Chemistry: molecular biology and microbiology – Apparatus – Including measuring or testing
Reexamination Certificate
2000-06-01
2001-08-21
Redding, David A. (Department: 1744)
Chemistry: molecular biology and microbiology
Apparatus
Including measuring or testing
C435S288700, C435S305100, C435S305400, C435S808000, C204S403060, C324S446000, C324S692000, C356S246000
Reexamination Certificate
active
06277629
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to an apparatus for measuring physiological parameters, the apparatus having a test chamber connected to at least one inlet opening and at least one outlet opening and bordered by walls, wherein at least one wall of the test chamber is constructed as a semiconductor chip, which has an active side having planar sensors facing the test chamber, on which biological cells located in a nutrient medium can be adherently deposited, in order to measure physiological parameters directly on the cells, and wherein at least one additional sensor is allocated to a wall lying opposite the semiconductor chip in order to measure global physiological parameters.
Such an apparatus is already known from German published patent application DE 44 17 079 A1. It has a test chamber in which animal or plant biological cells can be kept vital in a nutrient medium over a long time period. There, the nutrient medium can be renewed through the inlet and outlet openings of the test chamber, for example using a fluid treatment. In the test chamber the cells are deposited adherently on the active side of the semiconductor chip having the planar sensors. For this purpose, the semiconductor chip can have, for example, on its active side a surface structuring, whose roughness corresponds approximately to the coarseness of the cells, so that they accept the semiconductor chip as neighbors and become better accumulated thereon.
The planar sensors allow an almost continuously flat chip surface, so that the cells can become deposited directly onto the planar sensors. It is thereby possible with the planar sensors to measure directly on the cells physical, electrical, or electrochemical cell parameters, for example ion concentrations, gas contents, cell potentials, or cell temperatures. Thus, the reaction of the cells can be tested in a simple manner for changed physical or chemical conditions, for example toxic substances, drugs, environmental toxins and the like contained in the nutrient medium. The cells thereby act as biological pre-amplifiers, which increase the measuring sensitivity of the planar sensors. Using the additional sensors allocated to the wall lying opposite the semiconductor chip, it is also possible to detect global physiological parameters in the nutrient medium. In this manner, additional information can be obtained about the cells.
Although the previously known apparatus has proven to be useful in practice, it nevertheless has disadvantages. It is still constructed in a comparatively complicated manner. The apparatus is therefore relatively expensive, which limits its usage possibilities.
SUMMARY OF THE INVENTION
Therefore, an object of the invention is to create an apparatus of the type mentioned at the outset, which is constructed in a simple and cost-effective manner.
This object is achieved in that the wall of the test chamber lying opposite the semiconductor chip is formed by a second semiconductor chip, which has an active side facing toward the test chamber and having at least the additional sensor, that a seal surrounding the test chamber is arranged as a distance spacer between the semiconductor chips, that the semiconductor chips are held in the sealing position using a mounting that grasps over them on the outside, and that the semiconductor chips each have electric connection contacts outside of the test chamber, which contact with the opposing contacts of the mounting.
Thus, all sensors of the apparatus can be integrated in the semiconductor chips, wherein the semiconductor chips form, at the same time, the boundary walls of the test chamber. In an advantageous manner, the seal arranged between the semiconductor chips also functions at the same time as a distance spacer, so that between the semiconductor chips a defined chamber volume is formed without having to have cavities in the semiconductor chips. The semiconductor chips can thus be constructed as cost-effective planar chips. It is also advantageous that the clearance distance between the semiconductor chips, and thus the height of the test chamber, is defined by the thickness of the seal. Thus, test chambers having different heights can be made with the same semiconductor chips, where respectively only the dimensions of the seal and, optionally those of the, must be fitted correspondingly. Thus, in a simple manner, a plurality of test chambers having different dimensions can be prepared. The opposing contacts provided on the mounting and acting together with the connection contacts of the semiconductor chips allow, in a simple manner, an electrical connection between the semiconductor chips bordering the test chamber and/or the semiconductor chips and an external evaluation unit or a power supply unit. On the whole, a biomonitor results which is simply constructed and can be manufactured cost-effectively.
It is advantageous if at least one inlet channel having the inlet opening and/or at least one outlet channel having the outlet opening penetrates the seal. The inlet and outlet channels of the test chamber are thus arranged in the seal, so that wall openings in the semiconductor chip can be omitted.
In an expedient manner, the seal comprises an elastic material and is preferably constructed as an O-ring. As an inlet or outlet channel, a hollow needle, for example, can then be provided which penetrates the seal. The apparatus can then be handled in an especially flexible manner.
A preferred embodiment of the invention provides that the mounting has at least one holding clip or a holding clamp with at least two clamping parts, which have a smaller clearance distance in the starting position than the total thickness of the semiconductors spaced from each other by the seal and to be clamped between the clamping parts, and that the clamping parts can be moved away from each other against a restoring force. The mounting can then be combined with seals having various thicknesses, such that the clearance distance between the clamping parts becomes fitted to the overall thickness of the parts, which are to be clamped between the clamping parts, which varies depending on the thickness of the seal. Consequently, in a simple manner, a plurality of test chambers can be prepared having various chamber heights, i.e., with various distances between the semiconductor chips. Optionally, the chamber height of the apparatus can also be changed later by replacing the seal with a thicker or thinner seal. Thus, for example, certain experimental techniques, such as the determination of the metabolic activity of cells by the measurement of the pH-value and the oxygen concentration, require a high cell count to chamber volume ratio or an extremely small chamber height. In other applications, on the other hand, a larger chamber height can be advantageous, for example in order to reduce the flow shearing force exerted on the cells by the nutrient liquid stream.
It is expedient if the clamping parts are constructed as clamping legs, which can be deformed away from each other elastically springing against the restoring force of their material. The holding clip or holding clamp is then constructed in an especially simple manner and can be constructed, for example, as a U-shaped clamp in cross-section and/or as a clamping rail. The clamping legs can be connected together as a single piece.
It is especially advantageous if the opposing contacts are affixed to the clamping part. The restoring force of the holding clip or holding clamp can then be used both for pressing the opposing contacts onto the connection contacts of the semiconductor chips, as well as for pressing the semiconductor chips against the seal located between them. Optionally, a conducting rubber can be provided on the clamping part of the mounting, which produces the electrical contact with the connection contacts located on the semiconductor chips.
A preferred, especially advantageous embodiment of the invention provides that the first semiconductor chip provided for the adherent deposit of the biological cells has at least one array wit
Sieben Ulrich
Wolf Bernhard
Akin Gump Strauss Hauer & Feld L.L.P.
Micronas GmbH
Redding David A.
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