Hybrid Bioartificial Liver (February 19, 2004)

There are approximately 1-2 million deaths worldwide every year resulting from liver failure. As of November 6, 2009, the Organ Procurement and Transplantation Network listed 15, 911 candidates on the waiting list for a liver in the United States. However, only 4, 644 liver donors were listed (4, 490 deceased and 154 living). Clearly, there is a huge need for a device that can help alleviate such a wide divide.

The treatment of liver failure using the hybrid bioartificial liver (BAL) support device is a relatively new technology stemming from the increasingly poor outcomes in acute liver failure and the limited number of organs for transplantation. Currently, BAL is used as a bridge until liver transplantation is available or until liver regeneration is complete and has also been successful in treating acute liver failure. The bioartificial liver support system combines a biological component (hepatocytes) with a synthetic component (biomaterial).

The article glosses over various cells that could be used as the biological component, gives a brief summary of a few systems on the market, and introduces the discovery of immortalized human hepatocytes lines as a source of creating hepatocytes and the BAL device being worked on. The debate with what kind of cells can be used to create hepatocytes is one that resonates with the class lecture on organ transplantation. Human embryonic stem cells, somatic stem cells, differentiated tissue cells, and cells from tissues of animal species (primarily pig) are all potential sources for creating hepatocytes. With human embryonic stem cells, the problem is difficulty to control the pluripotency of the cells and their ability to proliferate leads to the question of the patient maybe developing cancer down the road. Somatic stem cells and differentiated tissue cells have high costs and the yield is not enough to be worthwhile.

Breeding transgenic pigs for porcine hepatocytes is a viable option, but their compatibility with humans is not 100%, they have the potential to infect human tissues with porcine endogenous retrovirus (PERV), and animal rights advocates protest the breeding of transgenic pigs. A type of system available, HepatAssist System (Figure 1), a BAL support system that uses porcine hepatocytes (based on 1997 Demetriou study). As of 2004 when the article was published, Phase II and III had already been completed and the clinical study is still ongoing. What was remarkable to me was that it required 9 billion frozen porcine hepatocytes!

The authors of the article discuss the process by which they are able to reversibly immortalize human hepatocytes. First, immortalized genes are proliferated in vitro until the desired number is reached. Then, the genes needed are removed by selection markers and finally, reversion occurs to generate human hepatocytes. The entire reaction would actually be applicable to a large scale at a low cost. This technology has great implications in furthering the development of a BAL because hepatocyte cell lines can possibly de-differentiate and lose their hepatocyte ability.

This is definitely a huge step in establishing the biological component of the BAL. However, I think that clinical studies will still be necessary and it will also be important to device the synthetic component that will work well with the human hepatocyte cell lines. The BAL support system design is similar to that in renal dialysis with the same principle of counter-current blood flow over a semipermeable membrane with functioning hepatocytes on the other side. Thus, the synthetic component must contain fibers of a material that can maximize the liver's excretory and metabolic functions. With regard to the current health care debate, the reform currently includes measures to help those with chronic diseases, which includes chronic liver failure. I am uncertain whether this will include increased funding for research into a BAL device, but I am hopeful that this is a step in the right direction.

-Robin

Naoya Kobayashi, Journal of Artificial Organs, 2/19/04
http://www.springerlink.com/content/hqva24y20gcjcn07/