Chemistry: molecular biology and microbiology – Apparatus – Bioreactor
Reexamination Certificate
1999-11-08
2002-07-30
Naff, David M. (Department: 1651)
Chemistry: molecular biology and microbiology
Apparatus
Bioreactor
C424S093700, C424S423000, C435S070300, C435S071100, C435S071200, C435S177000, C435S180000, C435S182000, C435S382000, C435S395000, C435S401000, C435S402000, C435S403000
Reexamination Certificate
active
06426214
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
This invention relates to devices useful for maintaining cells in a discrete space while permitting passage of cell nutrients and waste products in and out of the device. The devices of this invention are suitable for implanting in an individual who would benefit from exposure to products produced by the cells which diffuse out of the device. The invention also relates to purification of cell products from the in vitro growth of cells.
BACKGROUND OF THE INVENTION
Transplanted cells provide the potential for treating various diseases because of their ability to detect and respond to physiologically important substances in the host. Cell implantation therapy is particularly desirable because the cells can provide substances to replace or supplement natural substances which, due to their insufficiency or absence cause disease. The release of therapeutic substances from the transplanted cells may also be properly regulated provided the transplanted cells have the necessary receptors and ability to respond to endogenous regulators.
Patients having disease as a result of the loss or deficiency of hormones, neurotransmitters, growth factors or other physiological substances are considered to be among those who would achieve significant benefits from transplant therapy. For example, implantation of pancreatic islet cells could provide insulin as needed to a diabetic. Adrenal chromaffin cells or PC12 cells implanted in the brain may provide dopamine to treat patients with Parkinson's disease. Several other hormones, growth factors and other substances have been identified and are discussed in PCT application WO 92/19195 (which is incorporated herein by reference), as potential therapeutics which could be administered to an individual using transplanted cells.
Because cells which are implanted may be foreign to the host it is necessary to prevent the host immune system from attacking and thereby causing the death of the implanted cells. In addition, cells which secrete such therapeutic substances may have been derived from transformed cells or have been infected with viruses and may therefore present a potential threat to the host in the form of increasing the likelihood of tumor formation. At least four methods are possible to attenuate the host immune response for the purposes of protecting the transplant cell viability. One method involves immunosuppression to prevent transplant rejection. Immunosuppression may be accomplished through a variety of methods, including using immunosuppressive drugs such as cyclosporins. In another method, immunomodulation, the antigenicity of the implanted cells is altered. This could involve attaching antibody fragments to the implanted cells. The third method involves modulating the host immune system to obtain tolerance to the implanted cells. In a fourth method, the cells to be implanted are contained in a device which effectively isolates the implanted cells from the immune system. The ability of contained cells to manufacture and secrete substances of therapeutic value has led to the development of implantable devices for maintaining cells within an individual in need of treatment.
A common feature of isolation devices is a colony of living cells surrounded by a permeable membrane. The transport of nutrients, waste and other products across the membrane is driven by pressure and/or diffusion gradients. This movement of substances across the membrane is limited by the permeability of the membrane and the distance through which these substances must travel. If insufficient transport of these substances is provided for either the number or volume of cells, cell viability and function may be diminished.
Dionne, has reported that a dense metabolically active cell mass must not exceed certain maximum dimensions if the viability of the entire cell mass is to be maintained. “Effect of Hypoxia on Insulin Secretion by Isolated Rat and Canine Islets of Langerhans”,
Diabetes
, Vol. 42, 12:20, (January 1993). When large spheroidal cell agglomerates receive nutrition from an external source, cells at the center of the cell mass may not receive sufficient nutrition and die.
Most encapsulation devices feature larger cell chambers than will allow diffusion of a sufficient flux of nutrients to support a viable full density cell mass. A full density cell mass is the maximum number of cells which can be maintained in a fixed volume if the entire space available for cells is occupied by the cells to achieve a minimum of cell-free space. This number is approximated by dividing the total available volume for containing cells by the volume of a single cell.
In the cylindrical devices referred to by Aebischer in WO 92/19595, the diameter is larger than the maximum diameter which would support a viable full density cell mass. Accordingly, the cells of the device described in Wo 92/19595 must be in a diluted suspension at a lesser cell density. The diluted cell suspension has lower overall nutrient requirements per unit volume and thus maintains essentially full viability with the available nutrient transported through the permeable membrane. The larger than optimum cell container allows for easier manufacture and subsequent manipulation than would be possible if this device were made small enough to support an optimum, full density cell pack. Aebischer also refers to the use of a gelling substance in the cell suspension to immobilize the cells into a uniform dispersion to prevent aggregation of cells into clumps. Such clumps could otherwise become necrotic due to localized depletion of nutrients within these clumps.
Several immunoisolating devices have been developed for implanting cells in a host. U.S. Pat. No. 5,158,881, refers to a device in which cells are stated to be encapsulated within a semipermeable, polymeric membrane by co-extruding an aqueous cell suspension of polymeric solution through a common port to form a tubular extrudate having a polymeric outer coating which encapsulates the cell suspension. In one embodiment described in the U.S. Pat. No. 5,158,881 patent, the cell suspension and polymeric solution are extruded through a common extrusion port having at least two concentric bores, such that the cell suspension is extruded through the inner bore and the polymeric solution is extruded through the outer bore. The polymeric solution is stated to coagulate to form an outer coating. In another embodiment of the 5,158,881 patent, the tubular extrudate is sealed at intervals to define separate cell compartments connected by polymeric links.
A different approach to supply nutrients to an isolation device is to route a flowing blood supply or other physiologic fluid through one or more conduits within the cell mass. This internalized source of nutrient mimics the structure of the circulatory system of almost all complex organisms,by providing nutrient to the center of a cell mass or tissue. These nutrients then diffuse radially outward. In one such internally fed device described in WO 91/02498, the transplanted cells are contained in-between two concentric tubes. One end of the inner tube is grafted to an artery while the other end is grafted to a vein. A common problem with internally fed devices is the potential for thrombosis formation or clotting of blood within the artificial conduits which occurs in relatively short periods of time. The formation of such obstructing masses cut off the flow of nutrients to internally fed devices.
In another device described by Goosen, U.S. Pat. Nos. 4,673,566, 4,689,293 and 4,806,355, the cells are contained in a semisolid matrix which is encapsulated in a biocompatible semipermeable electrically charged membrane. The membrane is stated to permit the passage of nutrients and factors while excluding viruses, antibodies and other detrimental agents present in the external environment.
W084/01287 refers to devices for encapsulating genetically programmed living organisms. One of the devices referred to comprises a nutrient material surrounded by an inner membrane wall which is surrounde
Butler Mark D.
Mish Stanley L.
Gore Enterprise Holdings Inc.
Morgan & Finnegan L.L.P.
Naff David M.
Sonnenfeld Kenneth H.
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