ELAD® ConceptELAD is being developed to provide liver support continuously for up to thirty days to a patient with compromised liver function, potentially allowing time for the patient's native liver to regenerate to a healthy state, or to stabilize the patient until a suitable donor organ can be found for transplantation.
ELAD Design and OperationThe key to the ELAD system is the proprietary C3A human hepatocyte cell line, licensed from the Wistar Institute in Philadelphia and further developed by Baylor College of Medicine. This is an immortal cell line that is grown in ELAD cartridges, then stored and shipped worldwide from VTI's San Diego production facility. The cartridges are then incorporated into an extracorporeal blood pumping system at the patient's bedside. The cells have been shown to perform most of the metabolic functions of normal liver cells in laboratory experiments.
The ELAD® System, continuously separates plasma from cellular components by using an "ultrafiltrate" generator. While the cellular components are returned to the patient via the venous access, the ultrafiltrate is circulated through a set of ELAD cartridges containing the C3A cells and hollow fibers. 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.
C3A cell line biologic activity
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. The synthesis of serum proteins is a hallmark of the liver-specific phenotype and of C3A cells. 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. Indeed, one of the key parameters directing the selection of the C3A cell line was its ability to produce high levels of albumin. Albumin and transferrin concentrations in the tissue culture medium passing through the membrane of the cartridges are assayed frequently.
Pre-IND feasibility and safety study
The study was completed with three healthy sheep. The clinically configured ELAD System was connected to the vascular system of each animal. The ELAD System was then operated for an initial period of two hours with only inactive (no cells) cartridges. Then the inactive cartridges were replaced with active, C3A cell-filled cartridges, and the ELAD System operated for an additional four hours. The animals remained hemodynamically stable throughout the course of the study, whether inactive (cell-free) or active ELAD cartridges were connected to the ELAD System. At completion of the study, the animals appeared healthy, fully active, and otherwise completely normal. Samples from the animal's arterial blood line were removed at predetermined intervals throughout the study, as well as from the ELAD System ultrafiltrate recirculation loop. The concentrations of human albumin and transferrin in the sheep blood began to increase when active cartridges were connected, showing that human liver proteins from the ELAD System were being delivered to the animal.
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