Chemistry: electrical and wave energy – Apparatus – Electrolytic
Reexamination Certificate
1997-10-06
2001-08-28
Warden, Sr., Robert J. (Department: 1744)
Chemistry: electrical and wave energy
Apparatus
Electrolytic
C204S406000, C257S253000
Reexamination Certificate
active
06280586
ABSTRACT:
The invention relates to a measuring device for measuring or investigating physiological parameters using biological cells or chemical biologically active substances contained in an analyte. The measuring device includes at least one electrical or electronic sensor having a measurement output connectable to an evaluating device, wherein the sensor has at least one electrical or electronic measurement structure located on a substrate. The measurement structure is connected to function-specific receptor cells and/or target cells serving as biological sensors (discriminator) and together with these cells forms a sensor, such that the cells are an inherent part of the sensor and for measurement of the analyte under investigation can be brought into contact with the receptor cells and/or the target cells on their side facing away from the measurement structure.
BACKGROUND OF THE INVENTION
A measuring device of the type mentioned above is already known from the publication “Kraus et al, BIOSCOPE 1993, No. 1, Pages 24 to 33”. Although this measuring device is field-proven in practice, particularly due to its quick response time and the possibility of carrying out selective measurements in the analyte, it nevertheless presents drawbacks. Thus, the function-preserving immobilization of the receptor cells and/or target cells on the physical component of the sensor is extremely critical. One possibility of bringing the receptor cells or target cells into contact with the measurement structure of the measuring device consists, by way of example, in fixing the receptor cells and/or target cells on the measurement structure in an immobile fashion with a gel. This has the drawback, however, that the receptor cells and/or target cells are prestimulated and by this means supply only a comparatively faint signal upon contact with a substance to be detected. Another possibility of bringing the receptor cells and/or target cells into contact with the measurement structure consists in attaching the receptor cells and/or target cells to the measurement structure by mechanical means, for instance using a micromanipulator. This method is, however, comparatively complex, because the micromanipulator has to be manually positioned on the cells under a microscope. In addition, the size of the measuring device, which as such is very compact, is significantly increased by adding the micromanipulator.
A measuring device is also already known where the cells under investigation are contained in a biological buffer medium and where an auxiliary reagent is added to this buffer medium and, when certain chemical components are present, causes coloration of the buffer medium. Thus, by way of example, a calcium colorant can be contained in the buffer medium for detection of calcium ions. For measurement of a change in color brought about by the substance to be detected, the known measuring device has an optical sensor and a light source for transmitting light through the buffer medium. A drawback of this measuring device is particularly that it is of some size and is therefore not sufficiently versatile in use for certain measurements. In addition, the measurement is not free from reactive effect, since some of the auxiliary reagents required are toxic and influence the cells under investigation or the cellular targets. The high photon densities can also lead to changes in the measurement system.
In addition, sensors on enzymatic basis or with microbial structure are known. However, they permit only a single signal analysis, i.e. these sensors always measure only one analyte. What is more, such sensors are vulnerable, because the measurement of a spurious signal does not permit any dependable analyte recognition.
SUMMARY OF THE INVENTION
The object underlying the invention is therefore to provide a measuring device of the type set forth at the outset, which is compact in size, where the influence upon the medium under investigation by the measuring device is reduced and which, apart from a selective evaluation, also displays a high measuring sensitivity.
This object is accomplished in that provided between the receptor cells and/or target cells and the measurement structure is a structured, microporous interlayer which the target cells and/or receptor cells accept as neighbor for adherence.
Such a sensor, in principle comprising a sensor element on the input side, similar to an electrical discriminator and a transducer composed by the electrical or electronic measurement structure, allows measurements with very high measuring sensitivity. As a result, animal or vegetable cells as a constituent of the sensor, which are spontaneously adherent or were rendered adherent to the measurement structure, permit a highly sensitive, dynamic substance recognition, since the parallel signal processing mechanisms of the cells are utilized as a discriminator unit.
A further advantage is constituted by the fact that cell membrane-bound receptors after loading with an analyte are immediately recycled by the cells and a new receptor is transported to the cell surface. This effect can be optimized in a steered fashion by biotechnological measures (e.g. by transgenic receptors). Compared with conventional and also microbial sensors, sensor structures which are highly dynamic and display high sensitivity through the internal signal amplifying mechanism of the cells are possible.
In the measuring device according to the invention, the sensor hence cooperates with the target cells or receptor cells which are arranged directly on the measurement structure and, upon contact with the analyte or medium under investigation, are influenced by certain substances contained therein. The changes thereby brought about in the target cells or receptor cells are directly measurable by the sensor, so that the electric signal delivered by the sensor allows conclusions to be drawn on the substances and/or cells contained in the analyte. Depending on the special properties of the function-specific receptor cells and/or target cells coupled to the sensor, a wide range of substances can be measured or detected. In this way, for instance, receptor cells can be provided for the detection of opiates, atracin, steroids or oestrogens. By means of special target cells, biological (e.g. toxic), chemical (e.g. heavy metals etc.) and physical (e.g. radiation) components can be detected.
Since the measuring device according to the invention is very small in size, it can be handled particularly well and can also be used at places difficult of access. In addition, only a correspondingly small amount of the medium under investigation is required for the measurement. Since no auxiliary reagents have to be added to the substance under investigation, or more specifically to the analyte, the measuring device operates practically non-reactively. The interlayer provided is in particular a macromolecular porous layer which on the one hand induces adhesion of the cells and on the other hand is proportioned in the pore size so as to be permeable for certain ions, molecules or cell areas. By way of example, an SiO
2
layer sputtered or applied to the measurement structure, an Al
2
O
3
layer or a Ta
2
O
5
layer can also be provided as the interlayer. By means of the structured interlayer, the electronic measurement structure is conditioned in such a way that the target cells or receptor cells accept the measurement structure as neighbor and become better attached to it. The porosity of the interlayer allows that the ions, molecules or cell areas to be measured of the target cells or receptor cells can reach the electrically active areas of the measurement structure.
It is especially advantageous if a plurality of sensors with measurement structures are arranged, particularly as a sensor array, on a common substrate. Such a sensor array can be manufactured particularly cost-advantageously as an integrated circuit and allows the measurement of a wide range of chemical or biological substances in a most confined space. In this context, there is the possibility that a plurality of
Baumann Werner
Ehret Ralf
Sieben Ulrich
Wolf Bernhard
Akin, Gump. Strauss, Hauer & Feld, L.L.P.
Micronas GmbH
Olsen Kaj K.
Warden, Sr. Robert J.
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