Chemistry: molecular biology and microbiology – Apparatus – Including measuring or testing
Reexamination Certificate
1999-05-11
2002-04-23
Beisner, William H. (Department: 1744)
Chemistry: molecular biology and microbiology
Apparatus
Including measuring or testing
C422S082020, C324S450000, C204S403060
Reexamination Certificate
active
06376233
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a device for conducting research on cell specimens and similar samples, which has a microtiter plate or a similar receptacle device with a plurality of individual containers for cell specimens, and having a measuring device for recording changes in the individual specimens, wherein at least one sensor is provided with each receptacle container.
Various medical-biochemical test procedures can be conducted with the aid of so-called microtiter plates. Microtiter plates have a plurality of receptacle tubes arranged alongside one another, into which the cell specimens, for example a suspension of metastatic cells, are introduced. Subsequently, an indicator solution, for example a fluorescent dye, is added. To study whether certain substances can influence the metastatic cells, especially kill them, various cytotoxic substances are added. The introduction of cell specimens, indicator solution and medications takes place in a sampling technique conducted by means of an automatic device. Cell changes can be detected in a fluoroscopic procedure or with the aid of a spectrometer.
Besides chemotherapy testing, microtiter plates can also be studied for research on cancer cells as to their metastatic tendency. In this case, a test substrate consisting of a layer of cells or embryonal HM-cell cultures or a collagen matrix, is positioned in the containers upon which the metastasic cells are then placed. According to the degree of change, a measure for the invasion index or the metastatic index can be derived. This procedure, in which biological layers of another substance are more or less influenced, is also called biocorrosion. Studies, for example of plastics for biocompatibility, are also possible therewith. That is, it is studied whether or not cells penetrate into the plastic under investigation.
With these various studies, a fluoroscopy process is usually provided for the evaluation, with measurement assessment by a microplate reader or by means of a spectrometer. Consequently, on the one hand, a not inconsiderable equipment expenditure is necessary for the functional suitability of the overall device, and on the other hand, the measurement assessments do not in all cases provide information to the extent desired, for example even about the running reaction process. It is furthermore disadvantageous that with commercially available microtiter plates, comparatively large sample amounts are necessary. Appropriate sample amounts, however, are not always available, for example of biopsy material.
A device is known from German published patent application DE 39 15 920 A, which has a micromechanical structure with a plurality of depressions situated in a block of semiconductor material as sample containers The sample containers are installed in the block through chemical etching. These receptacles are nonetheless suited only for very small sample amounts. Moreover, special sampling facilities are necessary.
A microelectronic device is known from published International (PCT) application WO-A-9601836, which likewise has a plurality of individual containers as sample containers, which as microcontainers are suited exclusively for accommodating the smallest sample amounts. The electrodes provided in the microcontainers can basically only be used for conductivity measurements. This device is equipped for DNA examination, and among others, no physiological measurements on living cells can be conducted with it.
SUMMARY OF THE INVENTION
An object of the present invention is to create a device of the type mentioned at the beginning which makes possible a plurality of different examinations at a reduced overall cost, including continuous monitoring of a reaction process, and which is also simpler to handle.
For accomplishing this objective, it is proposed in accordance with the invention that the measurement facility has semiconductor sensors with at least one interdigital condenser situated on one or more substrate plates, and that a honeycomb-like tube structure consisting of a bottomless upper part of a commercially available microtiter plate is mounted on the semiconductor substrate plate and tightly connected with the substrate plate.
By using a microtiter plate “upper part,” the facilities previously used in connection with microtiter plates, especially the automatic sampling machine, can continue to be used. Moreover, correspondingly more test fluid can be accommodated according to need. Semiconductor sensors offer a plurality of different measuring possibilities so that appropriate sensors can be provided according to the application and measuring object. Such sensors can also be realized in the smallest designs, so that it is correspondingly possible to work with even the smallest sample amounts. Thus, studies on cells, for example, are also still possible even if these can only be taken from a patient in a very small amount, for example as biopsy material. It is also advantageous that the receptacle device with the individual containers and the practically integral measuring facility form a complete functional unit and also a compact construction unit, which is also simpler to handle. The sensors are hereby respectively part of the measuring chamber, so that these no longer need to be brought into connection with a separate measurement facility for evaluation. Also advantageous is that a measurement during a running reaction process, and moreover measurement simultaneously with all individual containers, is possible.
With the aid of interdigital condensers as sensors, measurements of changes in shape of the cells can in particular be conducted, and furthermore, impedance and capacitance changes of the cell membrane can be measured. Antibodies which accumulate on cells can also be detected, since they change the dielectric constants in the area of the interdigital structure. Preferably the electrodes of the interdigital condensers intermesh in pairs with one another.
Expediently, several, preferably different sized, interdigital condensers are provided. These have a distinct sensitivity, so that accordingly a larger measuring area is covered, and a higher resolution in the individual measurement areas is made possible.
Preferably, it is provided that the sensors, at least for some receptacles, are situated on a common wafer-like semiconductor substrate plate. On such a semiconductor substrate plate, a plurality of sensors can be accommodated by known manufacturing technology in a narrow space, so that a precondition for an especially compact design of the device is thereby present. The semiconductor substrate plate with the individual sensors hereby practically forms a measurement structure allocated to the receptacles.
A preferred embodiment provides that the device have at least one semiconductor substrate plate with a plurality of small bowl-shaped receiving depressions situated within it as containers, and that the sensors allocated to the depressions, overall forming a measurement structure, be a component of the substrate plate.
It is also possible with this device, in particular, to work with the smallest sample amounts. Moreover, such a device can be manufactured completely with semiconductor technology. Furthermore, an extremely compact construction is realizable therewith.
According to a refinement of the invention, there can also be provided herein, in the area of an individual container or a receptacle depression, several, preferably different, sensors, in particular as a sensor array, so that different parameters can be recorded simultaneously during the examination. Such a sensor array can be manufactured especially economically as an integrated circuit, and makes possible the measurement of different chemical or biological substances on the most constricted space.
Depending on the object of the investigation, there also exists the possibility, however, of arranging different sensors with the individual receptacles, wherein one or more receptacles have the same sensors in their respective area and different types of sensors
Sieben Ulrich
Wolf Bernhard
Akin Gump Strauss Hauer & Feld L.L.P.
Beisner William H.
Micronas Intermetall GmbH
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