Chemistry: molecular biology and microbiology – Apparatus – Bioreactor
Reexamination Certificate
2000-09-05
2003-10-14
Beisner, William H. (Department: 1744)
Chemistry: molecular biology and microbiology
Apparatus
Bioreactor
C435S286500, C435S295100, C435S302100, C435S001200, C435S403000
Reexamination Certificate
active
06632658
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a method for holding a substance in suspension and to a bioreactor for holding a substance in suspension.
The artificial production of tissue material, designated in English as “tissue engineering”, is increasingly gaining in importance in order to produce biological substitutes for damaged tissue or damaged organs. Artificial tissue material can be produced in that cell cultures in vitro are deposited at or in a tissue carrier, also termed a matrix. The tissue carrier consists for example of a synthetic polymer or of a biological material such as collagen. A tissue carrier of this kind is also designated as a “scaffold”. The cells are sown out onto the tissue carrier and begin to multiply if the environmental parameters are physiologically favorable. The tissue carrier can be designed in such a manner that the latter disintegrates with time, so that after a certain time only the tissue part which is formed from the cells is present. The tissue carrier and/or the tissue carrier which is formed on it is designated as “substance” in the following. The conditions which are required for the cell growth are produced in a bioreactor, within which the required oxygen and a nutrient medium are supplied to the substance and within which the substance remains from several days to weeks until the desired size has been reached. The geometrical shape which the artificially produced tissue material assumes during growth is substantially influenced through the measures by means of which the substance is held in the bioreactor.
Thus in the following the term “substance” will be understood to mean both the tissue carrier per se and the tissue carrier with cells deposited on it, or, if the tissue carrier is designed to be decomposable, the artificially produced cell culture or the artificially produced tissue part respectively.
SUMMARY OF THE INVENTION
The object of the present invention is to propose a method for holding a substance in a bioreactor which enables an advantageous growth. It is furthermore an object of the present invention to propose a biodreactor which has advantageous properties with respect to the growth of cell cultures.
The object is satisfied in particular by a method for the holding in suspension of a substance in a bioreactor in that the substance is acted upon with a fluid and the flow of the fluid acts counter to gravity or buoyancy in such a manner that the substance is held in suspension.
The method in accordance with the invention has the advantage that the substance is held without contact in the bioreactor in that the fluid, usually a liquid, has a flow which is developed in such a manner that the substance is held without contact by the flow, which acts counter to gravitation. In this the substance is usually also kept continually in motion so that its position changes continually. The method in accordance with the invention has the advantage that the cells grow uniformly at or in the substance respectively and the growth of the substance is favored. Disadvantageous in the previously known methods for the artificial production of tissue is that it had been possible to produce only flat, substantially two-dimensional structures.
In a particularly advantageously designed method the fluid has an increasingly slower flow speed in the direction opposite to gravitation. This flow behavior is for example produced in that the flowing fluid is led from below into a hollow body having the shape of a truncated cone which widens upwardly. The cross-section of the hollow body, which widens upwardly, causes the flow speed in the hollow body to be reduced with increasing height. The substance is continually held in suspension in the inner space of the hollow body, with the side walls of the hollow body limiting a lateral movement of the substance, so that the substance is always located in the upwardly flowing liquid. With increasing cellular growth the weight of the substance increases, so that the substance moves slightly downwards in the inner space of the hollow body and finds again a new equilibrium position there. The substance thus automatically seeks the respective equilibrium position. It can however prove advantageous to monitor the position of the substance with a sensor and to influence the speed of the upwardly flowing fluid by means of the measured signal. Thus the speed of the fluid can for example be regulated in such a manner that the substance is continually held in suspension in a predetermined position.
In an advantageous method, in addition to the upward flow within the bioreactor a downward flow is also produced, with a gaseous fluid such as air or oxygen being supplied to the downwardly flowing fluid, usually a liquid. The speed of the downwardly flowing fluid is advantageously chosen such that the gaseous fluid which is input is slowed down or no longer rises at all, so that the gaseous fluid remains relatively long in the flowing fluid and can be taken up or absorbed respectively by the latter.
The object in accordance with the invention is further satisfied in particular by a bioreactor comprising a container for a substance which is to be acted upon with a fluid, with the container comprising a first flow chamber to which a flowing fluid can be supplied and with the first flow chamber being designed in such a manner that the fluid which flows upwardly therein has a lower speed with increasing height. In a particularly advantageous design the flow chamber has a cross-section which widens upwardly.
In a further advantageous design a flow guiding means is arranged within the bioreactor and forms a flow chamber which widens upwardly. In addition this flow guiding means preferably forms a further, second flow chamber within the bioreactor, with the second flow chamber diverging downwardly and with a gaseous fluid being introduceable into the second flow chamber.
In a further, advantageous embodiment a drivable pump wheel is arranged within the bioreactor, with the help of which the flow of the fluid within the bioreactor can be produced. The pump wheel is advantageously magnetically coupled to a drive which is arranged outside the housing of the bioreactor. The bioreactor housing and the pump wheel are advantageously conceived as a disposable or once-only product respectively so that the latter can be disposed of after a single use. These parts can be manufactured economically. For example the pump wheel comprises a vaned wheel of plastic into which is cast a permanent magnet. All expensive components such as the drive apparatus are arranged outside the bioreactor. The design of the bioreactor as a disposable product has the advantage that no laborious cleaning process is required and that a contamination of the artificially produced tissue material is largely excluded. The avoidance of contamination is of decisive importance since the substance remains for example 4 to 8 weeks in the bioreactor, until sufficient tissue material has been formed. Since the bioreactor has no immune reaction system, the smallest contaminations such as bacteria, fungi or viruses can already result in the produced artificial tissue dying off or being contaminated. Through the design of the bioreactor as an expendable product, artificial tissue material can be economically and reliably produced.
The invention will be explained in the following with reference to a plurality of exemplary embodiments.
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Maruyama, Toshiro, et al., “Liquid fluidization in conical vessels”,The Chemical Engineering Journal, 46, 15-21 (1991).
Beisner William H.
Levitronix LLC
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