affecting the 4-week survival rate after LT. [ABSTRACT FROM AUTHOR]

Artificial liver support system (ALSS) therapy is widely used in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). We aimed to develop a predictive score to identify the subgroups who may benefit from plasma exchange (PE)-centered ALSS therapy. A total of 601 patients were retrospectively enrolled and randomly divided into a derivation cohort of 303 patients and a validation cohort of 298 patients for logistic regression analysis, respectively. Five baseline variables, including liver cirrhosis, total bilirubin, international normalized ratio of prothrombin time, infection and hepatic encephalopathy, were found independently associated with 3-month mortality. A predictive PALS model and the simplified PALS score were developed. The predicative value of PALS score (AUROC = 0.818) to 3-month prognosis was as capable as PALS model (AUROC = 0.839), R score (AUROC = 0.824) and Yue-Meng' score (AUROC = 0.810) (all p > 0.05), and superior to CART model (AUROC = 0.760) and MELD score (AUROC = 0.765) (all p < 0.05). The PALS score had significant linear correlation with 3-month mortality (R2 = 0.970, p = 0.000). PALS score of 0–2 had both sensitivity and negative predictive value of > 90% for 3-month mortality, while PALS score of 6–9 had both specificity and positive predictive value of > 90%. Patients with PALS score of 3–5 who received 3–5 sessions of ALSS therapy had much lower 3-month mortality than those who received 1–2 sessions (32.8% vs. 59.2%, p < 0.05). The more severe patients with PALS score of 6–9 could still benefit from ≥ 6 sessions of ALSS therapy compared to ≤ 2 sessions (63.6% vs. 97.0%, p < 0.05). The PALS score could predict prognosis reliably and conveniently. It could identify the subgroups who could benefit from PE-centered ALSS therapy, and suggest the reasonable sessions. Trial registration: Chinese Clinical Trial Registry, ChiCTR2000032055. Registered 19th April 2020, http://www.chictr.org.cn/showproj.aspx?proj=52471. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The purpose of this study was to find out whether 3-dimensional (3D)-printed models improved the learners' ability to identify liver segments. METHODS: A total of 116 physicians from 3 disciplines were tested in a cross-over trial at baseline and after teaching with 3D models and 2-dimensional (2D) images. Adjusted multilevel-mixed models were used to compare scores at baseline and after 3D and 2D. RESULTS: Accuracy in identifying hepatic segments was higher with 3D first than 2D (77%vs69%; P50.05) and not significantly improved by a combination of 3D and 2D. Increased confidence in segment identification was highest in trainees after 3D (P 5 0.04). DISCUSSION: 3D-printed models facilitate learning hepatic segmental anatomy. [ABSTRACT FROM AUTHOR]

Patients with liver failure may suffer citrate accumulation when using regional citrate anticoagulation for artificial liver support system therapy (RCA-ALSS therapy). This study aimed to develop a predictive scoring system to stratify the risk of citrate accumulation. A total of 338 patients treated with RCA-ALSS therapy were retrospectively enrolled and randomly divided into derivation and validation cohorts. Longer duration of citrate accumulation (LDCA) was defined as the presence of citrate accumulation 2 h after RCA-ALSS therapy. Four baseline variables were found to be independently associated with LDCA: gender, international normalized ratio of prothrombin time, serum creatinine, and serum chloride. A predictive R-CA model and its simplified R-CA score were developed. The R-CA model (AUROC = 0.848) was found to be superior to the MELD score (AUROC = 0.725; p = 0.022) and other univariate predictors (AUROCs < 0.700; all p ≤ 0.001) in predicting LDCA. The R-CA score (AUROC = 0.803) was as capable as the R-CA model (p = 0.369) and the MELD score (p = 0.174), and was superior to other univariate predictors (all p < 0.05) in predicting LDCA. An R-CA score of 0–2 had a negative predictive value of 90.2% for LDCA. Our R-CA score reliably predicts LDCA in patients with RCA-ALSS therapy, and it is easy to use. Patients with R-CA score of 0–2 can safely receive RCA-ALSS therapy, while others should be carefully evaluated before treatment. Trial registration: Chinese Clinical Trial Registry, ChiCTR2000029179. Registered 17 January 2020, https://www.chictr.org.cn/showproj.aspx?proj=48084. [ABSTRACT FROM AUTHOR]

Liver failure remains a big challenge worldwide. In China, hepatitis B is still a nationwide problem which affects nearly 100 million people.1 Exacerbation of chronic HBV infection-caused acute-on-chronic liver failure (ACLF) accounts for the majority of ACLF in China,2,3 which leads to high mortality and heavy burden on society. In addition to hepatitis B-re-lated ACLF (HBV-ACLF), the incidence of acute liver fail-ure due to drug-induced liver injury (DILI) and other causes is on the rise.4 With the deeper understanding of HBV-ACLF, some unique characteristics have been found which are dif-ferent to the ACLF caused by drugs or alcohol which are the main causes in western country. [ABSTRACT FROM AUTHOR]

Background Researches on artificial livers greatly contribute to the clinical treatments for liver failure. This study aimed to evaluate the research output of artificial livers and citations from 2004 to 2017 through a bibliometric analysis. Methods A list of included articles on artificial livers were generated after a comprehensive search of the Web of Science Core Collection (from 2004 to 2017) with the following basic information: number of publications, citations, publication year, country of origin, authors and authorship, funding source, journals, institutions, keywords, and research area. Results A total of 968 included articles ranged from 47 citations to 394 citations with a fluctuation. The publications were distributed in 12 countries, led by China (n = 212) and the US (n = 207). There were strong correlations of the number of citations with authors (r2 = 0.133, p < 0.001), and countries (r2 = 0.275, p < 0.001), while no correlations of the number of citations with the years since publication (r2 = 0.016, p = 0.216), and funding (r2 < 0.001, p = 0.770) were identified. Keyword analysis demonstrated that with the specific change of “acute liver failure,” decrease in “bioartificial livers” and “hepatocyte,” and increase in “tissue engineering” were identified. The top 53 cited keyword and keyword plus (including some duplicates counts) were identified, led by bioartificial liver (405 citations) and hepatocyte (248 citations). The top 50 cited keywords bursts were mainly “Blood” (2004–2008), “hepatocyte like cell” (2008–2015), and “tissue engineering” (2014–2017). All keywords could be classified into four categories: bioartificial livers (57.40%), blood purification (25.00%), clinical (14.81%), and other artificial organs (2.78%). Discussion This study shows the process and tendency of artificial liver research with a comprehensive analysis on artificial livers. However, although it seems that the future of artificial livers seems brighter for hepatocyte transplantation, the systems of artificial livers now are inclined on focusing on blood purification, plasma exchange, etc.

Objectives: To determine the most efficient design of a hollow fiber-based bioreactor device for a bioartificial liver support system through comparative bioengineering evaluations.Results: We compared two types of hollow fiber-based bioreactors, the interwoven-type bioreactor (IWBAL) and the dialyzer-type bioreactor (DBAL), by evaluating the overall mass transfer coefficient (K) and the convective coefficient (X). The creatinine and albumin mass transfer coefficients and convective coefficients were calculated using our mathematical model based on the homoporous theory and the modified Powell method. Additionally, using our model, we simulated the mass transport efficiency in clinical-scale BALs. The results of this experiment demonstrate that the mass transfer coefficients for creatinine and albumin increased proportionally with velocity with the IWBAL, and were consistently greater than that found with the DBAL. These differences were further enhanced in the simulation of the large-scale model.Conclusions: Our findings indicate that the IWBAL with its unique 30° cross hollow fiber design can provide greater solute removal and more efficient metabolism when compared to the conventional DBAL design. [ABSTRACT FROM AUTHOR]

Drug-induced liver- and cardiotoxicity remain among the leading causes of preclinical and clinical drug attrition, marketplace drug withdrawals and black-box warnings on marketed drugs. Unfortunately, animal testing has proven to be insufficient for accurately predicting drug-induced liver- and cardiotoxicity across many drug classes, likely due to significant differences in tissue functions across species. Thus, the field of in vitro human tissue engineering has gained increasing importance over the last 10 years. Technologies such as protein micropatterning, microfluidics, three-dimensional scaffolds and bioprinting have revolutionized in vitro platforms as well as increased the long-term phenotypic stability of both primary cells and stem cell-derived differentiated cells. Here, we discuss advances in engineering approaches for constructing in vitro human liver and heart models with utility for drug development. Design features and validation data of representative models are presented to highlight major trends followed by the discussion of pending issues. Overall, bioengineered liver and heart models have significantly advanced our understanding of organ function and injury, which will prove useful for mitigating the risk of drug-induced organ toxicity to human patients, reducing animal usage for preclinical drug testing, aiding in the discovery of novel therapeutics against human diseases, and ultimately for applications in regenerative medicine. This article is part of the theme issue 'Designer human tissue: coming to a lab near you'. [ABSTRACT FROM AUTHOR]

Background/Aims: Multiple organ failure (MOF) is a primary threat to the survival of patients with systemic inflammation. Blood purification is employed in the treatment of MOF, as an artificial kidney or artificial liver. This study focuses on the effects of continuous blood purification (CBP) on ameliorating MOF through regulating the p38 mitogen-activated protein kinase (MAPK) signaling pathway in a rat model. Methods: A rat model of MOF was successfully established by endotoxin injection after hemorrhagic shock resuscitation. The mRNA expressions of inducible nitric oxide synthase (iNOS) and p38 MAPK of liver, kidney, and lung tissues in each group were measured by RT-qPCR at each measuring time point. To evaluate the activation of p38 MAPK signaling pathway, protein levels of phosphorylated p38 (p-p38) MAPK and p38 MAPK was measured by western blot analysis. The serum levels of nitric oxide and TNF-α were determined. Results: After CBP treatment, the levels of SGPT, SGOT, Cr, and BUN were significantly declined, while the PaO2 value was increased. Expressions of p38 MAPK mRNA, iNOS mRNA, p-p38 MAPK protein and p38 MAPK protein, and nitric oxide and TNF-α levels were markedly elevated in MOF, an effect blunted by CPB. Meanwhile, pathological sections of liver, kidney, and lung tissues after CPB treatment ameliorated swelling and inflammation. Conclusion: Our study proved that CBP could downregulate the p38 MAPK signaling pathway, suppress iNOS expression, reduced the serum levels of nitric oxide and TNF-α, thus ameliorate symptom of MOF. [ABSTRACT FROM AUTHOR]

Objective To compare two means of performing therapeutic plasma exchange (TPE) in patients with liver failure. Method This open-label monocentric randomized trial, conducted in a single prestigious general healthcare facility, recruited liver failure patients with an indication to receive artificial liver support therapy for TPE. All patients underwent TPE procedures and were administered in a random sequence: heparin-free or systemic heparinization with unfractionated heparin. The primary endpoint was completion of TPE sessions, and the secondary endpoints included the safety and efficacy. Results In the period of the studying, there were 164 patients being recruited in and underwent total of 398 randomized TPEs: 168 with unfractionated heparin and 230 with heparin-free. In unfractionated heparin group, there were 3 cases (1.79%) being interrupted due to uncontrollable intraoperative pulmonary hemorrhages and gastrointestinal bleeding. In heparin-free group, 228 (99.13%) were completed successfully and 2 of them (0.87%) were switched from heparin-free to unfractionated heparin eventually. No significant differences were found between the two groups for either RRs or IRs (P > 0.05). Conclusion Heparin-free regimen is feasible and safer than systemic heparinization with unfractionated heparin in the process of TPEs in patients with liver failure. [ABSTRACT FROM AUTHOR]

The article reports on the research to develop artificial livers and hearts. It states that transplant surgeon Paulo Fontes in collaboration with stem cell biologist Eric Lagasse at the University of Pittsburgh developed a different strategy to grow mini livers in living organisms which can be used as a supplement of liver tissue in patients with end stage liver disease. It also cites that Nicholas Cohrs is among a coterie of scientists who are hoping to develop artificial heart.

The creation of in vitro functional hepatic tissue simulating micro-environmental niche of native liver is a keen area of research due to its demand in bioartificial liver (BAL) and cell-based tissue engineering. Here, we investigated the potential of novel blend (BA) silk scaffold fabricated by blending mulberry ( Bombyx mori , BM) silk fibroin with cell adhesion motif (RGD) rich non-mulberry ( Antheraea assamensis , AA) silk fibroin, in generating a functional liver construct. Three-dimensional (3D) porous silk scaffolds (BM, AA and BA) were physico-chemically characterized and functionally evaluated using human hepatocarcinoma cells (HepG2) and primary neonatal rat hepatocytes. The growth and distribution of hepatocytes within the scaffolds were tracked by FESEM, alamar blue proliferation assay and live/dead staining. Hemocompatible BA scaffolds supported the formation of high density hepatocyte clusters, facilitating cell-matrix and cell-cell interactions. Blend scaffolds evinced enhanced liver-specific functions of cultured hepatocytes in terms of albumin synthesis, urea synthesis and cytochrome P450 enzyme activity over 21 days. Subcutaneous implantation of scaffolds demonstrated minimal macrophage infiltration in blend scaffolds. These findings substantiate that the integral property of blend (BA) scaffold offers a befitting environment by influencing spheroidal growth of hepatocytes with enhanced biological activity. Collectively, the present study provides a new 3D bio-matrix niche for growing functional liver cells that would have future prospects in BAL as well as regenerative medicine. Statement of Significance An end stage liver disease called cirrhosis perturbs the self-healing ability and physiological functions of liver. Due to the scarcity of healthy donors, a functional in vitro hepatic construct retaining the liver-specific functions is in great demand for its prospects in bioartificial liver (BAL) and cell-based tissue engineering. Physicochemical attributes of a matrix influence the behavior of cultured hepatocytes in terms of attachment, morphology and functionality. Mulberry and non-mulberry silk fibroin presents unique amino acid sequence with difference in hydrophobicity and crystallinity. Considering this, the present study focuses on the development of a suitable three-dimensional (3D) bioactive matrix incorporating both mulberry silk fibroin and cell adhesion motif (RGD) rich non-mulberry silk fibroin. Porous silk blend scaffolds facilitated the formation of hepatocyte clusters with enhanced liver-specific functions emphasizing both cell-cell and cell-matrix interactions. Hemocompatibility and integral property of blend scaffolds offers a biological niche for seeding functional liver cells that would have future prospects in biohybrid devices. [ABSTRACT FROM AUTHOR]

Abstract: In addition to immune barriers, molecular incompatibilities between species are predicted to limit pig liver survival in primate xenotransplantation models. Assessment and measurement of synthetic function of genetically modified porcine livers after ex vivo perfusion with human blood have not previously been described. Eight porcine livers from α1,3‐galactosyl transferase knockout and human membrane cofactor (GalTKO.hCD46), six livers from GalTKO.hCD46 and N‐glycolylneuraminic acid knockout (GalTKO.hCD46.Neu5GcKO), and six livers from GalTKO.hCD46 with humanized decay‐accelerating factor (hCD55), endothelial protein C receptor (hEPCR), tissue factor pathway inhibitor (hTFPI), and integrin‐associated protein (hCD47) (GalTKO.hCD46.hCD55.hEPCR.hTFPI.hCD47) pigs were perfused with human blood under physiologic conditions. Timed blood samples were tested for liver enzymes and for pig‐specific albumin production via Western blot. Porcine albumin levels increased with time in all experiments. By densitometry, GalTKO.hCD46.Neu5GcKO livers had the highest albumin levels, measured both as total produced, and when controlled for perfusion duration, compared to GalTKO.hCD46 (P = .068) and GalTKO.hCD46.hCD55.hEPCR.hTFPI.hCD47 livers (P = .04). Porcine livers perfused with human blood demonstrated the synthetic ability to produce albumin in all cases. GalTKO.hCD46.Neu5GcKO pig livers demonstrated the most robust albumin production. This suggests that the Neu5GcKO phenotype provides a protective effect on the graft due to decreased human antibody recognition and graft injury. [ABSTRACT FROM AUTHOR]

New cell sources for the research and therapy of organ failure could significantly alleviate the shortage of donor livers that are available to patients who suffer from liver disease. Liver carcinoma derived cells, or hepatoma cells, are the ideal cells for developing bioartificial liver systems. Such cancerous liver cells are easy to prepare in large quantities and can be maintained over long periods under standard culture conditions, unlike primary hepatocytes. However, hepatoma cells possess only a fraction of the functions of primary hepatocytes. In a previous study, by transducing cells with liver-enriched transcription factors that could be inducibly overexpressed—hepatocyte nuclear factor (HNF)1α, HNF1β, HNF3β [FOXA2], HNF4α, HNF6, CCAAT/enhancer binding protein (C/EBP)α, C/EBPβ and C/EBPγ—we created mouse hepatoma cells with high liver-specific gene expression called the Hepa/8F5 cell line. In the present study, we performed functional and genetic analyses to characterize the Hepa/8F5 cell line. Further, in three-dimensional cultures, the function of these cells improved significantly compared to parental cells. Ultimately, these cells might become a new resource that can be used in basic and applied hepatic research. [ABSTRACT FROM AUTHOR]

Background and aims: We developed a bio-artificial liver (BAL) using a radial-flow bioreactor and rescued mini-pig models with lethal acute liver failure (ALF). The point of the rescue is the recovery from hepatic encephalopathy (HE). HE on ALF has sometimes resulted in brain death following brain edema with astrocyte swelling. Several factors, including ammonia and glutamine, have been reported to induce astrocyte swelling and injury. However, many clinicians believe that there are any other factors involved in the development of HE. Therefore, the aim of this study was to identify novel HE-inducible factors, particularly those inducing astrocyte dysfunction. Methods: Mini-pig plasma samples were collected at three time points: before the administration of toxins (α-amanitin and LPS), when HE occurred after the administration of toxins, and after treatment with extracorporeal circulation (EC) by the BAL. To identify the causative factors of HE, each plasma sample was subjected to a comparative proteome analysis with two-dimensional gel electrophoresis and mass spectrometry. To assess the direct effects of candidate factors on the astrocyte function and injury, in vitro experiments with human astrocytes were performed. Results: Using a proteome analysis, we identified alpha-1 antichymotrypsin (ACT), which was increased in plasma samples from mini-pigs with HE and decreased in those after treatment with EC by BAL. In in vitro experiments with human astrocytes, ACT showed growth-inhibitory and cytotoxic effects on astrocytes. In addition, the expression of water channel protein aquaporin-4, which is induced in injured astrocytes, was increased following ACT treatment. Interestingly, these effects of ACT were additively enhanced by adding arginine-vasopressin (AVP) and were canceled by adding an AVP receptor antagonist. Conclusions: These results suggest that ACT is involved in astrocyte injury and dysfunction in concert with AVP during the development of acute HE. [ABSTRACT FROM AUTHOR]

Carbon-based nanomaterials have recently attracted tremendous attention in adsorption, separation and biological fields. However, such modification is not always straightforward when the surface is not chemically reactive. Given this reason, most carbon materials modification processes employ reactive linkers or coupling agents, which are complicated and time-consuming. Herein, we report on a dopamine-polyethyleneimine (PEI) coating strategy to fabricate micrometer-sized magnetic carbon fiber (MSMCF)-based extracorporeal blood-cleansing sorbent for hemoperfusion. Results showed that the dopamine/PEI-coated MSMCF had a twisted fiber shape with a size range of 80–120 μm in diameter and porous structure with a specific surface area of 146 m2 g−1. Adsorption behavior of dopamine/PEI-modified MSMCF was examined by using bilirubin as a toxin model compound. Equilibrium data were well fitted to the Langmuir isotherm model with a maximal adsorption capacity of 335.1 mg g−1at ambient temperature. The as-obtained material had relatively high bilirubin adsorption selectivity against albumin at a normal albumin concentration. In particular, the dopamine/PEI-coated MSMCF has excellent adsorption capacity and hemocompatibility compared to the MSMCF decorated only by dopamine or PEI. Therefore, this work may pave the way for enhancing the property of the extracorporeal blood-cleansing sorbent during hemoperfusion. [ABSTRACT FROM AUTHOR]

The creation of artificial liver tissue is an active area of research due to the shortage of donors for liver transplantation. Here we investigated whether a simple and efficient cell coating technique developed in our laboratory could be used to generate functional vascularized liver tissue. This technique creates three-dimensional tissue by loading cells sterically onto other cells that have been coated with layer-by-layer (LbL) nanofilms of fibronectin and gelatin, two extracellular matrix proteins. We used this technique to construct homogenous, dense, well-vascularized liver tissue from cryopreserved human primary hepatocytes, human umbilical vein endothelial cells, and normal human dermal fibroblasts. Using LbL cell coating technique resulted in higher cellular function in terms of human albumin production ( P < 0.01) and cytochrome P450 activity ( P < 0.01) in vitro. Furthermore, after being transplanted subcutaneously into NOD/SCID mice, the vascularized liver tissue showed greater albumin production in the early stage than non-vascularized tissue or a hepatocyte suspension ( P < 0.01). Histological examination demonstrated that compare to non-vascularized tissue, there were many less-morphologically changed and intact hepatocytes in the vascularized tissue. This cell coating technique would be applicable to the generation of vascularized functional liver tissue for regenerative medicine in the future. [ABSTRACT FROM AUTHOR]

Aim: Hepatitis B virus-related acute-on-chronic liver failure has high short-term mortality. Artificial liver support systems (ALSS) may improve outcome and avoid liver transplantation, but predicting short-term prognosis in such patients is difficult. This study aimed to determine whether the neutrophil–lymphocyte ratio (NLR), an inflammation marker, predicted mortality in patients treated with ALSS. Methods: A total of 560 patients with hepatitis B virus-related acute-on-chronic liver failure were enrolled, 338 were treated with ALSS and the others treated with standard of care(SOC). Clinical variables and the NLR were evaluated for prognostic value. Results: Thirty-day mortality was 28.4% in ALSS and 55.4% in SOC patients. The NLR was lower in survivors than in ALSS or SOC patients who died. Univariate and multivariate analysis found that NLR and the chronic liver failure sequential organ failure assessment scores(CLIF-SOFA) were independently associated with 30-day mortality. Among patients with NLRs ≤ 3, 3–6, and >6, 30-day mortality was 7.7%,23.1%, and 69.2% in ALSS and 25.5%, 50.0%, and 75.0% in SOC patients. Among patients with NLRs ≤ 3 or 3–6, mortality was lower in ALSS than in SOC patients (P < 0.01). Mortality rates of ALSS and SOC patients with NLRs > 6 did not different (P >0.05). The area under curve of NLR and CLIF-SOFA was 0.82 and 0.88 in ALSS group, 0.78 and 0.86 in SOC group. The results suggest that liver function in most patients with NLRs ≤ 3 recovered with ALSS treatment, and patients with NLRs > 6 needed emergency liver transplantation. Conclusion: NLR was an independent predictor of mortality in ALSS patients and may assist physicians in determining treatment options. [ABSTRACT FROM AUTHOR]

The proper functioning of the liver and tissues containing hepatocytes greatly depends upon the intricate organization of the cells. Consequently, controlling the shape of three-dimensional (3D) cellular constructs is an important issue for in vitro applications of fabricated artificial livers. However, the precise control of tissue shape at the microscale cannot be achieved with various commonly used 3D tissue-engineered building units, such as spheroids. Here, we present the fabrication of hepatic lobule-shaped microtissue (HLSM) containing rat liver (RLC-18) cells. By using cell-microcapsule technology, RLC-18 cells were encapsulated in the core region of poly- l -lysine-alginate microcapsules. After 14 days of long-term cultivation, RLC-18 cells self-assembled into HLSM, and the cells fully occupied the microcapsule. By monitoring the cell number and albumin secretion during culture and characterizing the dimensions of the fabricated tissue, we demonstrated that the HLSM showed higher hepatic function as compared with normal cell spheroids. We also showcased the assembly of these microtissues into a 3D four-layered hepatic lobule model by a facile micromanipulation method. Our technology for fabricating 3D multilayer hepatic lobule-like, biofunctional tissue enables the precise control of tissue shape in three dimensions. Furthermore, these constructs can serve as tissue-engineered building blocks for larger organs and cellular implants in clinical treatment. [ABSTRACT FROM AUTHOR]

Background: Liver failure (LF) is associated with prolonged hospital stay, increased cost and substantial mortality. Due to the limited number of donor organs, extracorporeal liver support is suggested as an appealing concept to "bridge to transplant" or to avoid transplant in case of recovery. ADVanced Organ Support (ADVOS) is a new type of albumin dialysis, that provides rapid regeneration of toxin-binding albumin by two purification circuits altering the binding capacities of albumin by biochemical (changing of pH) and physical (changing of temperature) modulation of the dialysate. It was the aim of this study to evaluate feasibility, efficacy and safety of ADVOS in the first 14 patients ever treated with this procedure.Methods: Patients included suffered from acute on chronic LF (n = 9) or "secondary" LF (n = 5) which resulted from non-hepatic diseases such as sepsis. The primary endpoint was the change of serum bilirubin, creatinine and serum BUN levels before and after the first treatment with ADVOS. The Wilcoxon Signed Rank test for paired samples was used to analyze the data.Results: A total of 239 treatments (1 up to 101 per patient) were performed in 14 patients (6 female, 8 male). Mean age 54 ± 13; MELD-score 34 ± 7; CLIF-SOFA 15 ± 3. Serum bilirubin levels were significantly decreased by 32% during the first session (26.0 ± 15.4 vs. 17.7 ± 10.5 mg/dl; p = 0.001). Similarly, serum creatinine (2.2 ± 0.8 vs. 1.6 ± 0.7 mg/dl; p = 0.005) and serum BUN (49.4 ± 23.3 vs. 31.1 ± 19.7 mg/dl; p = 0.003), were significantly lowered by 27% and 37%, respectively. None of the treatment sessions had to be interrupted due to side effects related to the procedure.Conclusion: ADVOS efficiently eliminates water- and protein-bound toxins in humans with LF. ADVOS is feasible in patients with advanced LF which is emphasized by a total number of more than 100 treatment sessions in one single patient. [ABSTRACT FROM AUTHOR]

The differentiation of human pluripotent stem cells toward the hepatocyte lineage can potentially provide an unlimited source of functional hepatocytes for transplantation and extracorporeal bioartificial liver applications. It is anticipated that the quantities of cells needed for these applications will be in the order of 109-1010 cells, because of the size of the liver. An ideal differentiation protocol would be to enable directed differentiation to the hepatocyte lineage with simultaneous cell expansion. We introduced a cell expansion stage after the commitment of human embryonic stem cells to the endodermal lineage, to allow for at least an eightfold increase in cell number, with continuation of cell maturation toward the hepatocyte lineage. The progressive changes in the transcriptome were measured by expression array, and the expression dynamics of certain lineage markers was measured by mass cytometry during the differentiation and expansion process. The findings revealed that while cells were expanding they were also capable of progressing in their differentiation toward the hepatocyte lineage. In addition, our transcriptome, protein and functional studies, including albumin secretion, drug-induced CYP450 expression and urea production, all indicated that the hepatocyte-like cells obtained with or without cell expansion are very similar. This method of simultaneous cell expansion and hepatocyte differentiation should facilitate obtaining large quantities of cells for liver cell applications. [ABSTRACT FROM AUTHOR]

Several artificial liver support concepts have been evaluated both in vitro and clinically. Single pass albumin dialysis (SPAD) has shown to be one of the most simple approaches for removing albumin-bound toxins and water-soluble substances. Being faced with acute liver failure (ALF) in everyday practice encouraged our attempt to define the optimal conditions for SPAD more precisely in a standardized experimental setup. Albumin concentration was adjusted to either 1%, 2%, 3%, or 4%, while the flow rate of the dialysate was kept constant at a speed of 700 mL/h. The flow rate of the dialysate was altered between 350, 500, 700, and 1000 mL/h, whereas the albumin concentration was continuously kept at 3%. This study revealed that the detoxification of albumin-bound substances could be improved by increasing the concentration of albumin in the dialysate with an optimum at 3%. A further increase of the albumin concentration to 4% did not lead to a significant increase in detoxification. Furthermore, we observed a gradual increase of the detoxification efficiency for albumin-bound substances, from 350 mL/h to 700 mL/h (for bilirubin) or 1000 mL/h (for bile acids) of dialysate flow. Water-soluble toxins (ammonia, creatinine, urea, uric acid) were removed almost completely, regardless of albumin concentration or flow rate. In conclusion, this study confirmed that SPAD is effective in eliminating albumin-bound as well as water-soluble toxins using a simulation of ALF. Furthermore, this project was successful in evaluating the most effective combination of albumin concentration (3%) and dialysate flow (700 mL/h-1000 mL/h) in SPAD for the first time. [ABSTRACT FROM AUTHOR]

Background: Antithyroid drugs carry a potential risk of hepatotoxicity. Propylthiouracil (PTU) is commonly prescribed for patients with hyperthyroidism. PTU, however, can induce liver injury, ranging from mild asymptomatic elevation of aminotransferases to acute liver failure (ALF).Case Presentation: This case reports on a 16-year-old Chinese girl with hyperthyroidism, who was admitted to our hospital for jaundice, nausea, and fatigue associated with severe hyperbilirubinemia and coagulopathy. She had been prescribed PTU 5 months earlier. There was no history of hypersensitivity to drugs, viral liver diseases, blood transfusion, or surgery. On the basis of her symptoms and the clinical data, she was diagnosed with PTU-induced ALF. Due to the limited number of available donor organs for liver transplantation, she was started on treatment with artificial liver support system (ALSS). After four sessions of ALSS, her clinical signs and symptoms were found to be markedly improved, and she was discharged 25 days after admission. Four months later, her liver function normalized.Conclusion: Although PTU-induced liver failure is rare in clinical practice, liver function should be appropriately monitored during treatment with PTU. PTU-induced ALF in this patient was successfully managed with an ALSS, suggesting that the latter may be an alternative to liver transplantation. [ABSTRACT FROM AUTHOR]

Reported here is a new theranostic agent, 1, which consists of a Gd3+-texaphyrin core conjugated to a doxorubicin prodrug via a disulfide bond. Conjugate 1 was designed to undergo cleavage in the presence of glutathione (GSH), a species typically upregulated in cancer cells. As prepared, conjugate 1 displays no appreciable fluorescence. However, when exposed to excess GSH an increase in the fluorescence intensity at 592 nm is observed that is ascribed to release of free doxorubicin. To improve the solubility and enhance the tumor targeting of 1, it was loaded into folate-receptor-targeted liposomes to produce FL-1 (for folate liposome loaded with 1). As inferred from both fluorescence turn on studies and independent HPLC analyses, FL-1 was found to undergo selective uptake and cleavage to release free Dox in the KB and CT26 cell lines, which express folate receptors on the cell surface, relative to the HepG2 and NIH3T3 cell lines, which show low expression of those receptors. FL-1 was found to produce a greater antiproliferative effect in the case of the KB and CT26 cell lines as compared to that in the HepG2 and NIH3T3 cell lines. FL-1 was also found to provide enhanced magnetic resonance imaging in vivo under conditions of T1 contrast in the early stage of metastatic cancer progression. Finally, time-dependent tumor regrowth studies involving both subcutaneous and metastatic liver cancer mouse models revealed that FL-1 is capable of reducing the tumor burden in vivo. [ABSTRACT FROM AUTHOR]

The clinical efficacy and safety of different combinations of non-bio artificial liver in the treatment of acute liver failure was examined. A total of 61 cases were selected under blood purification treatment from the patients with severe acute liver failure admitted to the severe disease department of the hospital from December, 2010 to December, 2015. Three types of artificial liver combinations were observed, i.e., plasma exchange plus hemoperfusion plus continuous venovenous hemodiafiltration (PE+HP+CVVHDF), PE+CVVHDF and HP+CVVHDF. The heart rate (HR), mean arterial pressure (MAP), respiratory index (PaO2/FiO2), liver and kidney function indicator, as well as platelet and coagulation function were compared. A comparison before and after the treatment using the three methods, showed improvement in the HRs, MAPs, PaO2/FiO2, total bilirubins (TBIL) and alanine aminotransferases (ALT) (P<0.05), of which TBIL and ALT were decreased more significantly (P<0.01) in the PE+CVVHDF and PE+HP+CVVHDF groups. Only changes in the PE+HP+CVVHDF and PE+CVVHDF groups were statistically significant after prothrombin time and albumin treatment (P<0.05). The difference between the decrease in TBIL in the PE+HP+CVVHDF group and that in the HP+CVVHDF group was statistically significant (P<0.05). Treatment of the 61 patients using the artificial liver support system yielded a survival rate of 62.3% (38/61), and a viral survival rate of 35.0% (7/20); with the non-viral survival rate being 75.6% (31/41). In conclusion, following the treatment of three types of artificial livers, the function was improved to varying degrees, with the PE+HP+CVVHDF and the PE+CVVHDF method being better. By contrast, after the treatment of non-viral liver failure, the survival rate was significantly higher than the patients with viral liver failure. [ABSTRACT FROM AUTHOR]

An artificial liver support system is based on the functional hepatocytes being cultured inside a bioreactor; this technique has being used as an effective therapy for treating chronic liver diseases in recent times. This work evaluates different parameters such as cell viability and metabolic function of the hepatocytes when cultured on a hybrid scaffold. The scaffold was built using a polypyrrole plasma coated polymer layer seeded with endothelial matrix for efficient three-dimensional hepatocyte growth within a radial flow bioreactor. The flow rate inside the bioreactor was 7 ml / min. The parts for the bioreactor where either built using food-grade steel and/or glass or the scaffolds comprise a Poly (L-lactic acid)-coated polypyrrole iodine layer or not for HepG2 culture. The results show that the Poly (L-lactic acid)-coated scaffolds increased cell proliferation by 30%, protein production by 16% and albumin secretion by 40% compared with the non-coated scaffold. All experiments were performed thrice and data was analysed by ANOVA and Tukey statistic models with a p<0.05. The obtained results demonstrated that radial flow bioreactors in conjunction with hybrid scaffolds improve hepatocytes' physiological and functional properties and could be used as an alternative therapy for patients with liver diseases. [ABSTRACT FROM AUTHOR]

Artificial liver support gained considerable interest in recent years due to the development of various albumin dialysis systems, which prolong survival of some patients with acute liver failure (ALF). Τhis study aims to examine the role of peritoneal albumin dialysis in a postoperative ALF model. ALF was induced in 14 female Landrace pigs by a combination of major liver resection (70-75% of total parenchyma) and ischemic-reperfusion injury on the liver remnant. Animals were randomly divided in two groups ( n = 7 each). Both were monitored for 12 h of reperfusion and received peritoneal dialysis for 6 h, beginning 6 h after reperfusion. The albumin group received an albumin-rich solution and the control group received albumin-free solution. The control group gradually developed intracranial hypertension, whereas, in the albumin group, rise in the intracranial pressure was substantially attenuated ( P < 0.01, t = 12 h). Albumin-treated animals had significantly lower levels of ammonia ( P < 0.01), total bile acids ( P < 0.01), free fatty acids ( P < 0.05), lactate ( P < 0.01), and total bilirubin ( P < 0.05). Liver malondialdehyde and protein carbonyl were significantly reduced ( P = 0.007 and P = 0.001 at t = 12 h) after albumin dialysis. Results suggest that this method may become a useful adjunct in the management of ALF, thus, justifying further study. [ABSTRACT FROM AUTHOR]

Background: Several models have been proposed to predict the short-term outcome of acute-on-chronic liver failure (ACLF) after treatment. We aimed to determine whether better decisions for artificial liver support system (ALSS) treatment could be made with a model than without, through decision curve analysis (DCA).Methods: The medical profiles of a cohort of 232 patients with hepatitis B virus (HBV)-associated ACLF were retrospectively analyzed to explore the role of plasma prothrombin activity (PTA), model for end-stage liver disease (MELD) and logistic regression model (LRM) in identifying patients who could benefit from ALSS. The accuracy and reliability of PTA, MELD and LRM were evaluated with previously reported cutoffs. DCA was performed to evaluate the clinical role of these models in predicting the treatment outcome.Results: With the cut-off value of 0.2, LRM had sensitivity of 92.6 %, specificity of 42.3 % and an area under the receiving operating characteristic curve (AUC) of 0.68, which showed superior discrimination over PTA and MELD. DCA revealed that the LRM-guided ALSS treatment was superior over other strategies including "treating all" and MELD-guided therapy, for the midrange threshold probabilities of 16 to 64 %.Conclusions: The use of LRM-guided ALSS treatment could increase both the accuracy and efficiency of this procedure, allowing the avoidance of unnecessary ALSS. [ABSTRACT FROM AUTHOR]