Welcome to ASAIO’s Bioartificial Liver webpage. Bioartificial Liver is distinguished from Artificial Liver by the use of liver cells (porcine, human, or human cell line) that are expected to provide metabolic, synthesis, and immune modulation support in addition to the detoxification support provided by an artificial liver alone. Considerable progress has been made in the engineering design and development of bioartificial liver approaches with a multitude of different bioreactor configurations and perfusion methods. Many systems have moved through laboratory scale demonstration of different modes of liver function and into preclinical large animal evaluation. These systems are poised to join the first generation of devices based upon hollow fiber technology that are currently in various stages of clinical evaluation.
In keeping with the generalized format for ASAIO Editorial Contributions the News section contains current news items of exceptional interest (to the editor) and discussion board items (Case Reports / Commentaries) that are listed under their own headings. To further participate in the discussion, you must be an ASAIO member and access the Case Reports / Commentaries tab. In addition, information about new technologies and approaches being developed in academic centers around the world and company activities directed toward bringing bioartificial liver to clinical reality are provided, respectively, in the Academic Research Activities and Company Activities subsections. Finally, a bibliography covering citations over the past two years (or so) is provided under the Bibliography tab.
Current News
Discussion Board
The Case Reports / Commentaries tab is available to ASAIO members only. This is an opportunity to learn what the Bioartificial Liver community is thinking about and to provide your insights and comments on topics of current interest. Please join us.
Current Discussion Board:
There are no currently active clinical evaluations of bioartificial liver devices in the United States. Both Excorp Medical and Vital Therapies (see Company Activities) have ongoing trials that are currently inactive but are expected to be reactivated in the near future.
The only completed Phase III efficacy trial, of the Circe Biomedical HepatAssist, was nonsignificant for the primary clinical endpoint of 30-day survival. Post-hoc analysis on a relative risk basis did, however, find significant improvement in survival for the fulminant liver failure subgroup. These results prompt a discussion about design of clinical trials - what are the appropriate stratifications? what are the appropriate clinical outcomes? what are the appropriate statistical measures? - as exemplified by the current discussion editorial:
O’Grady J. Bioartificial liver in acute liver failure: impostor or simply misunderstood? Hepatology. 2005 Feb;41(2):383-5.
If you would like to read the discussion and/or add your own comments, please log in.
Academic Research Activities
Alphabetical listing of academic sites with activities in bioartificial liver research and development. Links are provided to academic research with permission. If you are an academic researcher and would like to have your website link here, please send an e-mail to the web page editor.
Argibay Group (Instituto de Ciencias Básicas y Medicina Experimental, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina (ICBME)): A bioartificial liver device is assembled with a cartridge regularly used for pediatric hemofiltration, as the synthetic component, and 2-day-cultured hepatic spheroids as the biological component, placed in the extracapillary space of the cartridge. The architecture and functionality of pig liver spheroids were analyzed.
The main characteristics of the spheroids are: (a) tightly compacted architecture, with smooth surface and excretion pores, showing two regions, an external cuboidal epithelia, and beneath it, several layers of classical healthy polyhedral parenchymal cells with polygonal shape, rounded and prominent nucleus and lower cytoplasm/nucleus ratio; (b) presence of reticular and collagen fibers; (c) Ck19(+) cells forming duct-like structures; (d) ß and ?-catenins and pan-cadherins in different regions of the spheroids; (e) bile canaliculi with microvilli, tight junctions, zonula adherens and desmosome-like junctions; (f) well-maintained mitochondria, peroxisomes, endoplasmic reticulum, glycogen granules; (g) a complex inner bile canaliculi network.
Detoxification capability was demonstrated through metabolism of diazepam and ammonium. Temazepam was detected from the 4th hour of circulation of the device. Ammonium detoxification reached almost 70% decrease after 9 hours operation of the device. Urea production was detected from the 4th hour and thereafter. After 9 hours of operation of the BAL, the spheroids showed high viability (as seen by the trypan blue exclusion method), and presence of glycogen granules with PAS stain.
All of the above mentioned analyses on the structure and the functionality of spheroids demonstrate that these developed spheroids, far from being simple cell aggregates, can reach an organization level similar to that of the hepatic tissue. Consequently, the improved spheroid morphology and function may provide an appropriate model for the development of bioartificial liver device.
Currently we are in the preclinical administrative step.
Demetriou Group (Cedars Sinai): To be added.
Hu Group (University of Minnesota): To be added.
Nyberg Group (Mayo Clinic): Scott L. Nyberg, M.D., Ph.D. is the Director of the Artificial Liver Support Program at Mayo Clinic, Rochester, MN. The broad, long term objective of the Mayo Liver Support Program is to develop a cell-based extracorporeal bioartificial liver (BAL) for supporting patients with acute and chronic forms of liver failure. Our lab is currently involved with optimization of a novel BAL design, the spheroid reservoir BAL, and to establish its efficacy in a preclinical model of acute liver failure. Optimization includes both bench and animal studies to identify the ideal operating conditions for the BAL. Efficacy studies will involve testing the optimized spheroid reservoir BAL in a pre-clinical model of liver failure. Reversal of hepatic encephalopathy and improvement in survival of animals in acute liver failure are the endpoints that will be used to assess efficacy. Demonstration of efficacy in a pre-clinical model of acute liver failure will provide a basis for future clinical trials of the spheroid reservoir BAL.
Pittsburgh Liver Support Group (University of Pittsburgh): Recognizing that only palliative care is available to support liver function in patients with acute liver failure, any etiology, and that no currently accepted or FDA-approved therapy directed toward support of such patients is available, the Pittsburgh Liver Support Group (PLSG) was established with the mission to make the University of Pittsburgh Medical Center the recognized, world-leading center for validation and clinical deployment of liver support technology through (a) clinical use and evaluation of in-house and vendor technologies and therapeutic modalities, and (b) translational engineering to improve existing technology and bring new technologies to clinical reality.
The Pittsburgh Liver Support Group (PLSG) is collaborative effort involving clinicians and researchers from the Thomas E Starzl Transplantation Institute, the McGowan Institute for Regenerative Medicine, and the Departments of Surgery and Pathology. The executive committee for the PLSG includes Jörg Gerlach, Jack Patzer, George Mazariegos, Peter Linden, Shushma Aggarwal, and Ibtesam Hilmi.
Company Activities
Alphabetical listing of companies with activities in bioartificial liver research and development. Links are provided to companies with permission. If you a would like to have your company website linked here, please send an e-mail to the web page editor.
Arbios Systems, Inc.: Arbios Systems, Inc. is engaged in the development of liver assist devices to meet the urgent need for therapy that facilitates recovery from liver failure of all etiologies and severity. Arbios Systems, Inc. developed three novel liver assist devices for the treatment of liver failure. SEPETTM is a blood purification device that facilitates removal of substances that accumulate during liver failure and damage the liver, brain, and other organs. HepatAssist-2TM is a hybrid bioartificial liver capable of providing both liver cell functions and blood purification. LIVERAIDTM is being developed as a next generation hybrid bioartificial liver that combines liver cell therapy and expanded blood detoxification in a proprietary cartridge with unique fiber-in-fiber geometry. Both devices utilize matrix-anchored porcine liver cells which are procured and cryopreserved using proprietary technology.
Excorp Medical, Inc.: At Excorp Medical, Inc., we have developed a system for the temporary metabolic support of patients in acute liver failure in an 8-year collaboration with the leading University in liver transplantation and tissue engineering. We have completed laboratory, preclinical and initial FDA-authorized Phase I/II human clinical studies and have established the proof of principle for the technology along with proprietary protection and sufficient clinical and technical information to enter the final stages of development and product launch.
Our product is an extracorporeal system, comprising a simple blood loop, which allows us to continuously circulate a patient's whole blood through a bioreactor containing pig liver cells. A membrane barrier separates the two species but still allows the pig liver cells to process the toxins accumulating in the blood as a result of liver failure. Procedures are expected to be 12 hours in duration and repeated 2-3 times during a given episode of liver failure. The clinical goal is to protect the patient's brain, heart, lungs and kidneys from the effects of the failing liver for a period long enough for the native liver to regenerate. The skills required to operate the system are not greatly different from those needed for kidney dialysis, a procedure performed millions of times per year around the world.
Vital Therapies, Inc.: Vital Therapies, Inc. is developing the first - human liver - cell-based - Extracorporeal Liver Assist Device (ELAD®). It contains the proprietary C3A human immortalized hepatocyte cell line that can be grown in unlimited quantities, stored, and shipped worldwide while maintaining the function of human liver cells.
ELAD® treatment is comprised of four hollow fiber cartridges containing a total of 440 grams of cells grown on the outside of the hollow fibers. The patient’s plasma flows through the inside of the hollow fibers with a specific pore size to allow appropriate transfer of toxins and nutrients. During ELAD® therapy the proprietary C3A human hepatocyte cell line cells provide liver function by metabolizing toxins plus synthesizing proteins and other liver specific products essential for life. This enables continuous treatment for ten days or more without the cells losing their ability to perform the metabolic and synthesizing functions of normal liver cells.
52 patients in four human clinical trials received ELAD® treatment. Phase 1 and 2 controlled FDA trials demonstrated safety and significant patient benefits. Compared to controls, patients treated with ELAD® showed statistically significant improvements in bridge to transplant as well as a significant difference in mortality based on Kaplan-Myers analysis.
ELAD® product development is initially occurring in China and market approval is expected by mid 2006. Concurrent development in the US is targeted for market approval in late 2007.
