Chemistry: molecular biology and microbiology – Apparatus – Differentiated tissue perfusion or preservation apparatus
Reexamination Certificate
1999-10-25
2002-10-29
Prats, Francisco (Department: 1651)
Chemistry: molecular biology and microbiology
Apparatus
Differentiated tissue perfusion or preservation apparatus
C435S001100, C435S347000, C435S373000, C435S374000, C210S601000, C210S602000, C210S632000, C210S646000
Reexamination Certificate
active
06472200
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to a device and method for performing a biological modification of a fluid and, more particularly, to an artificial installation, which supplements, augments or replaces organ function. Specifically, the artificial installation may contain liver micro-organ cultures. Further specifically, the artificial installation may contain a viable kidney micro-organ component. Further specifically, the artificial installation may contain a dialysis component as commonly used in hemodialysis. The kidney micro-organ culture and dialysis unit together perform physiologically as a kidney substitute.
Further, the present invention relates to a device and method for supplementing, augmenting or replacing both hepatic and renal function via use of a single artificial installation containing both liver and kidney micro-organ cultures.
Further, the present invention relates to a device and method for supplementing, augmenting or replacing both hepatic and renal function via use of a single artificial installation containing both liver and kidney micro-organ cultures in a ratio of approximately 6:1.
Further, the present invention relates to an artificial installation containing a combined liver and kidney micro-organ culture additionally containing a dialysis component.
Further, the present invention relates to a method of preparing viable tissue which can be stored in an artificial installation for supplementing, augmenting or replacing organ function without culturing the tissue prior to storage and for transplantation at a later stage into a host.
A number of organs in the body, such as the liver and kidney, modify body fluids such as blood. The kidney is a multifunctional organ, excreting nitrogenous waste in the form of urea, excreting excess inorganic salts, and actively secreting erythropoietin and other substances, such as, but not limited to rennin and tissue plasminogen activator. The liver removes toxic substances from the blood and performs many biochemical functions such as, but not limited to, detoxifying ammonia into urea, bilirubin metabolism, glycogen storage, lipid synthesis, drug metabolism, albumin secretion and clotting factor secretion. Hepatic and renal functions are closely related, with many metabolic byproducts and toxins passing from the liver, via the circulatory system, to the kidney for excretion into the urine. Thus, the liver and kidney are essential organs, and the synergy between these two organs is crucial. Patients with liver or kidney failure are at high risk for mortality if immediate intervention is not effected.
There are many causes of liver failure, including, for example, exposure to toxic substances, hepatitis, and genetic defects (Kasai, et al.,
Artif. Organs,
18:348-54, 1994). Currently, 70% of patients with acute liver failure die because of no available treatment (Kasai, et al.,
Artif. Organs,
18:348-54, 1994). Furthermore, 10-30% of patients die while awaiting donor liver organs (LePage, et al.,
Am. J. Crit. Care,
3:224-7, 1994; Sussman, et al.
Artif. Organs,
18:390-6, 1994; and Uchino & Matsushita,
Asaio J.,
40:74-7, 1994).
A bedside life-support device that could temporarily perform liver function during liver failure is called an Extracorporeal Liver Device—ELD. The development and commercialization of such a device would clearly be of enormous benefit for a number of reasons (Fox et al,
Am. J. Gastroenterol.,
88:1876-81, 1993). An ELD would benefit the roughly 2,000 patients with fulminant liver failure (FH) in the U.S. each year (Hoofnagle, et al.,
Hepatology,
21:240-52, 1995). It could also be used as a bridge to liver transplantation for patients awaiting donor organs.
An ELD that would function for several weeks could in addition allow for recovery to normal functioning of the patient's own liver. Since it is unlikely that every hepatocyte is destroyed in a damaged liver, adequate liver support for two to three weeks could allow surviving hepatocytes to repopulate the damaged liver. Fewer than a dozen hepatocytes are required to repopulate the liver in an animal model of lethal hepatic disease Sandgren et al.,
Cell,
66:245-56, 1991). A patient with 90-95% liver necrosis should be able to recover sufficient function to survive independently after only a few days of support (Sussman et al.
Artif. Organs,
18:390-6, 1994).
In an attempt to provide such an ELD, several purely mechanical, non-biological blood-treatment devices have been developed. In the most basic form, the purpose of these devices is to selectively remove toxins and add nutrients across a membrane with a relatively small pore size. One of the most advanced of these non-biological devices has been developed by Hemocleanse™ and has recently received FDA approval. In a randomized, controlled clinical trial using the Hemocleanse™ apparatus, removal of metabolites was limited and there was no significant effect on blood ammonia levels (Hughes et al.,
Int. J. Artif. Org.,
17:657-662, 1994). Clearly, liver function is extremely complex and is unlikely to be replaced by a solely mechanical or a chemical device at this time.
Other currently available ELDs use biological materials as a starting point. For example, one of the most clinically tested device, called ELAD (for extracorporeal liver assist device) uses a transformed immortalized human cell line as a source for hepatocyte-like cells (Sussman, et al.
Artif. Organs,
18:390-6, 1994). Initial trials of this device were performed under “Emergency Use of Unapproved Medical Devices”, or “Investigational Device Exemption”. Efficacy was not determined, but no serious adverse side effects were observed except for clotting that was managed by drug treatment. While the use of an immortalized human cell line is convenient because it provides an expendable source of cells, there are two major reasons why it may not be ideal. Firstly, there are obvious safety and regulatory concerns about using immortalized cell lines in clinical practice. Secondly, immortalized cells would not be expected to rein all the normal physiological characteristics of primary hepatocytes, particularly after industrial scale expansion (Sussman et al.,
Artif Organs,
18:90-6, 1994).
A second general approach for obtaining liver cells as a source for an ELD, is the isolation of liver cells or tissue from intact livers. In previous attempts, cells from livers have usually been disassociated using enzymes such as collagenase, which disrupts the normal micro architecture of the liver. Some attempts have been used to use liver pieces, but the shape of these pieces have not been designed for proper surface area to volume ratios necessary for optimal tissue maintenance (Lie et al.,
Res Exp Med
(
Berl
) 185:483-94, 1985).
One current limitation is the ability of current methods of culturing mammalian liver cells to provide conditions which allow cells to assemble into tissues which simulate the spatial three-dimensional form of actual tissues in the intact organism. Conventional tissue culture processes limit, for similar reasons, the capacity for cultured tissues to express a highly functionally specialized or different state?? considered crucial for mammalian cell differentiation and secretion of specialized biologically active molecules of research and pharmaceutical interest. Unlike microorganisms, the cells of higher organisms such as mammals form themselves into high order multi-cellular tissues. Although the exact mechanisms of this self-assembly are not known, in the cases that have been stated so far, development of cells into tissues has been found to be dependent on orientation of the cells with respect to each other or another anchorage substrate and/or the presence or absence of certain substances such as hormones. In summary, no conventional culture process used in the organ assist devices to date is capable of simultaneously achieving proper functioning of the cells in vitro while at the same time maintaining critical cell/cell/substrate interactions and
G.E. Ehrlich Ltd.
Prats Francisco
Yissum Research Development Company of the Hebrew University of
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