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The BioArtificial Liver

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					 The BioArtificial Liver

Susana Candia
Jahi Gist
Hashim Mehter
Priya Sateesha
Roxanne Wadia
                 Biology of the Liver

                                                          Left lobe
        Right lobe
                                                          Falciform Ligament
      Gallbladder
                                                           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%
                     Budd-Chiari                            Other diseases
                      Syndrome                                   10%
                                                                                 Primary Biliary
   Alcoholic Liver        4%                                                        Cirrhosis
      disease                                                                         16%
        4%

 Cholangiocarcinoma
         4%

  Primary Sclerosing                                                                 Other cirrhosis
      cholangitis                                                                    (nonalcoholic)
         5%                                                                              12%
                 Chronic Active                                Biliary atresia
                   Hepatitis    Hepatocellular                      11%
                      8%         carcinoma
                                    9%         Retransplantation
                                                     11%
     Liver Transplantation Now
                                   Liver Transplant Statistics in 2000

                           20000
                           18000
                           16000
                           14000

                Patients
                           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)   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
         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




• 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
                                   substantial: $700
3500                               million in the United
3000                               States and $1.4 billion
2500                               worldwide.
2000
1500
                                 • Liver transplants have
1000
                                   more than doubled in
500                                the past ten years, with
  0                                the transplant waitlist
                                   growing in a similar
   ar
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                                   fashion
  Current and Future Challenges
• GOAL: To produce a fully implantable
  bioartificial liver.

            Cell viability
Problems:
            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

				
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posted:11/9/2011
language:English
pages:17