ARTIFICIAL ORGANS
1
The Liver
Sarah Waller
Nathan De Jong
WHAT IS THE LIVER?
The largest internal organ, weighing around 3 lbs
in an adult male
| Forms a key part in metabolism and digestion
| Also filters and regulates blood
|
y
Works closely with the kidneys and pancreas
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LOCATION
|
At the top of the
abdominal cavity
y
|
Divided into two lobes by
the falciform ligament
y
|
Inferior to the diaphragm
Connects it to the
diaphragm
Each lobe consists of
many lobules
3
LOBULES
Hexagonal in shape
| Consist of:
|
Hepatocytes around a central vein (leads to hepatic
vein)
y Sinusoids (highly permeable capillaries) – also
contain Kupffer cells
y Branches of the hepatic artery and the hepatic portal
vein
y Bile ducts
y
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LOBULES
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HEPATOCYTES
Hepato = Liver, cytes = cells
| The main functional cell of
the liver
|
y
|
Protein synthesis, filtration,
etc.
Arranged in plates one cell
thick next to sinusoids –
contact with blood
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KUPFFER CELLS
Also known as stellate
reticuloendothelial cells
| Filter the blood
| Phagocytes
| Destroy:
|
Worn out blood cells
y Bacteria
y Other foreign matter
y
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WHAT DOES THE LIVER DO?
|
Metabolism
y
Carbohydrates, lipids and proteins
Drug and hormone processing
| Bile production
| Storage
| Phagocytosis (Kupffer cells)
| Activation of Vitamin D
|
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METABOLISM
|
Carbohydrates
y
Regulates blood sugar levels by converting glucose
to glycogen or vice versa
|
y
Stores glycogen or releases glucose into blood
Can also convert fructose, galactose, some amino
acids and lactic acid to glucose
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METABOLISM
|
Lipids
Breaks down fatty acid into ATP
y Synthesizes lipoproteins to transport lipids and
cholesterol
y Stores lipids if necessary
y
|
Proteins
Remove the NH2 from amino acids for ATP
production or conversion to carbohydrates or fats
y NH3 that results is converted into urea
y
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METABOLISM
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PROCESSING
|
Drugs and hormones
Detoxifies blood and excretes waste into bile
y Alters or excretes certain hormones when necessary
y
|
Bilirubin and bile salts
y
Absorbs bilirubin from old blood cells
|
Work of the Kupffer cells
Synthesizes bile salts
y Bilirubin and bile salts are components of bile
y
|
Used in the small intestine for digestion
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STORAGE
|
Hepatocytes are used as storage for
Glycogen (when blood sugar is high)
y Vitamins A, B12, D, E and K
y Minerals – iron and copper
y
|
Helps with the synthesis of Vitamin D as well as
storing it
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LIVER FAILURE
|
General symptom is jaundice
y
|
Yellow colouring to eyes and skin due to build-up of
bilirubin
Acute Liver Failure
y
Rapid progression into worse symptoms
|
|
E.g. confusion, stupor or coma
Chronic Liver Failure
Slow, gradual, consistent decay of the liver
y Usually leads to cirrhosis or cancer of the liver
y
|
Cirrhosis: distorted or scarred liver; hepatocytes are
replaced by fibrous or adipose connective tissue
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LIVER FAILURE
|
Hepatitis: inflammation of the liver caused by
Viruses
y Drugs and chemicals
y
|
Genetic disorders
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VIRUSES
Five strains of the Hepatitis virus (A-E)
| Hep A
|
Infectious, caused by fecal contamination
y Fairly mild, no lasting damage
y
|
Hep B and C
Transmitted through bodily fluids (sexual contact,
contaminated needles, saliva)
y Lasts for many years, and can eventually cause
cirrhosis or liver cancer
y Vaccines are available through recombinant DNA
technology
y
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VIRUSES
|
Hep D
Transmitted like Hep B and C
y Person must already have Hep B to contract Hep D
y Causes severe liver damage, essentially intensifies
Hep B
y
|
Hep E
Transmitted like Hep A
y No chronic effect on the liver
y High mortality rate in pregnant women
y
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DRUGS AND CHEMICALS
Metabolized by the liver
| Alcohol is the most common
chemical abuse
|
y
|
Long-term abuse leads to
cirrhosis or cancer
Also commonly caused by
allergic reactions to
medication
y
Tends to have acute effects,
rather than chronic
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GENETIC DISORDERS
|
Commonly is a failure to excrete specific ions
y
Ex. Wilson’s Disease
The liver retains Cu+ ions, instead of excreting them via
bile, which damages it
| Eventually re-releases the Cu into the bloodstream,
poisoning the body
|
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WHAT ARE THE TYPES OF LIVER
SUPPORT?
Liver Transplants
| Liver Dialysis
| Bio-Artificial Liver
| Stem Cell grown liver
| Fully Artificial Liver?
|
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HISTORY OF LIVER TRANSPLANTS
|
Main figure was Dr. Thomas
Starzl
Performed hundreds of canine
liver transplants in the 50’s
y Attempted first human liver
transplant in 1963
y Successfully completed first
human liver transplant in 1967
(first one-year survival)
y Limited success for next decade
y
|
One-year survival rate never
exceeded 50%
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CYCLOSPORINE
|
1979 – Cyclosporine is approved by the FDA
Immunosuppressive agent
y Vastly decreases rejection rate and with it, mortality
rate
y
1983 – Liver transplantation is accepted as a
viable treatment option for End Stage Liver
Disease
| 1989 – Tacrolimus is approved
|
y
|
Success rates continue to improve
Today – 5-10 year survival rate is 80%
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LIVER TRANSPLANTS
|
Supply and demand
Over 17,000 individuals on waiting list 2005
• 5,000 donated yearly
• Need for a more available resource
•
|
Types of transplants
o
Deceased-donor grafts
•
•
•
Whole organ
Reduced-size
Split-liver
Live-donor grafts
o Xenografts
o
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LIVER TRANSPLANTS
|
Reduced-size grafts
•
Developed for pediatric cases
Left lobe (segments 2 and 3) or
segments 2-4 are transplanted
into children from an adult
liver.
This technique can also be used
in live-donor transplants.
If successful the liver will grow
to full size in 6-8 weeks.
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LIVER TRANSPLANTS
|
Split-liver transplants
o
Developed in order to increase the number of
transplants per donation
Right side
to an adult
patient
Left side to
a pediatric
patient
More success with left lobe transplants.
Is it fair to give a patient the right lobe knowing there is less
chance of survival?
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LIVER TRANSPLANTS
|
Reasons why an individual may not qualify
o
o
o
o
o
o
o
o
Chronic liver disease
HIV Infected
Types of cancer
Uncontrolled sepsis
Cardiac/Pulmonary Disease
Active alcoholism or substance abuse
Advanced age
Severe Obesity
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LIVER DIALYSIS
|
What is it?
Extracorporeal device
o Similar to kidney dialysis
o Detoxifies blood from hydrophilic and hydrophobic
toxins
o
|
How it works
o
Makes use of the properties of albumin in the blood
Hydrophobic toxins are attracted to the
hydrophobic areas of albumin.
It acts as an adsorber
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LIVER DIALYSIS
Blood runs through the
hollow fibres
Human albumin is contained
outside of the fibres
Water soluble toxins diffuse
through semi-permeable
membrane
Non water soluble toxins
bond to the membrane
proteins an get picked up by
the internal albumin
Meanwhile, the albumin is filtered in a series of adsorbers and a
separate dialysis circuit.
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LIVER DIALYSIS
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LIVER DIALYSIS
|
Benefits
Reduces plasma toxicity in blood
o Allows for liver regeneration
o
|
Drawbacks
Only for detoxification
o Only one function of the liver is replicated
o Does not produce albumin
o
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BIO-ARTIFICIAL LIVER
|
What is it?
An artificial device that uses biological materials in
order to produce a desired function
o Devices vary in structure and cell line between
suppliers
o
Invention of the year by
TIME Magazine in 2001
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BIO-ARTIFICIAL LIVER
|
How it works
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BIO-ARTIFICIAL LIVER
|
How it works
Bioreactor Animation
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BIO-ARTIFICIAL LIVER
|
Types of design
o
|
Main areas of variation are in the bioreactor shape
and method of cementing used
The hepatocytes in each bioreactor are different
but most are differentiated from either porcine
(pig) or human liver cells
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PORCINE CELLS
|
Very similar in structure to human hepatocytes
Porcine Liver cells
Pigs metabolize hormones,
chemicals and toxins nearly
the same as homo sapiens
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IMMORTALIZED HUMAN CELLS
Normal Liver Cells
Immortalized
Cells are immortalized by SV40 virus large T-antigen which binds to
the DNA of the cells and promotes transcription and in turn
replication.
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PROS AND CONS
Immortalized
Human Cells
Pros
Porcine
Hepatocytes
Biochemicals produced Readily available
are the same
Less chance of
Easily reproduced
immunogenic response
Cons
Not an abundant
resource
May transfer porcine
retroviruses
Difficult to grow in
culture
May lack a speciesspecific response
Outperformed by
porcine cells
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STEM CELL LIVER
|
British scientists stimulated umbilical cord stem
cells in a Bioreactor to form liver cells
y
|
Essentially created a mini liver – size of a penny
A full-sized liver has not been grown yet
y
Within the next 15 years, livers could be grown and
transplanted into humans
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FULLY ARTIFICIAL LIVER
|
“One science journalist speculated that the
equipment needed to simulate the functions of a
single human liver would occupy a large office
building”
|
With over 500 essential functions, a fully
artificial liver seems impractical and near
impossible
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FUTURE?
|
Research is being done to see which bioreactor
shape and cell line is most beneficial and cost
effective
|
Promising progress with stem cell research in
this area
|
We will always be dependant on liver transplants
but maybe not so heavily in the future
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QUESTIONS?
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SOURCES
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http://www.radiologyassistant.nl/en/4375bb8dc241d
http://www.emedicine.com/PED/topic2904.htm
http://biomed.brown.edu/Courses/BI108/BI108_2002_Groups/liver/we
bpage/intro.html
http://160.114.99.91/astrojan/protein/pictures/albumin3.jpg
http://www.hepalife.com/index.php
http://www.xenotechllc.com/Product-IHH
http://biomed.brown.edu/Courses/BI108/BI108_1999_Groups/Liver_Te
am/Liver.html
http://www.alinfoundation.com/
http://www.biomed.metu.edu.tr/courses/term_papers/bioartfliver_kenar.htm
http://www.dailymail.co.uk/news/article-413551/British-scientistsgrow-human-liver-laboratory.html
http://www.uams.edu/liverservice/history/
http://chealth.canoe.ca/condition_info_details.asp?disease_id=176
http://www.ispub.com/ostia/index.php?xmlFilePath=journals/ijpharm/
vol2n1/transplant.xml
www.elmhurst.edu/~chm/vchembook/images/590metabolism.gif
http://www.columbia.edu/cu/21stC/issue-1.2/resources/starzl.gif
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