Reactor module with capillary membranes

Details Reactor module with capillary membranes Reactor module with capillary membranes

2003-06-20

2004-11-23

Redding, David A. (Department: 1744)

Chemistry: molecular biology and microbiology

Carrier-bound or immobilized enzyme or microbial cell;...

C435S176000, C435S289100, C435S297400

Reexamination Certificate

active

06821762

ABSTRACT:

This application is based on PCT/EP01/04271, filed Apr. 14, 2001, and claims priority to German Patent Application Number 10023505.0, filed May 13, 2000.
FIELD OF THE INVENTION
The present invention describes a reactor module able to function as a component of an artificial organ as well as a reactor containing this reactor module.
BACKGROUND OF THE INVENTION
Diseases, especially of internal organs, occur often in humans and are often life-threatening. Organ transplantations are often needed, and often fail due to the limited availability of natural replacement organs. External systems for supporting the damaged or failed organ functions often prove to be insufficient, since they significantly reduce the patient's quality of life, and are also unable to participate in the biochemical processes of the body. Looking at the example of the liver, during recent years, hybrid life support systems have been developed. With these systems, liver cells are cultivated in artificial modules, whereby different metabolism, elimination, and synthesis processes of the liver may be replaced in patients with acute liver failure. The existing systems are based on an extracorporal circuit to which the patient is connected. The reactor used consists of a housing in which the liver cells are located. The patient's blood or plasma is in direct contact with the cells. It is hereby known that the hepatocytes are immobilized in or on small spheres, for example alginate (Selden et al., Ann N Y Acad Sci (1999) 875, 353-363; Naka et al, Artificial Organs (1999) 23, 822-828, and Sakai et al., Cell Transplantation (1999) 8, 531-541). Also known is the simulation of the parenchymal structure of the liver with multi-dimensionally arranged capillary bundles (Custer and Mullon, Adv Exp Med Biol (1998) 454, 261-271; Busse and Gerlach, Ann N Y Acad Sci (1999) 875, 326-339, Flendrig et al., Int J Artif Organs (1999) 22, 701-708; Margulis et al., Resuscitation (1989) 18, 85-94; Ellis et al., Hepatology (1996) 24, 1446-1451; Gerlach et al., Transplantation (1994) 58, 984-988).
The described artificial organs, in which natural cells are immobilized on a sub-structure, for example polymer hollow fibers or capillaries, have the disadvantage that the cells often can only be immobilized with difficulties. The reason for this is, among other things, that the fluctuations in diameter that are associated with flow-through pulses in the polymer hollow fibers usually make immobilization more difficult and also could lead to denaturation effects in the cells.
SUMMARY OF INVENTION
The present invention is therefore based on the technical problem of making available a reactor module for use in artificial organs that overcomes said disadvantages.
The present invention solves the underlying technical problem by providing a reactor module, comprising at least one ceramic hollow fiber and at lest one biological cell, whereby at least one biological cell is immobilized on the surface of the at least one ceramic hollow fiber. In an especially preferred embodiment, the at least one biological cell is a liver cell, i.e. a hepatocyte. Naturally, other cells, for example renal cells, conjunctive tissue cells, fibroblasts, immune cells, intestinal cells, skin cells, pancreatic cells, spleen cells, or blood cells also can be used according to the invention.
In another preferred embodiment of the invention, many cells, in particular a cell layer, in particular a monolayer, are immobilized on the surface of the at least one ceramic hollow fiber.
The invention is among other reasons advantageous in that the inherent stiffness of the used ceramic hollow fibers enables its defined spatial positioning within a reactor space. In contrast to polymer hollow fibers or capillaries, this does not result in fluctuations in the diameter associated with flow-through pulses, so that the immobilized cells cannot be negatively affected. The ceramic hollow fibers can be adapted with respect to their geometry, their outer and inner diameter, and their porosity and pore size to any cell species, thus making the reactor module according to the invention suitable for many applications. In addition, the ceramic hollow fiber provides a surface that can be modified with many different processes of a physical and electrical or chemical nature. This makes it possible to achieve improved immobilization of the cells. Finally, ceramic hollow fibers have pores that enable a removal of metabolic products and, as the case may be, also the supply of nutrients.
According to the invention, it is provided that the cells to be immobilized are brought into contact with the ceramic hollow fibers, grow onto the surface of the hollow fibers, proliferate, and form a monolayer. The toxic metabolic products emitted by the immobilized cells are able to reach the inside of the hollow fibers via the defined pores contained in the hollow fibers, and can be removed from there, or can be supplied via the defined pores with nutrients from inside the hollow fibers.
In connection with the present invention, a biological cell means the structural and functional unit of the organisms, which is characterized by its growth, proliferation, and metabolic capability. Such cells can be eukaryotic cells, such as animal, plant, or yeast cells. In connection with the present invention, cells also mean prokaryotic cells, such as bacteria cells. In an especially advantageous embodiment, the cells are human or animal cells, in particular liver cells, fibroblasts, connective tissue cells, intestinal cells, blood cells, immune cells, skin cells, spleen cells, kidney cells, or pancreatic cells. Naturally, the cells may also be naturally occurring cells or cells manipulated with gene technology. The cells may be healthy or diseased, for example immortalized or carcinogenic. The cells may be differentiated or dedifferentiated, omnipotent, pluripotent, or unipotent.
In connection with the present invention, an immobilization means a spatial fixation of the at least one biological cell on or at the surface of the ceramic hollow fiber. The immobilization may be reversible or irreversible. It may be performed by simple cultivation and growing to the surface of the hollow fiber, but may also be brought about or accelerated with chemical or physical processes.
In connection with the present invention, a ceramic hollow fiber means a hollow fiber made from ceramic materials, i.e. a hollow fiber consisting of inorganic and primarily non-metallic compounds or elements that preferably contains more than 30% by volume of crystalline materials. According to the invention, both oxidic as well as non-oxidic ceramic materials can be used. Such non-oxidic materials, for example, may include silicium carbide SiC or silicium nitride Si
3
N
4
that may be produced, for example, by pyrolysis from polycarbosilanes or, respectively, from polysilazanes. Naturally, it is also possible to produce oxidic ceramic membranes with hollow fiber geometry, whereby, for example, a ceramic powder is mixed with a binder, and this pasty mass is extruded. This is followed by sintering, whereby a dense green fiber with a ceramic structure is produced, whose pore size may be varied depending on various parameters, such as amount and nature of the sintered binder, the sinter regime, the powder morphology, etc.
It may also be provided that ceramic materials with cellulose as a binder are used, whereby these are dissolved in a solvent, for example N-methyl-morpholine-N-oxide (NMMNO). This cellulose solution is mixed with ceramic powder and further processed in an actually known manner (DE 4426966 TITK of Feb. 1, 1996).
In another embodiment, the invention furthermore relates to a previously mentioned reactor module, whereby the capillary membranes have an inner diameter of 0.1 to 4 mm, preferably 0.5 to 1 mm. In another embodiment, the pore size of the hollow fiber used in the reactor module according to the invention is 0.05 to 1 &mgr;m, preferably 0.1 to 0.5 &mgr;m.
In another embodiment of the present invention, the surface of the hollow fibe

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