Imidazole-Functionalized Quaternary Ammonium Salts Modified Polyether Sulfone Microspheres for Highly Efficient Bilirubin Removal in Whole Blood.

Liver failure is a common clinical syndrome of severe liver diseases, which belongs to one of the critical medical conditions. Immune response plays a leading role in the pathogenesis of liver failure. Lactic acid as a target for the treatment and prediction of liver failure has not attracted enough attention. Since the emergence of the concept of "histone lactation," lactic acid has shown great promise in immune response and escape. Therefore, targeted lactic acid may be a reliable agent to solve immune and energy metabolism disorders in liver failure. Based on the relationship between lactic acid and immune response, the cross-talk between lactic acid metabolism, its compounds, and immune regulation and its significance in the diagnosis and treatment of liver failure were expounded in this article to provide new ideas for understanding and treating liver failure.

Acute poisoning (AP) may cause failure of the liver and kidney, and even death. This study aimed to investigate the efficacy of artificial liver support system (ALSS) on the treatment of liver failure after acute poisoning. A total of 31 patients with liver failure caused by AP were admitted to emergency ICU, central ICU, and Department of Gastroenterology from 2005 to 2009 in Zhongshan Hospital Affiliated to Xiamen University, China. Among them, 13 patients served as a treatment group, and used ALSS in addition to detoxification treatment and protective treatment of liver function, and the other 18 patients served as a control group receiving detoxification treatment and protective treatment of liver function. In the treatment group, 10 patients (76.9%) were cured or improved, 2 died, and 1 was discharged against advice. In the 18 patients in the control group, 7 (38.9%) were cured or improved, 3 died, and 8 were discharged against advice. There was a significant difference in the rates of improvement between the two groups (P<0.05). ALSS is a safe and effective clinical method for the treatment of acute toxic liver failure.

Objective To analyze the small molecular metabolic compounds of nonbioartificial liver for treatment of hepatic failure and make further efforts to study the clinical efficacy, mechanism of action, and pathogenesis of hepatic failure. Methods 52 patients who met the standard of artificial liver treatment for liver failure were enrolled; these patients included 6 cases of acute liver failure (11.54%), 3 cases of subacute liver failure (5.77%), acute-on-chronic liver failure in 10 cases (19.23%), and 33 cases of chronic liver failure (63.46%). Treatment modes included plasma exchange in 34 patients (65.38%), bilirubin adsorption in 9 patients (17.31%), and hemofiltration in 9 patients (17.31%). The clinical efficacy of artificial liver was assessed by monitoring the effects in the near future. Significant changes in metabolic compounds of liver failure in the treatment before and after artificial liver were screened by using Ultra-Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). Related metabolic pathways were analyzed by MetaboAnalyst. Results After artificial liver treatment, the liver function and coagulation function of liver failure patients were significantly improved (P < 0.01), the Meld score was lower than that before treatment, and the difference was statistically significant (P < 0.05). Serum metabolomics identified 29 small metabolic compounds and 12 metabolic pathways with variable projection importance (VIP) greater than 1 before and after artificial liver treatment. There were 11 metabolic compounds of VIP over 1 and 7 metabolic pathways in the different modes of artificial liver treatment for chronic liver failure. Among them, bile acid metabolism, fatty acid metabolism, and amino acid metabolism are the main sources. Conclusion Artificial liver treatment can effectively improve liver function and blood coagulation function and Meld score, clinical symptoms and signs in patients with liver failure; the curative effect of artificial liver was verified, which reflected the clinical value of artificial liver in the treatment of liver failure. Artificial liver treatment of liver failure on fatty acids and primary bile acid synthesis pathway was the most significant. The difference of fatty acid, primary bile acid synthesis pathway, and phenylalanine metabolic pathway in different artificial liver patterns of chronic liver failure was the most significant. This provides a new basis for understanding the mechanism of hepatic failure and the mechanism of liver failure by artificial liver treatment.

Hepatocyte transplantation

Efficient adsorbents for excess bilirubin removal are extremely important for the treatment of hyperbilirubinemia. However, traditional adsorbents, such as activated carbons and ion-exchange resins, still suffer from dissatisfactory adsorption performance and poor blood compatibility. Herein, we adopted a rational design strategy guided by density functional theory (DFT) calculations to prepare blood-compatible quaternary ammonium group grafted electrospun polyacrylonitrile nanofiber adsorbents. The calculation analysis and adsorption experiments were used to investigate the structure-function relationship between group types and bilirubin adsorption, both indicating that quaternary ammonium groups with suitable configurations played a crucial role in bilirubin binding. The obtained nanofiber adsorbents showed the bilirubin removal efficiency above 90% even at a coexisting BSA concentration of 50 g L-1. The maximum adsorption capacities were 818.9 mg g-1 in free bilirubin solution and 163.7 mg g-1 in albumin bound bilirubin solution. The nanofiber adsorbents also showed considerable bilirubin removal in dynamic adsorption to reduce the bilirubin concentration to a normal level, which was better than commercial activated carbons. Our study demonstrates the high feasibility of a theory-driven design method for the development of grafted electrospun nanofibers, which have good potential as bilirubin adsorbents in hemoperfusion applications.

Bilirubin is an endogenous toxin in the human body. Elevated levels of bilirubin in the blood can cause irreversible damage to the nervous system and the brain. Therefore, we present the development of a novel polysulfone (PSF) dual-functional blood purification membrane for bilirubin removal. Initially, a PSF hollow fiber membrane with excellent biocompatibility was prepared using a non-solvent induced phase separation method, then graft β-cyclodextrin (β-CD) onto the outer surface, establishing a bilirubin adsorption functional layer. In the “filtration-adsorption” mode, the external surface of the membrane demonstrated pronounced bilirubin adsorption capacity, reaching 12.68 mg/g, accompanied by a bilirubin competitive adsorption coefficient (tN) of 8.74. Furthermore, the inner surface of the PSF hollow fiber membranes with β-CD onto their external surfaces (EβH) exhibited favorable blood compatibility. Notably, the designed PSF dual-functional membrane overcame the trade-off effects between biocompatibility and bilirubin removal in traditional blood perfusion. In conclusion, this membrane demonstrates efficient toxin removal and enhanced biocompatibility, offering substantial potential for advancing blood purification technologies and improving therapeutic outcomes.

Liver failure, marked by a rapid or progressive decline in liver function, leads to complications such as hyperbilirubinemia and infections, contributing to approximately 2 million global deaths each year. Current hemoperfusion methods for hyperbilirubinemia treatment are limited by their low adsorption selectivity and inadequate biosafety, necessitating better treatments. In this study, a chitosan-based HKUST-1 aerogel (HC) was developed as a highly selective, biosafe, and antibacterial adsorbent. The integration of HKUST-1 with chitosan formed an aerogel that achieved high bilirubin adsorption in vitro along with significant biosafety, anticoagulant properties, and antibacterial activity against Staphylococcus aureus and Escherichia coli. In an animal model of hyperbilirubinemia, the HC aerogel demonstrated 42.4% bilirubin clearance from whole blood. These findings suggest that the HKUST-1/chitosan aerogel is a promising candidate for liver failure treatment, effectively combining bilirubin adsorption with infection control in complex blood environments.

Background and Aims The artificial liver treatment based on blood purification is an important and commonly used treatment for liver failure. Aggressive management of hyperbilirubinemia is one of the key steps to reduce mortality in patients with liver failure. Herein, targeting bilirubin in nano-sized, we synthesized a TiO2/Ti3C2 nanocomposite from Ti3C2 MXenes via hydrothermal oxidation for bilirubin clearance from whole blood. Method Firstly, Ti3C2 MXene was prepared by hydrofluoric acid etching method reported in our previous work [1]. Then, it was transferred into Teflon-lined stainless-steel autoclaves (2 mg/ml, 30 ml) and was undergone the hydrothermal process at 180 °C for 6 h and 12 h. TiO2/Ti3C2 nanocomposites were obtained after lyophilization. Hemocompatibility evaluation assays include hemolysis ratio test, complement activation (human complement fragment 5a (C5a)), contact activation (Thrombin–anti-thrombin (TAT) complex) and platelet activation (platelet factor 4 (PF 4)) were systemically conducted in vitro to evaluate the feasibility of the novel nanocomposites (0.5 mg/ml) in contact with blood. We evaluated the bilirubin adsorption capacity of original Ti3C2 (0 h) and TiO2/Ti3C2 (6 h and 12 h) at the concentration of 0.5 mg/ml, respectively, in bilirubin solution (250 mg/l, 10 ml) for 2 h at 37 °C in an air bath away from light. The sphere-forming properties of TiO2/Ti3C2 with polyethersulfone (PES), a commonly used blood purification material, were first verified using a liquid-liquid inversion method. Results TiO2/Ti3C2 (6 h and 12 h) showed better hemocompatibility than the original Ti3C2 (0 h) (Figure 1). The bilirubin adsorption capacities by the original Ti3C2 (0 h) and TiO2/Ti3C2 (6 h and 12 h) were 354.11 mg/g, 492.83 mg/g and 492.52 mg/g, respectively. From the original Ti3C2 (0 h) to TiO2/Ti3C2 (6 h), the clearance rate of bilirubin improved from 70.82% to 98.57%. Therefore, we chose TiO2/Ti3C2 (6 h) to verify the sphere-forming properties of TiO2/Ti3C2 with PES. TiO2/Ti3C2-PES spheres were constructed successfully by a liquid-liquid inversion method. More 3D porous structure on the surface and uniform distribution of TiO2/Ti3C2 (Ti element) in the substrate were observed via a scanning electron microscope (SEM) images and energy dispersive spectroscopy (EDS) mapping images (Figure 2). Conclusion The TiO2/Ti3C2 nanocomposite showed excellent bilirubin clearance capability, superior hemocompatibility, and the great application potential in the form of spheres for hemoperfusion, which may provide a promising choice in the performance enhancement of artificial liver characterized by bilirubin clearance. Importantly, the above properties are adjustable by the heating temperature and the time period, other application forms and strategies of the TiO2/Ti3C2 nanocomposite to target bilirubin in nano-sized are worth being explored and expected.

Liver failure is characterized by rapid progress and extremely high mortality. Glucocorticoids are currently used in the treatment of liver failure to improve the prognosis, but they have not been widely recognized. This paper reviews the advances on pathogenesis of liver failure, the timing, efficacy and adverse effects of glucocorticoids treatment, so as to increase clinician's knowledge of glucocorticoids in treatment of liver failure, in order to increase the awareness and rational administration of glucocorticoids in treatment of liver failure. Key words: Glucocorticoids; Liver failure; Therapy

Acute liver failure and acute-on-chronic liver failure are conditions in which the loss of metabolic function of the liver leads to the accumulation of several toxins such as bilirubin. Patients with sepsis or multiple organ dysfunction syndrome have a greater risk of developing liver failure, and hyperbilirubinemia is associated with poor prognosis. Bilirubin removal may not only alleviate signs and symptoms of liver dysfunction but also act as an index of removal of albumin-bound toxins. Conjugated and unconjugated bilirubin, due to their molecular weight and albumin-binding capacity, respectively, cannot be removed by classic dialysis; therefore, different extracorporeal techniques have been developed to remove bilirubin from the blood. Plasma adsorption perfusion is an extracorporeal liver support technique in which bilirubin is removed from the plasma through a specific adsorbing cartridge. Double plasma molecular adsorption system adds a broad-spectrum adsorption column for the removal of inflammatory mediators and antibodies and other medium toxins. Their use in the treatment of hyperbilirubinemia has been established with several emerging data indicating their efficacy when compared to other extracorporeal techniques. However, bilirubin adsorption kinetics has not been sufficiently elucidated, and more studies are needed to improve the quality of treatment in terms of timing and prescriptions.

The efficacy of plasma bilirubin sorption for the treatment of patients with hepatic dysfunction can be determined by a quantitative evaluation of bilirubin adsorption. The objective of this study is to examine the effects of temperature (4-42 degrees C) and albumin concentration (0.5-5.0 g%) on bilirubin removal from solution by an anion-exchange resin. For a constant albumin concentration, adsorption increased with temperature. The adsorption isotherm curves did not show saturation at the lower temperatures. At a constant temperature, adsorption increased with decreasing albumin concentration. A one-parameter model was used to describe the data for bilirubin adsorption at all temperatures and for all initial concentrations of bilirubin and albumin. This parameter increased monotonically with temperature and decreased monotonically with albumin concentration. From a practical clinical point of view, bilirubin sorption may be increased by operation of the sorbent column at above ambient temperature.

Evaluation of extracorporeal liver support systems in the treatment of liver failure. A systematic review

Liver failure progresses quickly with high mortality. Li’s artificial liver systems (Li-ALS), which including Li’s non-bioartificial liver (Li-NBAL), Li’s bioartificial liver (Li-BAL) and Li’s hybrid artificial liver (Li-HAL), play an important role in treatment of liver failure. Li-NBAL integrates various of purification methods such as plasma exchange, plasma perfusion, blood filtration modules and so on, providing a standardized treatment of liver failure, and the Li-HAL system has been used to treat animals with liver failure and achieved good results. Besides, this paper also reviews the research progress of the stem cell transplantation as a promising alternative in treatment of liver failure. Key words: Liver failure; Liver, artificial; Research progress

The mortality of patients with hepatic failure remains high. Often the patient's life can be saved only with extracorporeal liver support (ELS). ELS systems – MARS® и Prometheus® have proved their efficacy but their widespread use is constrained by their very high cost. Introduction in clinical practice of new affordable ELS systems is a topical issue. The objective: to compare clinical and laboratory effects of selective plasma exchange (SPE), plasmadialfiltration (PDF) with use of the selective membrane plasma separators EvaclioTM and MARS® and Prometheus® (FPSA) systems in the treatment of liver failure. Subjects and methods: 15 extracorporeal procedures of each type were performed in 52 patients with acute liver failure (14) and acute-on-chronic liver failure (38): MARS, FPSA, PDF, SPE with use of Evaclio ЕС-2C, and ЕС-3C, ЕС-4C. The clinical and laboratory parameters (total, direct and indirect bilirubin, total protein, albumin, creatinine, urea, etc.), severity of the condition according to MELD score were determined before and after the session and the next morning. Changes, side effects and complications of procedures were assessed and compared. Results. Reduction of concentration of direct bilirubin was comparable with FPSA, PDF and SPE on Evaclio ЕС-3C20 и ЕС-4C20 (38-42%), indirect bilirubin – with PDF and SPE on Evaclio ЕС-3C20 и ЕС-4C20 (29-34%). Low-molecular metabolites (urea, creatinine) were better removed with FPSA (35-44%) and PDF (40-42%). The reduction of their concentration with SPE was insignificant. The reduction of albumin level was the highest with FPSA (10.2%) and SPE on Evaclio ЕС-4C20 (14.3%). All investigated ELS methods did not exert a significant influence on the basic parameters of blood coagulation and quantity of blood cells. No side effects and complications were observed. Conclusion: Selective plasma exchange and plasmadiafiltration are generally comparable in clinical and laboratory effects in the treatment of liver failure with MARS and Prometheus system provided significantly lower costs.

Liver failure is characterized by rapid progression and high mortality. Excessive systemic inflammation is considered as the trigger of liver failure. Glucocorticoids (GCs) can rapidly suppress excessive inflammatory reactions and immune response. GCs have been applied in the treatment of liver failure since the 1970s. However, until now, the use of GCs in the treatment of liver failure has been somewhat unclear and controversial. New research regarding the molecular mechanisms of GCs may explain the controversial actions of GCs in liver failure. More results should be confirmed in a larger randomized clinical trial; this can aid the discovery of better definitions in terms of treatment schedules according to different clinical settings. Meanwhile, the timing and dosing of GCs in the treatment of liver failure should also be explored.