1. Vital Therapies
Hybrid Liver

2. Liver Physiology Most metabolically complex organ in the entire body
Largest internal organ
Responsible for over 500 discrete functions
Primary functions include:
Detoxification
Protein synthesis
Production of biochemicals
Other functions: liver produces albumin and is a major osmolar component of blood serum

3. Highly specialized tissue. Composed of two basic cell types:
Karat parenchymal cells (hepatic cells) – 80% of liver volume
Non-parenchymal cells – 6.5% of liver volume
Hepatic cells are responsible for liver function

4. Types of Disease Most liver diseases are chronic Common types include:
Hepatitis A, B, C, D, E
Alcohol damage
Fatty liver
Cirrhosis (final stage of chronic liver disease)
Cancer
Drug damage
Damage to hepatocytes
Two scenarios:
Mild and reversible
Sustained or more severe

5. Development of ALF
When a liver injury is sustained or more severe, regeneration may be incomplete or healing may occur with the development of negative consequences that can lead to acute liver failure

6. ALF Common signs and symptoms: Cerebral edema (can lead to a coma)
Coagulopathy (impairs blood clotting)
Renal failure
Hypoglycaemia (results from diminished glucose in the blood)
Testing for ALF
Testing positive for prolonged prothrombin time
Altered sensorium

7. The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. They are used to determine the clotting tendency of blood, in the measure of warfarin dosage, liver damage, and vitamin K status

8. Today’s Treatments
Currently, there are a limited number of treatments/therapies available to patients with ALF
Two main options:
Liver Dialysis (supportive treatment)
Primarily used as a bridge to transport
Cannot support a patient for an extended period of time
Transplantation
Ultimate goal
Limited supply
“According to the United Network for Organ Sharing, there were 6,000 liver transplants performed in 2006 however there were more than 16,000 patients on the waiting list. Consequently, each year only about one-third of the people who need a donor liver will receive one, and many patients die while waiting.”

9. Treatments Compared Liver Transplant Pros: Best way to treat ALF
High survival rates
Cons:
Limited supply
Reduced clotting factors
Immunosuppressants increase risk for infection
Possibility of host rejection
Bio-artificial Liver (enhanced liver dialysis)
Extends the patient’s life expectancy until transplant is made available
Better hepatocyte regeneration therapy
Temporary (bridge to transport)
Not long-term

10. Treatments in Progress
Liver Dialysis Unit (formerly BioLogic – DT)
HemoTherapies, uses noncellular charcoal
Molecular Absorbent Recycling System (MARS®)
Teraklin, uses human albumin
Extracorporeal Liver Assist Device (ELAD®)
Vitagen, uses immortalized human hepatocytes
HepatAssist 2000 system
Circe Biomedical, uses porcine hepatocytes
Bioartificial Liver Support System (BLSS®)
Excorp Medical, Inc., uses primary porcine hepatocytes
LIVERX2000 system
Algenix, Inc., uses primary porcine hepatocytes
Modular Extracorporeal Liver System (MELS®)
Charite Virchow Clinic-Berlin, uses human hepatocytes

11. ELAD versus the Market
The key characteristic of the ELAD device is its ability to stabilize liver function in patients with life-threatening, acute liver failure by processing toxins and synthesizing proteins that are key products of normal human liver function
The key to the ELAD system is the proprietary C3A human hepatocyte cell line. This is an immortal cell line that is grown in ELAD cartridges. The C3A cell line performs biochemical functions characteristic of human hepatocytes and can synthesize serum proteins. These cells synthesize a wide variety of proteins, such as albumin, an indicator of hepatocyte function and a convenient marker of cell viability and function
In vitro assays demonstrated that the C3A cell line performs biochemical functions characteristic of human hepatocytes, while in vivo experiments evaluated the safety of the entire ELAD System, as well as function of the C3A cells
C3A cell line vs. Porcine cell line
C3A cell line is a sub clone of regular liver cells (hepatocytes)
Porcine cells are xenogeneic and in order for them to be used in a bio-artificial liver device they need to be incubated in complement inactive serum/plasma

12. C3A Cell Line
The fibers, made of a semi-permeable membrane, permit passage, from the C3A cells to the patient's ultrafiltrate, of macromolecules and other cellular products such as albumin, Factor V, transferrin, antithrombin III, C3 complement, Î¬-1-antitrypsin, Î¬-fetoprotein, and others. The fibers also simultaneously permit passage of toxins and such nutrients as glucose and oxygen from the ultrafiltrate to the C3A cells. After circulation through the cartridges, the ultrafiltrate then flows through filters prior to recombining with the cellular components of the patient's blood and returning to the patient. This circulation is maintained continuously utilizing the same set of cartridges for the duration of ELAD therapy

14. Expected Improvements Post-Op
Various trials in patients with different stages/causes of acute hepatic failure
US/UK Pilot Studies in Fulminant Hepatic Failure
Improved overall survival regardless of transplantation status
Significant improvement in bridge-to-transplant/recovery with intact native liver
China Trial: Acute Liver Failure, 70% infected with hepatitis B
Significant improvement in transplant-free survival
Median survival for control: 37 days
No median transplant-free survival among ELAD
All survived beyond 3 year follow-up
Phase IIB Acute Alcoholic Hepatitis Trial
Control Median survival: 65 days
ELAD Median survival: 100+ days
Improved mental status

15. Expected Complications Post-Op
No current short-term safety problems
Clinical trial evaluating potential acute medical complications post-therapy
Hemodynamic instability, complement activation, and vital organ deterioration
Porcine-hepatocyte BAL: noted bleeding complications, hemodynamic instability
Complement activation
Previous issues with system clotting
More aggressive heparin treatment during therapy
1 report of hypotension during therapy
Corrected/reversed
1 report of tachypnea, tachycardia, and pyrexia during therapy
Stopped post-hemoperfusion
Minor complications solved after modifying ELAD treatment
Switch from whole blood to ultra-filtered blood
Highly cirrhotic with acute-on-chronic hepatitis diagnosis study
No suggested benefit for those with extensive cirrhosis

16. ELAD Limitations Hepatocyte acquisition
Best delivery, design, and components?

17. Future Developments Implantable devices
Vianney et al. study with allogeneic rat hepatocytes
Hollow fiber peritoneal implant
Longer-term solutions

18. Works Cited