Chemistry: molecular biology and microbiology – Apparatus – Including measuring or testing
Reexamination Certificate
2001-11-21
2002-06-25
Redding, David A. (Department: 1744)
Chemistry: molecular biology and microbiology
Apparatus
Including measuring or testing
C435S297100, C435S297400
Reexamination Certificate
active
06410307
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a membrane module for testing active substances on cells as well as its use.
2. Discussion of Related Art
In the area of cancer research or cancer therapy, for example, it is often necessary by rapid tests to investigate the effect of cytostatics on cancer or tumor cells of a cancer patient to evaluate the possible outcome of chemotherapy. It is therefore necessary to perform an active substance screening to determine the effect of a plurality of active substances in different dosages over time, i.e., with different pharmacokinetics on the cancer cells, and thus, to predict the response of patients to a given chemotherapy with considerable reliability.
Such patient-specific testing of known active substances differs from the active substance tests that are performed in so-called animal models in which the human tumor cells are encapsulated in hollow fiber membrane pieces and then implanted in a recipient animal as proposed, for example, in WO 94/25074 and U.S. Pat. No. 5,676,924. In this method, in contrast to direct implantation of such cells in a receiving animal, encapsulation prevents an immune response of the recipient animal and different tumor cells can be investigated simultaneously per each treatment of the receiving animal with a cytostatic. However, this procedure has limits owing to its naturally poor automation probability and frequently poor transmissibility of the test results to human beings.
Therefore, tests are being conducted to determine patient-specific and tumor-specific responses by means of in-vitro tests. In such tests, the effect of a test substance, for example, an active substance, on the cell cultures is investigated in using cell cultures of the tumor to be investigated. This is known as cell culture assays. In such investigations, standard culture vessels and methods are usually employed which, however, do not allow three-dimensional growth of the cells, i.e., real tumors cannot be simulated. The efficiency, for example, of cytostatics is influenced considerably by the spatial arrangement of the cells and their accessibility. In addition, an adjustment of pharmacokinetics, i.e., the influence of a certain concentration-time curve of the active substance or a combined therapy in which different active substances are to be investigated in succession over time, is not possible, or only with very limited possibility, with the known in-vitro methods.
In German Application 199 10 540.5, filed on the same day, a method for in-vitro testing of active substances using a membrane module is proposed by which the disadvantages of the known in-vitro tests are at least reduced. For example, tumor cells are placed in the cell culture space of the membrane module and membrane systems are used in a cell culture space for supplying a nutrient medium and for oxygenation, supplying cells with oxygen. At least one active substance to be investigated is added to the cell culture space using a specific concentration-time curve, and the cell vitality of the cells located in the cell culture space is monitored simultaneously.
Various membrane modules are known for growing cells. Thus, in DE-A-36 33 891, a device for cultivating animal cells is described by which cells are grown and valuable substances, i.e., products, are to be obtained from the cells. This device contains essentially parallel capillary membranes in a mat-shaped arrangement, whose ends are embedded in cast material and through which the cells are supplied with nutrient materials. In this device, other membranes can be used for improved oxygen supply to the cells. In the finished membrane module, the capillary membranes are essentially parallel to one another and to the housing axis.
U.S. Pat. No. 5,516,691 discloses a module for growing and using metabolic performance to obtain microorganisms, especially cells or bacteria. The module consists of an external housing and at least three independent membrane systems, wherein at least two membrane systems in the form of hollow fiber membranes form a thickly-packed network of layers overlying one another in a crossed pattern. The hollow fiber membranes are embedded at at least one end in cast material and communicate with at least one inlet or an inlet and an outlet. There are microorganisms, especially cells, in the external space between the hollow fiber membranes. The transport of nutrient materials, gases, and metabolic products to or from the cells located in the interior of the module takes place by the various hollow fiber membrane systems.
The membrane module according to U.S. Pat. No. 5,516,691 is preferably used for growing liver cells and is used in an extracorporal liver support system. The important thing here is to use the metabolic performance of the cells. This requires growing as large a number of cells as possible in a membrane module and thus preparing a large module volume for taking up the cells. In U.S. Pat. No. 5,516,691, a test module with the external dimensions 12×12 cm is described, in which 100 layers of hollow fiber membranes are located one on top of the other, and an additional 50 hollow fiber membrane layers are placed vertically from top to bottom to form a thickly packed network with the other layers. The membrane modules described have a complex structure, and are not suitable for active substance screening in which a plurality of membrane modules must be used.
Neither the module design in DE-A-36 33 891 nor the one in U.S. Pat. No. 5,516,691 can be used for testing active substances on cells, especially for active substance screening.
SUMMARY OF THE INVENTION
It is therefore the goal of the present invention to provide a membrane module suitable for testing active substances on cells and especially for screening such active substances. In particular, the present invention tests a plurality of active substances which are also investigated with different concentration/time curves.
This goal is achieved by a membrane module for testing active substances on cells consisting of a housing with an interior chamber bounded by a lid, a bottom, and a side wall and there is a system of first capillary membranes and a system of second capillary membranes, and possibly at least an additional system of capillary membranes inside the interior chamber, wherein each capillary membrane has a first and a second end as well as a lumen fillable with a fluid, and the capillary membranes are arranged in the interior chamber in a layer parallel to the bottom where cell culture space is formed around the capillary membranes in the interior of the housing in the extracapillary space, with the capillary membranes penetrate by at least one of their ends through the side wall of the interior chamber so that, separated by systems, at least one end is embedded in a casting material so the interior chamber is sealed fluid-tight from the outside, and wherein the lumens of the capillary membranes of each system are in a fluid connection with an inlet device and/or an outlet device, with the membrane module comprising the interior having a volume between 0.1 and 5 cm
3
.
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U.S. application No. 09/936,266, Co-pending.
H.J. Schmoll et al., “Compendium of Internal Oncology”, Spring 1996.
R. Pieters et al., “In Vitro Drug Sensitivity of Cells from Children with Leukemia Using the MTT Assay with Improved Culture Conditions”, Blood, vol. 76, No. 11, pp. 2327-2336.
Joseph J. Casciari et al., “Growth and Chemothera
Glockner Herma
Hauck Friedrich
Lemke Horst-Dieter
Wollbeck Rudi
Zimmerer Christoph
Acordis Industrial Fibers GmbH
Redding David A.
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