Transcript The BioArtificial Liver - Division of Biology and Medicine

The BioArtificial Liver
Susana Candia
Jahi Gist
Hashim Mehter
Priya Sateesha
Roxanne Wadia
Biology of the Liver
Right lobe
Gallbladder
Left lobe
Falciform Ligament
Kidneys
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
blood clotting
• 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
Liver?
Reasons for Receiving Liver Transplant
Alpha antitrypsin
Fulminant liver failure
deficiency
3%
3%
Other diseases
Budd-Chiari
10%
Syndrome
Alcoholic Liver
disease
4%
4%
Primary Biliary
Cirrhosis
16%
Cholangiocarcinoma
4%
Primary Sclerosing
cholangitis
5%
Biliary atresia
Chronic Active
11%
Hepatocellular
Hepatitis
carcinoma
8%
9%
Retransplantation
11%
Other cirrhosis
(nonalcoholic)
12%
Liver Transplantation Now
Patients
Liver Transplant Statistics in 2000
20000
18000
16000
14000
12000
10000
8000
6000
4000
2000
0
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
surgery.
•The risk of rejecion is always present.
What does a BioArtificial Liver need to do?
1)
2)
Cellular components must be purified and every component in it must
be clearly identified.
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
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.
Must be immunocompatible.
Blood must perfuse properly through system
5)
6)
7)
Enabling Technologies
• 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
matrix.
• 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
to charcoal.
• “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
status.
MARS®
• Limited to investigational use in
US.
• Hollow fiber membrane
hemodialyzer.
• Blood on one side, human
albumin on other.
• Albumin recycled through circuit
containing another dialyzer and
carbon and anion exchanger
adsorption columns.
• Removes both water-soluble and
protein bound substances
• Keep valuable proteins
• Trial have found it safe and
associated with clinical
improvement
ELAD®
• 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.
BLSS
• Extracorporeal hemofiltration hollow fiber
membrane bioreactor with 100 grams of primary
porcine hepatocytes
• Whole blood is filtered
• Contains blood pump, heat exchanger, oxygenator
to control oxygenation and pH, and hollow fiber
bioreactor
• 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
separation machine
• Blood separated; plasma processed
through charcoal filters to remove
particulates, bacteria, then enters
bioreactor
• Hepatocytes must be heated and
oxygenated
• FDA mandated full Phase III trials
LIVERx2000
• Hollow fiber cartridge
• Primary porcine hepatocytes
suspended in a cold collagen solution
and injected inside fibers
• Blood circulates outside the hollow
fibers
• Designed to treat both acute and
chronic liver failure
• Phase I/II clinical trials are underway
to test the safety of efficacy of this
device
• Anyone treated with the LIVERx2000
will be monitored for PERV
MELS
•
•
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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
Liver Transplants in US
3500
3000
2500
2000
1500
1000
500
Ye
ar
19
89
19
90
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91
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• Market for liver support
is estimated to be
substantial: $700
million in the United
States and $1.4 billion
worldwide.
• Liver transplants have
more than doubled in
the past ten years, with
the transplant waitlist
growing in a similar
fashion
Current and Future Challenges
• GOAL: To produce a fully implantable
bioartificial liver.
Problems:
Cell viability
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
be needed