The Bio Artificial Liver2

8/4/2019 The Bio Artificial Liver2

http://slidepdf.com/reader/full/the-bio-artificial-liver2 1/17

The BioArtificial Liver

Susana CandiaJahi Gist

Hashim Mehter

Priya Sateesha

Roxanne Wadia



Biology of the Liver

Left lobeRight lobe

KidneysGallbladder

Falciform Ligament

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 forblood clotting

• Producing immune factors and removing bacteria, helpingthe 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

Other diseases

10%

Fulminant liver failure

3%

Hepatocellular

carcinoma

9%

Primary Sclerosing

cholangitis5%

Retransplantation

11%

Biliary atresia

11%

Other cirrhosis

(nonalcoholic)12%

Primary Biliary

Cirrhosis16%

Alpha antitrypsin

deficiency

3%

Budd-Chiari

Syndrome

4%

Chronic Active

Hepatitis

8%

Cholangiocarcinoma

4%

Alcoholic Liverdisease

4%



Liver Transplantation NowLiver Transplant Statistics in 2000

02000

4000

6000

8000

10000

12000

14000

16000

18000

20000

Transplants Waiting List

P a t i e n t s

•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 aftersurgery.

•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 inUS.

• Hollow fiber membranehemodialyzer.

• Blood on one side, humanalbumin on other.

• Albumin recycled through circuitcontaining another dialyzer andcarbon and anion exchangeradsorption columns.

• Removes both water-soluble and

protein bound substances• Keep valuable proteins

• Trial have found it safe andassociated with clinicalimprovement



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 fibermembrane bioreactor with 100 grams of primaryporcine hepatocytes

• Whole blood is filtered

• Contains blood pump, heat exchanger, oxygenatorto 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 hollowfibers

• 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 supportis estimated to besubstantial: $700million in the United

States and $1.4 billionworldwide.

• Liver transplants havemore than doubled in

the past ten years, withthe transplant waitlistgrowing in a similarfashion

Liver Transplants in US

0

500

1000

1500

2000

2500

3000

3500

Y e a r

1 9 8 9

1 9 9 0

1 9 9 1

1 9 9 2

1 9 9 3

1 9 9 4

1 9 9 5

1 9 9 6

1 9 9 7



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

The Bio Artificial Liver2

Documents

Transcript of The Bio Artificial Liver2