Chemistry: molecular biology and microbiology – Apparatus – Bioreactor
Reexamination Certificate
1998-09-02
2001-03-27
Redding, David A. (Department: 1744)
Chemistry: molecular biology and microbiology
Apparatus
Bioreactor
C435S260000, C435S286500, C435S297400, C210S620000, C210S629000, C210S321800, C210S321890
Reexamination Certificate
active
06207448
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the field of biomedicine, and more particularly, to cell culture devices and artificial organs and methods therefore. Although the invention is subject to a wide range of applications, it is especially suited for use in a bioreactor, and will be particularly described in that connection.
BACKGROUND OF THE INVENTION
Various bioreactors used as cell culture devices and artificial organs are known. Typically, the known bioreactors utilize hollow-fiber technology. An array of hollow-fiber reactors exists as filters, membrane oxygenators, plasma separators, and cell line producers.
Commonly, a bundle of small-diameter hollow, porous fibers are contained in a housing that is rigid and sealed. The bundle of fibers is stretched so that the individual fibers run in parallel to each other. The ends of the bundle are sealed at each end so that two compartments are formed: intrafiber that is within the lumens of the fibers and extrafiber that is outside the fibers but still within the housing.
A biological component is loaded into the extrafiber compartment, and a perfusate is typically pumped through the intrafiber compartment. A mass transfer from the intrafiber compartment across the fiber wall into the extrafiber compartment is dependent primarily on convection. During convection, also known as Starling flow, only a small fraction of the perfusate moves to the extrafiber compartment and then returns back to the intrafiber compartment. The driving force behind this phenomenon is a pressure gradient that develops during perfusion along a long axis of the bioreactor. In the known hollow-fiber bioreactors, convection can be increased through the increase in the rate of axial flow.
However, when the conventional hollow-fiber bioreactor is seeded with a biological component, such as, cells, and used as an extracorporeal artificial organ, the rate of axial flow cannot be increased significantly without causing damage to blood cells (hemolysis) and biological component due to excessive sheering pressure.
A need therefore exists for a bioreactor, and a method therefore, that increases the mass transport across the fiber wall under low flow and low pressure conditions.
SUMMARY OF THE INVENTION
The present invention, which tends to addresses this need, resides in a bioreactor. The bioreactor described herein provides advantages over known bioreactors in that it provides increased mass transport across the fiber wall.
According to the present invention, the foregoing advantage is principally provided by forcing a perfusate from an intrafiber compartment into an extrafiber compartment and then forcing the perfusate in the extrafiber compartment back into the intrafiber compartment. This can be accomplished by the use of an elastic housing and a variable flow device for varying the flow of a perfusate through the intrafiber compartment. Thus, a bi-directional mass transport across the fiber wall is increased.
In accordance with one aspect of the invention, variably restricting the discharge of the perfusate from the intrafiber compartment. This can be accomplished by use of a flow restrictor. The variation in discharge results in peaks and valleys (pulsations) in the intrafiber pressure. During restriction of the discharge, the perfusate passes through the pores of the fibers because of the increase in flow resistance, the volume of perfusate in the extrafiber compartment increases causing the perfusate in the extrafiber compartment to distend the elastic housing. During loosening of the restriction of discharge, the elastic housing contracts to reverse the flow of the perfusate through the pores and force it back into the intrafiber compartment.
In accordance with one aspect of the invention, variably increasing the flow of the discharge of the perfusate through the intrafiber compartment. This can be accomplished by use of a pump. During increase in flow of the discharge, the perfusate passes through the pores of the fibers because of the increase in flow resistance, the volume of perfusate in the extrafiber compartment increases causing the perfusate in the extrafiber compartment to distend the elastic housing. During decrease in flow of the perfusate, the elastic housing contracts to reverse the flow of the perfusate through the pores and force it back into the intrafiber compartment.
In accordance with still another aspect of the invention, varying the flow of the perfusate according to a pressure of the extrafiber compartment. This can be accomplished by a pressure monitor that measures the pressure in the extrafiber compartment and the variable flow device being responsive to the measured pressure. Thus, the amount of bi-directional mass transport across the fiber walls can be controlled by the amplitude of pulsations in perfusion pressure.
In accordance with another aspect of the invention, the elastic housing includes a wall with perforations extending therethrough and an elastic material tightly surrounding the wall. During restriction of the discharge, the membrane distends. During loosening of the restriction of discharge, the membrane contracts.
In accordance with still another aspect of the invention, the elastic housing includes a wall with at least one expansion port extending therethrough and at least one extrafiber space expander coupled to a one of the at least one expansion port. During restriction of the discharge, the at least one expansion port distends. During loosening of the restriction of discharge, the at least one expansion port expands.
In accordance with the method of this invention, providing an elastic housing and varying the flow of the perfusate through the intrafiber compartment.
The method more particularly comprises measuring a pressure in the extrafiber compartment and varying the flow of the perfusate through the intrafiber compartment in response to the measured pressure.
Other features and advantages of the present invention will be set forth in part in the description which follows and accompanying drawings, wherein the preferred embodiments of the invention are described and shown, and in part become apparent to those skilled in the art upon examination of the following detailed description taken in conjunction with the accompanying drawings, or may be learned by practice of the invention. The advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.
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PCT Search Report dated Jan. 6, 2000.
Demetriou Achilles A.
Rozga Jacek
Cedars-Sinai Medical Center
Redding David A.
Sidley & Austin
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