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Bioartificial Liver
Liver Disease Bioartificial Liver PICM 19 Cell Line Bioreactor Animation Publications
Each year an estimated two million people die of liver disease. Today a bioartificial liver is closer to reality because of our patented PICM-19 liver stem cell line. The hepatic characteristics of the PICM-19 cell line have been shown to have potential application for use in a bioartificial liver device.
Liver Disease - A leading cause of death
 Prevalence of Liver Disease (Worldwide) |
 Liver Transplant Patients (United States) |
Each year an estimated two million people die of liver disease. The World Health Organization estimates that over 10% of the world's population has liver diseases, including more than 25 million Americans. In 2004, there were nearly 18,000 individuals on the US waiting list for a liver transplant. That year, about 1,300 people died while waiting for a suitable donor with no medical option for saving their life available.
The need for a bioartificial liver device able to remove toxins and improve survival results is more critical today than ever before. Limited treatment options, a low number of donor organs, the high price of transplants and follow up costs, a growing base of hepatitis, alcohol abuse, drug overdoses, liver cancer and other factors, all clearly indicate a strong need for a bioartificial liver device.
For 30 years the medical world has tried to create that life-saving device. Hepatocytes, or liver cells, are the key to a functioning bioartificial liver. But the liver is a complex organ: it takes in oxygen and nutrients, and returns metabolic byproducts to the plasma; it must regulate the balance of fluids, electrolytes, and glucoses. The liver synthesizes albumin, globulins, and heparin, and filters out ammonia and toxins.
Today a bioartificial liver is closer to reality because of our patented PICM-19 liver stem cell line. The hepatic characteristics of the PICM-19 cell line have been shown to have potential application for use in a bioartificial liver device.
HepaLife's Bioartificial Liver
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HepaLife's bioartificial liver currently under development, is designed to operate outside the patient's body. The machine mimics important functions of the human liver by circulating the patient's blood inside the bioreactor unit of the artificial liver device where it is exposed to HepaLife's patented PICM-19 liver cells.
Once inside the bioreactor unit, HepaLife's bioartificial liver device will ultimately process the patient's blood-plasma removing; toxins, enhancing metabolic function, and imitating the natural liver's function.
The HepaLife bioartificial liver device consists of three basic components:
- A plasma filter, separating the patient's blood into blood plasma and blood cells,
- the bioreactor filled with PICM-19 cells and the HepaDrive™,
- a perfusion system pumping the patient's plasma through
the bioreactor and controlling gas supply and temperature for best possible performance of the cells.
- Click here for an animation of HepaLife's bioartificial
liver circuit.
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HepaLife's PICM-19 embryonic liver stem cell line, derived from the pig epiblast, is the world's only cell line of its kind with full expansion and growth capacity, maintaining its hepatic function in repeated passage.
PICM-19 cells possess the ability to differentiate into monolayers of fetal hepatocytes or they can differentiate into functional bile ductules by self-organization of the cells into multicellular tubular structures, as those found in normal in vivo hepatocytes. Like hepatic cell lines derived from tumors, PICM-19 cells have the ability to replicate indefinitely; however, unlike tumor-derived cell lines or oncogene immortalized hepatocyte cell lines, PICM-19 cell cultures desirably stop cell replication after several days, and the cells differentiate into hepatocyte monolayers or bile ductules as would normally occur in a regenerating liver, in vivo.
The PICM-19 cell line has been maintained in continuous culture for several years. The PICM-19 cells have consistently demonstrated liver-specific activity over these years of continuous culture. The liver-specific activities exhibited by PICM-19 cells are very similar to those found in human liver cells. Among other liver-specific metabolic activities, PICM-19 cells have been shown to:
- Express high levels of inducible P450 and GGT; important indicators of hepatocyte and bile duct functions, respectively
- Express proteins and mRNA that are unique to the liver
- Exhibit in vivo-like response of the in-vitro produced ductules to secretin and cAMP inducers
- Detoxify high amounts of ammonia and synthesize urea and/or glutamine, vital functions of the human liver
- Exhibit in vivo-like responses to common drugs and toxins (e.g., acetaminophen, rifampicin, etc.)
- Tolerate room temperature for prolonged periods of time while retaining hepatic function which enables convenient handling and shipping.
The performance of the PICM-19 cell line is unmatched by any other cell line currently available for liver support.
 HepaLife Bioreactor |
 HepaDrive™: Perfusion system for the Bioreactor |
The design of a bioreactor which successfully maintains the PICM-19 liver cell’s full functionality —thereby simulating the natural liver function— is of great importance. The HepaLife multi-compartment bioreactor consists of three interwoven, independent capillary membrane systems. Two of them provide decentralized flow of the patient’s blood plasma and the third one provides oxygen supply to the PICM-19 cells, which are localized in the extracapillary space - the fourth compartment. This 3-dimensional spatial structure represents an artificial equivalent of the hepatic vasculature at the lobular level.
Click here for an animated cross section of Hepalife's bioreactor.
In contrast, conventional hollow fiber bioreactors consist of only two compartments, a cell compartment and a media or blood plasma compartment with no additional compartment for oxygen supply or carbon-dioxide removal.
In early tests of HepaLife's proprietary bioreactor, PICM-19 cells were seeded inside; over a 14-day period they successfully remained contact-inhibited, an important indicator of normal cell growth. The cells further differentiated into hepatocytes (liver cells) with normal structure and morphology. Most importantly, HepaLife's proprietary bioreactor and PICM-19 cell line system was able to remove toxic ammonia and synthesize urea. This ability is vital to successfully replicating the human liver's function in a bioartificial liver device.
The bioreactor used in the HepaLife bioartificial liver was first introduced into clinical use at the Charité Berlin, Germany using primary porcine and human liver cells. The bioreactor technology has been integrated into a modular extracorporeal liver support (MELS) system, combining biologic liver support with artificial detoxification technology.
In a phase I study utilizing primary porcine cells, eight human acute liver failure patients with coma stage II-IV, were treated to bridge the waiting time for a liver transplant. The overall treatment time was 8 to 46 hours. The condition of all patients stabilized during the course of treatment, and the patient and organ survival rates remain at 100%.
Following these studies a further clinical pilot study was performed on 9 patients using primary human liver cells. The overall treatment time was 7-144 hours. No adverse events were observed. In all cases of acute liver failure the patient's neurological status improved during treatment.
PICM-19 cell line:
- Talbot NC, Blomberg le A, Mahmood A, Caperna TJ, Garrett WM: Isolation and characterization of porcine visceral endoderm cell lines derived from in vivo 11-day blastocysts, In Vitro Cell Dev Biol Anim. 2007 Feb;43(2):72-86
- Talbot NC, Caperna TJ, Wells KD.: The PICM-19 cell line as an in vitro model of liver bile ductules: effects of cAMP inducers, biopeptides and pH, Cells Tissues Organs. 2002;171(2-3):99-116
- Talbot NC, Caperna TJ, Lebow LT, Moscioni D, Pursel VG, Rexroad CE Jr.: Ultrastructure, enzymatic, and transport properties of the PICM-19 bipotent liver cell line, Exp Cell Res. 1996 May 25;225(1):22-34
Bioreactor:
- Zeilinger K, Holland G, Sauer IM, Efimova E, Kardassis D, Obermayer N, Liu M, Neuhaus P, Gerlach JC: Time course of primary liver cell reorganization in three-dimensional high-density bioreactors for extracorporeal liver support: An immuno-histochemical and ultrastructural study, Tissue Eng. 2004 Jul-Aug;10(7-8):1113-24
- Sauer IM, Zeilinger K, Pless G, Kardassis D, Theruvath T, Pascher A, Goetz M, Neuhaus P, Gerlach JC: Extracorporeal liver support based on primary human liver cells and albumin dialysis--treatment of a patient with primary graft non-function, J Hepatol. 2003 Oct;39(4):649-53
- Irgang M, Sauer IM, Karlas A, Zeilinger K, Gerlach JC, Kurth R, Neuhaus P, Denner J: Porcine endogenous retroviruses: no infection in patients treated with a bioreactor based on porcine liver cells, J Clin Virol. 2003 Oct;28(2):141-54
- Sauer IM, Kardassis D, Zeillinger K, Pascher A, Gruenwald A, Pless G, Irgang M, Kraemer M, Puhl G, Frank J, Muller AR, Steinmuller T, Denner J, Neuhaus P, Gerlach JC: Clinical extracorporeal hybrid liver support - phase I study with primary porcine liver cells, Xenotransplantation. 2003 Sep;10(5):460-9
- Gerlach JC, Botsch M, Kardassis D, Lemmens P, Schon M, Janke J, Puhl G, Unger J, Kraemer M, Busse B, Bohmer C, Belal R, Ingenlath M, Kosan M, Kosan B, Sultmann J, Patzold A, Tietze S, Rossaint R, Muller C, Monch E, Sauer IM, Neuhaus P: Experimental evaluation of a cell module for hybrid liver support, Int J Artif Organs. 2001 Nov;24(11):793-8
- Gerlach JC.: Development of a hybrid liver support system: a review, Int J Artif Organs. 1996 Nov;19(11):645-54
- Gerlach J, Ziemer R, Neuhaus P: Fulminant liver failure: relevance of extracorporeal hybrid liver support systems, Int J Artif Organs. 1996 Jan;19(1):7-13
- Gerlach JC, Encke J, Hole O, Muller C, Ryan CJ, Neuhaus P: Bioreactor for a larger scale hepatocyte in vitro perfusion, Transplantation. 1994 Nov 15;58(9):984-8
