Chemistry: molecular biology and microbiology – Apparatus – Differentiated tissue perfusion or preservation apparatus
Reexamination Certificate
1999-07-15
2002-04-16
Prats, Francisco (Department: 1651)
Chemistry: molecular biology and microbiology
Apparatus
Differentiated tissue perfusion or preservation apparatus
C435S001100, C435S347000, C435S373000, C435S374000, C210S601000, C210S602000
Reexamination Certificate
active
06372482
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to a device and a method for performing a biological modification of a fluid, and more particularly to a device and method for assisting or replacing an organ which normally performs such a modification of the fluid.
A number of organs in the body, such as the liver, modify fluids such as blood. The liver is a particularly complex organ because it acts both as a filter and as an active metabolic unit. As a filter, the liver removes toxic substances from the blood. In addition, the liver performs many biochemical functions such as detoxifying ammonia into urea, bilirubin metabolism, glycogen storage, lipid synthesis, drug metabolism, albumin secretion and clotting factor secretion. Thus, the liver has many important functions within the body which render it essential. If the liver should fail, the body would be unable to continue operating.
There are many causes of liver failure, including 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 Assist Device (ELAD). 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 ELAD 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 ELAD 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 ELAD, 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 ELADs use biological materials as a starting point. For example, one of the most clinically tested ELADs 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 retain all the normal physiological characteristics of primary hepatocytes, particularly after industrial scale expansion (Sussman et. al.,
Artif Organs
, 18:390-6, 1994).
A second general approach for obtaining liver cells as a source for an ELAD, 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 differentiated 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 multicellular tissues. Although the exact mechanisms of this self-assembly are not known, in the cases that have been studied thus 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 proper microenvironment to allow excellent modeling of in vivo organ tissue structure and function.
In the liver, the unique juxtaposition of diverse cell populations and matrix components in harmony with the angio architecture results in a delicate bioecological system. It is therefore unlikely that standard cell cultures of hepatocytes will perform even the minimal liver functions. As mentioned previously, the cells of higher organisms such as mammals form themselves into high order multicellular tissues. An example of physical contact between a cell and a noncellular substrate (matrix) is the physical contact between an epithelial cell and its basal lamina. Examples of functional contact between one cell and another cell includes electrical or chemical communication between cells. For example, cardiomyocytes communicate with other cardiomyocytes via electrical impulses. In addition, many cells communicate with other cells via chemical messages, e.g., hormones, which either diffuse locally (paracrine signaling and autocrine signaling), or are transported by the vascular system to more remote locations (endocrine signaling). Examples of paracrine signaling between cells are the messages produced by various cells (known as enteroendocrine cells) of the digestive tract, e.g., pyloric D cells which secrete somatostatin which in turn inhibits the release of gastrin by nearby pyloric gastrin (G) cells.
This microarchitecture can be extremely important for the maintenance of a tissue explant of an organ in minimal media, e.g., without exogenous sources of serum or growth factors, because the liver tissue can be sustained in such minimal media by paracrine and autocrine factors resulting from specific cellular interactions within the micro-organ,
The pr
Prats Francisco
Yissum Research Development Company of the Hebrew University of
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