The BioArtificial Liver
Biology of the Liver
Inferior Vena Cava Abdominal Aorta
Graphic Courtesy of: http://www.ariess.com/s-crina/liver-anatomy.htm
What does the Liver do?
Among the most important liver functions are:
• Removing and excreting body wastes and hormones as well
as drugs and other foreign substances
• Synthesizing plasma proteins, including those necessary for
• Producing immune factors and removing bacteria, helping
the body fight infection
Other important but less immediate functions include:
• Producing bile to aid in digestion
• Excretion of bilirubin
• Storing certain vitamins, minerals, and sugars
• Processing nutrients absorbed from digestive tract
Why would someone need a BioArtificial
Reasons for Receiving Liver Transplant
Fulminant liver failure
Budd-Chiari Other diseases
Alcoholic Liver 4% Cirrhosis
Primary Sclerosing Other cirrhosis
Chronic Active Biliary atresia
Hepatitis Hepatocellular 11%
Liver Transplantation Now
Liver Transplant Statistics in 2000
Transplants Waiting List
•Patients are in waiting list ranked according to severity of
disease and life expectancy among other variables.
•Can be from a cadaveric donor or from a live donor.
•Involves heavy use of immunosuppressants during and after
•The risk of rejecion is always present.
What does a BioArtificial Liver need to do?
1) Cellular components must be purified and every component in it must
be clearly identified.
2) The cellular preparation must be clearly shown to not transmit any
infectious diseases of any kind.
3) The cellular component must stay viable and active
4) The synthetic component must be fully biocompatible, integrity of the
material and parts must also be demonstrated
5) The device must be able to introduce the therapeutic and regulatory
molecules that a healthy liver provides, and it must also filter substances
from the blood the way that the normal liver does.
6) Must be immunocompatible.
7) Blood must perfuse properly through system
• Hemodialysis/hemofiltration hollow fibers- controlled
interaction of cells and circulating fluids
• Maintenance and creation of a cell line
• Immortalizing cells
• Encapsulation-envelopment of hepatocytes in a polymeric
• Microcarriers- polymeric particles containing cells
Works in Progress: Points to Consider
Bioreactor designs/Membrane configurations
Cellular vs. Acellular system
Porcine vs. Human hepatocytes
Point in Development
Liver Dialysis Unit
• FDA approved in 1994
• Plate dialyzer with blood on one
side, dialysate is a mixture of
sorbents, activated charcoal being
the essential component.
• For a substance to be removed,
must be dialyzable and able to bind
• “Bridge to recovery” for treat acute
hepatic encephalopathy and
overdoses of drugs
• Post-market trials have shown the
LDU to be effective in improving
physiological and neurological
• Limited to investigational use in
• Hollow fiber membrane
• Blood on one side, human
albumin on other.
• Albumin recycled through circuit
containing another dialyzer and
carbon and anion exchanger
• Removes both water-soluble and
protein bound substances
• Keep valuable proteins
• Trial have found it safe and
associated with clinical
• Uses cultured human hepatocytes express normal liver-specific metabolic
pathways. hollow fiber dialyzer.
• Dialyzer cartridge connected to continuous hemodialysis machines, like those
used for renal therapy.
• Blood separated into a cellular component and a plasma component.
• Plasma through dialyzer, hepatocytes on outside of hollow fibers.
• Currently involved in a phase 2 clinical trial to evaluate the safety and efficiency.
• Extracorporeal hemofiltration hollow fiber
membrane bioreactor with 100 grams of primary
• Whole blood is filtered
• Contains blood pump, heat exchanger, oxygenator
to control oxygenation and pH, and hollow fiber
• Currently undergoing phase I/II clinical trials
• Patients show some improvement
HepAssist 2000 System
• Four components: a hollow fiber
bioreactor containing porcine
hepatocytes, two charcoal filters, a
membrane oxygenator, and a pump.
• Must be used in conjunction with a
commercially available plasma
• Blood separated; plasma processed
through charcoal filters to remove
particulates, bacteria, then enters
• Hepatocytes must be heated and
• FDA mandated full Phase III trials
• Hollow fiber cartridge
• Primary porcine hepatocytes
suspended in a cold collagen solution
and injected inside fibers
• Blood circulates outside the hollow
• Designed to treat both acute and
chronic liver failure
• Phase I/II clinical trials are underway
to test the safety of efficacy of this
• Anyone treated with the LIVERx2000
will be monitored for PERV
• Parallel plate design
• Human hepatocytes attached to semipermeable membranes on parallel plate
• Plasma separator, then plasma passes into the bioreactor
• In the bioreactor, the plasma flows over the semipermeable membrane where the
hepatocytes are adhered.
• Current trials in Europe show promise
Demographics and Cost
• Market for liver support
Liver Transplants in US is estimated to be
3500 million in the United
3000 States and $1.4 billion
• Liver transplants have
more than doubled in
500 the past ten years, with
0 the transplant waitlist
growing in a similar
Current and Future Challenges
• GOAL: To produce a fully implantable
Fibrosis around implanted capsules
Proteins greater than pore size cannot be released
To achieve density of cells needed to replace
liver, an estimated 1000m of hollow fibers would