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How does a Bioartificial Liver work?

The liver is a vital organ that plays myriad roles for the survival of human life as it controls and affects various metabolic and physiological regulatory processes in the body. These processes include protein synthesis, carbohydrate and fat metabolism, blood clotting, immune system, hormonal responses, detoxification (alcohol, chemical toxins, and drugs), and waste removal. 

Acute liver failure (ALF) is loss of liver function that occurs rapidly in a person who has no preexisting liver disease. It’s most commonly caused by a hepatitis virus infection or drugs, such as acetaminophen causing severe injury and necrosis of the hepatocytes. Also known as fulminant hepatic failure, ALF can cause serious complications, including excessive bleeding and increasing pressure in the brain. 

ALF is more complicated because patients present later and with conditions that are not as readily reversible as toxic injury.  Depending on the cause, ALF can sometimes be reversed with treatment and in certain cases, a liver transplant may be the only cure. However, liver transplant is not always feasible, as most of the time there is a shortage of organs. Sometimes the patients also have to be put on lifelong immunosuppression medication. Liver transplant procedures are also very expensive and have a high morbidity rate. 

Several artificial approaches such as plasmapheresis, hemodialysis, plasma exchange, filtration and hemoperfusion have been used instead of liver transplantation. However, these approaches showed limited success as a result of the insufficient replacement of all the metabolic functions of the liver and the lesser number of viable non-damaged liver cells.  Thus arose the need for an extra corporeal liver support system which came in the form of a bioartificial liver. 

The first bioartificial liver device was developed in 1993 by Dr. Achilles A. Demetriou at Cedars-Sinai Medical Center. The bioartificial liver helped an 18-year-old southern California woman survive without her own liver for 14 hours until she received a human liver. This artificial liver consisted of a 20-inch-long, 4-inch-wide plastic cylinder filled with cellulose fibers and pig liver cells. Blood was routed outside the patient’s body and through the artificial liver before being returned to the body. 

A bioartificial liver (BAL) is where plasma is passed over functionally active hepatocytes packed in a bioreactor. A BAL can be used to regenerate the damaged liver either as a treatment or used until a more suitable organ is available for transplant. There are several problems associated with developing a BAL. Human hepatocytes are the preferred cells for BAL devices, but to obtain sufficient human hepatocytes is impractical due to organ shortage. An appropriate bioreactor configuration that allows for mass production of functional hepatocytes is also required. 

In a study reported in the journal Science Translational Medicine, scientists from China have developed a novel set of hepatocytes called the Hepatocyte derived liver progenitor-like cells (HepLPCs) which were found to be an optimal cell source for a BAL. These HepLPCs showed both growth potential and physiologic function (able to do protein synthesis and clear out toxins). 

HepLPCs are genetically modified human liver cells. By carefully tweaking genes in mature cells, the scientists reprogrammed the cells, unspecialising them and producing rapidly-dividing liver stem cells. These were then grown as 3D spherical clumps of cells and maintained their metabolic functions. The liver spheres were grown in the artificial device, prior to treating liver failure in pigs and loaded into an artificial liver device. 

The device was termed an air-liquid interactive bioartificial liver and provided the growing liver cells with oxygen and nutrition and protection from biochemical stress. The device also promoted the direct interaction of the pig blood plasma with the liver spheres, enabling them to clean and detoxify the blood more efficiently. The animals that were given the artificial liver treatment had significantly less tissue damage and showed improved regeneration of their own livers after a drug-induced injury, resembling a drug overdose in humans, to their own livers. The device produced healing factors that were able to kick start organ regeneration in the host. These animals had an increased survival rate (80%) as compared to the control (20%). 

The biggest advantage of BALs is that it is quick to manufacture (around 2 weeks) and shows batch to batch consistency. These experiments prove the high potential of BALs as a candidate for treating acute liver failure. The next steps of the research would involve using BAL in humans who desperately need a working liver. 

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