Novel Bioartificial Liver Support System: Preclinical Evaluation

Abstract

Preclinical safety and efficacy evaluation of a novel bioartificial liver support system (BLSS) was conducted using a D-galactosamine canine liver failure model. The BLSS houses a suspension of porcine hepatocytes in a hollow fiber cartridge with the hepatocytes on one side of the membrane and whole blood flowing on the other. Porcine hepatocytes harvested by a collagenase digestion technique were infused into the hollow fiber cartridge and incubated for 16 to 24 hours prior to use. Fifteen purpose-bred male hounds, 1-3 years old, 25-30 kg, were administered a lethal dose, 1.5 g/kg, of D-galactosamine. The animals were divided into three treatment groups: (1b) no BLSS treatment (n = 6); (2b) BLSS treatment starting at 24-26 h post D-galactosamine (n = 5); and (2c) BLSS treatment starting at 16-18 h post D-galactosamine (n = 4). While maintained under isoflurane anesthesia, canine supportive care was guided by electrolyte and invasive physiologic monitoring consisting of arterial pressure, central venous pressure, extradural intracranial pressure (ICP), pulmonary artery pressure, urinary catheter, and end-tidal CO2. All animals were treated until death or death-equivalent (inability to sustain systolic blood pressure > 80 mmHg for 20 minutes despite massive fluid resuscitation and/or dopamine administration), or euthanized at 60 hours. All animals developed evidence of liver failure at 12-24 hours as evidenced by blood pressure lability, elevated ICP, marked hepatocellular enzyme elevation with microscopic massive hepatocyte necrosis and cerebral edema, elevated prothrombin time, and metabolic acidosis. Groups 2b and 2c marginally prolong survival compared with Group 1b (pairwise log rank censored survival time analysis, p = 0.096 and p = 0.064, respectively). Since survival times for Groups 2b and 2c are not significantly different (p = 0.694), the groups were combined for further statistical analysis. Survival times for the combined active treatment Groups 2b and 2c are significantly prolonged versus Group 1b (p = 0.047). These results suggest the novel BLSS reported here can have a significant impact on the course of liver failure in the D-galactosamine canine liver failure model. The BLSS is ready for Phase I safety evaluation in a clinical setting.

Translational Regenerative Medicine—Hepatic Systems

“…Extracorporeal Liver Assist Device (ELAD) [115] HepatAssist [116] Bioartificial Liver Support System [117] The Academic Medical Center-Bioartifical Liver (AMC-BAL) [118] Modular Extracorporeal Liver Support Device (MELS) [119] More than 200 patients have been treated with HepatAssist and over 40 with ELAD, making them the most common BAL devices used in clinical trials to date [108,120]. In all cases, most patients were bridged to liver transplantation while some patients recovered fully, thus avoiding the need for liver transplantation.…”

Problems and prospects of creation of extracorporal systems for support of functional livers status

“…Ограниченные клинические исследования на 5 пациентах c острой ПН продемонстрировали достаточную эффективность лечения с улучшением ряда биохимических и клинических симптомов без серьёзных осложнений [120]. Ни у кого из пролеченных пациентов в течение года не был обнаружен свиной ретровирус PERV.…”

Morphology, Viability and Functions of Suckling Pig Hepatocytes Cultured in Serum-Free Medium at High Density

“…This system also must be small in size and be available at all times. To develop a compact system, hepatocytes had to be cultured at high density [4, 22]. …”