involving hollow-fibre bioreactors. overall, they show promise but do not provide statistically significant evidence supporting their effectiveness. this is generally due to inherent design limitations, causing convectional transport issues, nutritional gradients, non-uniform seeding, inefficient immobilisation of cells, and reduced hepatocyte growth. as of writing, no cryogel-based devices have entered clinical trials. however, laboratory results have been promising, and hopefully trials will begin soon. hepatassist the hepatassist, developed at the cedars-sinai medical center, is a bal device containing porcine hepatocytes within a hollow-fibre bioreactor. these semi-permeable fibres act as capillaries, allowing the perfusion of plasma through the device, and across the hepatocytes surrounding the fibres. the system incorporates a charcoal column to act as a filter, removing additional toxins from the plasma. demetriou et al. carried out a large, randomised, multicentre, controlled trial on the safety and efficacy of the hepatassist device. 171 patients with alf stemming from viral hepatitis, paracetamol overdose or other drug complications, primary non-function (pnf), or of indeterminate aetiology, were involved in the study and were randomly assigned to either the experimental or control groups. the study found that at the primary end-point 30-day post admission mark, there was an increased survival rate in bal patients over control patients (71% vs 62%), but the difference was not significant. however, when patients with pnf are excluded from the results there is a 44% reduction in mortality for bal treated patients, a statistically significant advantage. the investigators noted that exclusion of pnf patients is justifiable due to early retransplantation and lack of intercranial hypertension, so hepatassist would give little benefit to this group. for the secondary end-point of time-to-death, in patients with alf of known aetiology there was a significant difference between bal and control groups, with bal patients surviving for longer. there was no significant difference for patients of unknown aetiology, however. the conclusions of the study suggest that such a device has potentially significant importance when used as a treatment measure. while the overall findings were not statistically significant, when the aetiology of the patients was taken into account the bal group gained a statistically significant reduction in mortality over the control group. this suggests that while the device may not be applicable to patients as an overall treatment for liver dysfunction, it can provide an advantage when the heterogeneity of patients is considered and is used with patients of specific aetiology. extracorporeal liver assist device the extracorporeal liver assist device (elad) is a human-cell based treatment system. a catheter removes blood from the patient, and an ultrafiltrate generator separates the plasma from the rest of the blood. this plasma is then run through a separate circuit containing cartridges filled with c3a cells, before being returned to the main circuit and re-entering the patient. thompson et al. performed a large open-label trial, measuring the effectiveness of elad on patients with severe alcoholic hepatitis resulting in aclf. their study involved patients screened at 40 sites across the us, uk, and australia, and enrolled a total of 203 patients. patients were then randomised into either elad (n=96) or standard medical care (n=107) groups, with even distribution for patients in terms of sex, meld score, and bilirubin levels. of the 96 patients in the elad group, 45 completed the full 120 hours of treatment – the rest were unable to complete the full regimen due to a variety of reasons, including withdrawal of consent or severe adverse events, though 37 completed >72 hours of treatment, with results showing minimal difference in mortality between those receiving either >72 hours or the full 120 hours of treatment. the study was unable to complete its goal, finding no statistically significant improvement in mortality rates for patients that received elad treatment over those receiving standard care at 28 and 91 days (76.0% versus 80.4% and 59.4% versus 61.7%, respectively). biomarker measurements showed a significantly reduced level of bilirubin and alkaline phosphatase in elad patients, though neither improvement translated into increased survivability rates. outcomes for patients with meld score <28 showed trends towards improved survival on elad, whereas those with meld >28 had decreased survivability on elad. these patients presented with raised creatinine from kidney failure, suggesting a reason why elad decreased survival chance over standard care. unlike artificial els devices and hepatassist, elad does not incorporate any filtration devices, such as charcoal columns and exchange resins. therefore, it cannot replace the filtration capability of the kidneys and cannot compensate for multi-organ failure from more severe presentations of aclf, resulting in increased mortality rates. while the results of the study cannot provide conclusive evidence to suggest that a bal device like elad improves the outcome of severe aclf, it does suggest that it can aid the survival of patients with a less severe form of the disease. in those patients with a meld <28, beneficial effects were seen 2–3 weeks post treatment, suggesting that while c3a incorporating bal devices are unable to provide short-term aid like artificial albumin filtration devices, they instead provide more long-term aid in recovery of the patient’s liver. a randomized, phase 3 trial of the elad device in patients with severe alcoholic hepatitis failed to show benefit on overall survival and development was discontinued. liver dialysis artificial liver support systems are aimed to temporally replace native liver detoxification functions and they use albumin as scavenger molecule to clear the toxins involved in the physiopathology of the failing liver. most of the toxins that accumulate in the plasma of patients with liver insufficiency are protein bound, and therefore conventional renal dialysis techniques, such as hemofiltration, hemodialysis or hemodiafiltration are not able to adequately eliminate them. liver dialysis has shown promise for patients with hepatorenal syndrome. it is similar to hemodialysis and based on the same principles, but hemodialysis does not remove toxins bound to albumin that accumulate in liver failure. like a bioartificial liver device, it is a form of artificial extracorporeal liver support. a critical issue of the clinical syndrome in liver failure is the accumulation of toxins not cleared by the failing liver. based on this hypothesis, the removal of lipophilic, albumin-bound substances such as bilirubin, bile acids, metabolites of aromatic amino acids, medium-chain fatty acids and cytokines should be beneficial to the clinical course of a patient in liver failure. this led to the development of artificial filtration and absorption devices. liver dialysis is performed by physicians and surgeons and specialized nurses with training in gastroenterological medicine and surgery, namely, in hepatology, alongside their colleagues in the intensive or critical care unit and the transplantation department, which is responsible for procuring and implanting a new liver, or a part (lobe) of one, if and when it becomes available in time and the patient is eligible. because of the need for these experts, as well as the relative newness of the procedure in certain areas, it is usually available only in larger hospitals, such as level i trauma center teaching hospitals connected with medical schools. between the different albumin dialysis modalities, single pass albumin dialysis (spad) has shown some positive results at a very high cost; it has been proposed that lowering the concentration of albumin in the dialysate does not seem to affect the detoxification capability of the procedure. nevertheless, the most widely used systems today are based on hemodialysis and adsorption. these systems use conventional dialysis methods with an albumin containing dialysate that is later regenerated by means of adsorption columns, filled with activated charcoal and ion exchange resins. at present, there are two artificial extracorporeal liver support systems: the molecular adsorbents recirculating system (mars) from gambro and fractionated plasma separation and adsorption (fpsa), commercialised as prometheus (prom) from fresenius medical care. of the two therapies, mars is the most frequently studied, and clinically used system to date. prognosis/survival while the technique is in its infancy, the prognosis of patients with liver failure remains guarded. liver dialysis is currently only considered to be a bridge to transplantation or liver regeneration (in the case of acute liver failure) and, unlike kidney dialysis (for kidney failure), cannot support a patient for an extended period of time (months to years). devices artificial detoxification devices currently under clinical evaluation include the single pass albumin dialysis (spad), molecular adsorbent recirculating system (mars)®, prometheus system, and dialive. single pass albumin dialysis (spad) single pass albumin dialysis (spad) is a simple method of albumin dialysis using standard renal replacement therapy machines without an additional perfusion pump system: the patient's blood flows through a circuit with a high-flux hollow fiber hemodiafilter, identical to that used in the mars system. the other side of this membrane is cleansed with an albumin solution in counter-directional flow, which is discarded after passing the filter. hemodialysis can be performed in the first circuit via the same high-flux hollow fibers. molecular adsorbents recirculation system the molecular adsorbents recirculation system (mars) is the best known extracorporal liver dialysis system. it consists of two separate dialysis circuits. the first circuit consists of human serum albumin, is in contact with the patient's blood through a semipermeable membrane and has two filters to clean the albumin after it has absorbed toxins from the patient's blood. the second circuit consists of a hemodialysis machine and is used to clean the albumin in the first circuit, before it is recirculated to the semipermeable membrane in contact with the patient's blood. comparing spad, mars and cvvhdf spad, mars and continuous veno-venous haemodiafiltration (cvvhdf) were compared in vitro with regard to detoxification capacity. spad and cvvhdf showed a significantly greater reduction of ammonia compared with mars. no significant differences could be observed between spad, mars and cvvhdf concerning other water-soluble substances. however, spad enabled a significantly greater bilirubin reduction than mars. bilirubin serves as an important marker substance for albumin-bound (non-water-soluble) substances. concerning the reduction of bile acids no significant differences between spad and mars were seen. it was concluded that the detoxification capacity of spad is similar or even higher when compared with the more sophisticated, more complex and hence more expensive mars. albumin dialysis is a costly procedure: for a seven-hour treatment with mars, approximately €300 for 600 ml human serum albumin solution (20%), €1740 for a mars treatment kit, and €125 for disposables used by the dialysis machine have to be spent. the cost of this therapy adds up to approximately €2165. performing spad according to the protocol by sauer et al., however, requires 1000 ml of human albumin solution (20%) at a cost of €500. a high-flux dialyzer costing approximately €40 and the tubings (€125) must also be purchased. the overall costs of a spad treatment is approximately €656—30% of the costs of an equally efficient mars therapy session. the expenditure for the mars monitor necessary to operate the mars disposables is not included in this calculation. prometheus the prometheus system (fresenius medical care, bad homburg, germany) is a device based on the combination of albumin adsorption with high-flux hemodialysis after selective filtration of the albumin fraction through a specific polysulfon filter (albuflow). it has been studied in a group of eleven patients with hepatorenal syndrome (acute-on-chronic liver failure and accompanying kidney failure). the treatment for two consecutive days for more than four hours significantly improved serum levels of conjugated bilirubin, bile acids, ammonia, cholinesterase, creatinine, urea and blood ph. prometheus was proven to be a safe supportive therapy for patients with liver failure. dialive dialive (yaqrit limited, london, uk) incorporates albumin removal and replacement and, endotoxin removal. it is at "technology readiness level" (trl) 5, which means it is validated in the disease environment. the mars system mars was developed by a group of researchers at the university of rostock (germany), in 1993 and later commercialized for its clinical use in 1999. the system is able to replace the detoxification function of the liver while minimizing the inconvenience and drawbacks of previously used devices. in vivo preliminary investigations indicated the ability of the system to effectively remove bilirubin, biliary salts, free fatty acids and tryptophan while important physiological proteins such as albumin, alpha-1-glicoproteine, alpha 1 antitrypsin, alpha-2-macroglobulin, transferrin, globulin tyrosine, and hormonal systems are unaffected. also, mars therapy in conjunction with crrt/hdf can help clear cytokines acting as inflammatory and immunological mediators in hepatocellular damage, and therefore can create the right environment to favour hepatocellular regeneration and recovery of native liver function.