DE102018218122A1 - Device and method for the analysis of biological, chemical and biochemical substances - Google Patents

Abstract

The invention relates to a device (6) for analyzing biological, chemical and biochemical substances, comprising a microelectronic sensor system (1) with at least one semiconductor sensor (4), at least one application-specific integrated circuit (5) coupled to the at least one semiconductor sensor (4) Signal processing of an electrical signal generated by means of the at least one semiconductor sensor (4), at least one technical interface (3) for applying at least one biological, chemical or biochemical substance in a detection range of the at least one semiconductor sensor (4) and at least one setting device (17) for setting a dynamic range and / or a signal resolution of the electrical signal generated by means of the at least one semiconductor sensor (4). The invention further relates to a method for analyzing biological, chemical and biochemical substances by means of a microelectronic sensor system ms (1).

Description

The invention relates to a device for analyzing biological, chemical and biochemical substances.

The invention further relates to a method for analyzing biological, chemical and biochemical substances.

Various devices and methods for analyzing biological, chemical and biochemical substances are known from the prior art.

One such method is the so-called patient-oriented laboratory diagnostics, also known as point-of-care testing, in short: PoCT. This includes diagnostic tests that are carried out in the immediate vicinity of a patient and not in a central laboratory, but also so-called rapid tests, such as pregnancy tests, blood coagulation tests or blood sugar tests. Point-of-care testing is also used for diagnostic examinations in other areas of application, for example in food and environmental analysis. The point-of-care testing is characterized by a particularly fast availability of analysis results for a user.

Another method is the so-called in vitro diagnostics, which is characterized by precise and quantitative laboratory analyzes, but requires expensive and large laboratory equipment and a long analysis time. In in-vitro diagnostics, among other things, optical analyzes are carried out, using ultraviolet spectrophometers, spectrophometers with a visual spectrum, infrared spectrophometers, for example so-called NIR spectrophometers, which operate in the near infrared wavelength range, and microarray scanners as laboratory devices be used. However, such laboratory devices are too large, too cost-intensive for point-of-care testing applications and require operation by trained specialist personnel.

The invention is based on the object of specifying an improved device and an improved method for analyzing biological, chemical and biochemical substances compared to the prior art.

With regard to the device, the object is achieved according to the invention by the features specified in claim 1 and with respect to the method by the features specified in claim 11.

Advantageous embodiments of the invention are the subject of the dependent claims.

The device according to the invention for analyzing biological, chemical and biochemical substances comprises a microelectronic sensor system with at least one semiconductor sensor, at least one application-specific integrated circuit coupled to the at least one semiconductor sensor for signal processing of an electrical signal generated by means of the at least one semiconductor sensor, at least one technical interface for application a biological, chemical or biochemical substance in a detection range of the at least one semiconductor sensor and at least one setting device for setting a dynamic range and / or a signal resolution of the electrical signal generated by means of the at least one semiconductor sensor.

The device enables analyzes of biological, chemical and biochemical substances with the aid of optical and non-optical methods, such as, for example, electromagnetic, electrical, magnetic and / or electrochemical methods, in order to use them to detect pathogenic changes in biological, chemical and / or biochemical substances. Due to the setting of the dynamic range and / or the signal resolution, the device enables a large number of optical, electromagnetic, electrical, magnetic, electrochemical and biochemical analysis methods to be carried out, with a number of necessary preparation steps, material consumption for sample preparation and a number of technical, for example optical, components being significant can be reduced. The setting options have an impact, for example, on a structure, a sequence and a function of the detection method and an entire biochemical analysis method, that is to say on technical components, such as optics of a detection / diagnosis system or a technical interface of the microelectronic sensor system, on a quantity of Samples, for a lot of additionally required substances, a number and duration of preparation steps and thus for a duration of the entire analysis process as well as for a pure detection time.

The application-specific integrated circuit, also referred to as ASIC for short, together with the semiconductor sensor enables biological, chemical and / or biochemically induced signals to be translated into an electrical signal based on components and / or reactions in an analysis sample directly on the technical interface of the microelectronic Sensor system, which for example a surface of the Semiconductor sensor is, among other things, an improved signal-to-noise ratio and thus a higher sensitivity. Immediate and advanced signal processing can reduce additional disturbances, such as noise, and amplify and digitize a useful signal. The latter simplifies communication and further processing in digitally operating sensor systems for data processing / visualization outside of the application-specific integrated circuit. In particular, a digitized useful signal is also more robust against external interference.

Furthermore, biological, chemical and biochemical analyzes can be carried out down to the molecular level by means of the device. The device thus makes a significant contribution to improving medical diagnostics in point-of-care testing applications and in-vitro diagnostic applications, since a large part of a technical complexity is integrated in the microelectronic sensor system.

For example, the microelectronic sensor system comprises one or more semiconductor sensors, which are designed, for example, as photodiodes and, for example, are designed in a standardized semiconductor process, for example as a complementary metal oxide semiconductor, or CMOS for short.

In a further possible embodiment, the microelectronic sensor system is arranged directly below the biological, chemical or biochemical substance, hereinafter referred to as analyte, and is in direct contact with this and / or other constituents in an analysis sample.

• - eine biologisch, chemisch und/oder biochemisch funktionale Struktur und/oder
• - eine Fänger-Struktur und/oder
• - eine Ziel-Struktur und/oder
• - eine Markierungs-Struktur und/oder
• - zusätzliche zur Interaktion der benannten Strukturen führende und/oder die Analyse beeinflussende, jedoch nicht zwangsweise nachweisrelevante Strukturen.

The analyte is in particular part of a sample or analysis sample to be analyzed. The sample or analysis sample to be analyzed can include the following components without claiming to be complete:

• - A biologically, chemically and / or biochemically functional structure and / or
• - a catcher structure and / or
• - a target structure and / or
• - a marking structure and / or
• - Additional structures leading to the interaction of the named structures and / or influencing the analysis, but not necessarily relevant to evidence.

The biological, chemical and / or biochemical structures can include, among others, atomic, molecular, gene-based, protein-based, cell-based, natural and / or synthetically produced components, individually or in combination.

According to a possible embodiment of the device, at least one semiconductor sensor is designed as an optical semiconductor sensor and a radiation source is provided for emitting light in the direction of the at least one semiconductor sensor. An optical semiconductor sensor, for example a photodiode, has one or more specially created layers, for example made of Si ₃ N ₄ and / or SiO ₂ and / or other materials or material combinations, the optical properties of the semiconductor sensor with regard to its optical signal transmission behavior, such as a spectral sensitivity and / or selectivity, signal disturbance variable properties and signal amplification influence, in particular improve. This means that optical semiconductor sensors use a so-called internal photoelectric effect in order to convert electromagnetic radiation, such as light in the visible wavelength range, but also in the infrared and / or ultraviolet wavelength range, and / or X-ray radiation into an electrical signal.

Alternatively or additionally, at least one semiconductor sensor is designed as a non-optical semiconductor sensor. For example, the non-optical semiconductor sensor comprises at least one ion-sensitive field effect transistor, ISFET for short, which is a typical semiconductor component, for example a MOSFET, and one or more ion-sensitive layers, for example formed from silicon oxide (SiO ₂ ), silicon nitride (Si ₃ N ₄ ), Aluminum oxide (Al ₂ O ₃ ), tantalum (V) oxide (Ta ₂ O ₅ ), zirconium (IV) oxide (ZrO ₂ ), hafnium (IV) oxide (HfO ₂ ), ruthenium (IV) oxide ( RuO ₂ ), iridium (IV) oxide (IrO ₂ ), titanium (IV) oxide (TiO ₂ ), titanium nitride (TiN), titanium oxynitride (TiON) and / or other layers suitable as technical interfaces. Due to their technical interface, ISFETs have the property of converting changes in ion quantities into an electrical signal in a medium, possibly in an ion-specific manner, on their sensor surface. That is why they are suitable, among other things, as pH sensors, in which they have sensitivity and, if appropriate, selectivity for hydrogen ions. For example, electrochemical sensors such as oxygen sensors integrated in the non-optical semiconductor have one or more electrode structures with defined dimensions, the material of which is a metal used in the non-optical semiconductor and the technical interface of which is, for example, noble metals such as gold, silver, platinum, iridium and others , and / or other materials. Due to the refinement of the electrode material, the non-optical semiconductors, for example, have a particularly high electrochemical stability, for example in the case of redox reactions, and influence them on account of their Electrode material properties do not falsify an actual detection reaction.

The use of non-optical semiconductor sensors and a configurable signal processing path matched to them enables a non-optical, in particular electromagnetic, electrical, magnetic and / or electrochemical analysis of biological, chemical and / or biochemical analysis samples. Such a use of non-optical analysis methods enables a user to carry out analysis options in which, where appropriate, higher sensitivities and / or signal resolutions can be achieved and / or other dynamic ranges can be used, which may be limited in optical analysis methods.

If non-optical semiconductor sensors are used exclusively in the microelectronic sensor system, all optical system components that are necessary for optical analyzes can be omitted. As a result, system complexity and consequently possible sources of error can be reduced, and cost savings can be achieved by dispensing with optical components and a reduced number of necessary system components.

• - eine Verwendung einer geringeren Menge von Substanzen für eine Nachweisreaktion und/oder eine Verwendung von kostengünstigeren Substanzen für eine Nachweisreaktion und/oder
• - eine verringerte Anzahl von Vorbereitungsschritten und/oder Vorbereitungsschritte mit verringertem Zeitaufwand und/oder kostengünstigere Vorbereitungsschritte
• - eine Verringerung einer Detektionszeit und/oder einer Zeitdauer des gesamten Analyseverfahrens und/oder eines Kostenaufwands des gesamten Analyseverfahrens

erreicht werden.Compared to optical analysis methods, a different material for analysis samples for a detection reaction and / or a different type and number of preparation steps are or are required in certain applications. Depending on a specific application, the use of a smaller amount of analysis sample material and / or the use of less expensive analysis sample material and / or

• use of a smaller amount of substances for a detection reaction and / or use of less expensive substances for a detection reaction and / or
• - A reduced number of preparatory steps and / or preparatory steps with reduced expenditure of time and / or less expensive preparatory steps
• a reduction in a detection time and / or a time period of the entire analysis method and / or a cost of the entire analysis method

can be achieved.

Furthermore, the use of non-optical semiconductor sensors has an impact on the specificity and selectivity of the analysis method and thus on the correctness of results and on the robustness of the analysis method.

The use of at least one optical semiconductor sensor in combination with at least one non-optical semiconductor sensor has effects on the validity of measurement data determined by means of the analysis method. The combined use of optical and non-optical semiconductor sensors enables analysis methods to be used which simultaneously use combined optical and non-optical effects for the analysis of biological, chemical and / or biochemical analysis samples. As a result, different methods with different materials and substances as well as different numbers and duration of preparation steps do not have to be used in order to take advantage of the combined use of optical and non-optical semiconductor sensors. This may lead to a reduction in a detection time and / or a time duration of the entire analysis method and / or to a reduction in the cost of carrying out the analysis method. Furthermore, the combined use of optical and non-optical semiconductor sensors has an impact on the specificity and selectivity of the analysis method and thus on the correctness of results and on the robustness of the analysis method.

When optical and non-optical semiconductor sensors are used in combination, measurement data acquisition for an individual analyte is made possible via at least two different measurement principles in accordance with the semiconductor sensors used, which provides meaningfulness about the behavior and / or properties of the analyte and / or other structures in the analysis sample elevated.

When optical and non-optical semiconductor sensors are used in combination, measurement data acquisition for several analytes is made possible, which increases the significance of the behavior and / or properties of the analytes themselves and / or of other structures to be analyzed within the analysis sample.

In contrast to solutions known from the prior art, which are based on the detection of luminescent light, which arises due to the use of so-called markers, which are bound to the actual substance to be examined, when illuminated with the radiation source, it is with the Device particularly possible to carry out analyzes of biological, chemical and biochemical substances using another method, for example an optical method in the form of a light absorption measurement, and thus to detect pathogenic changes in biological, chemical and / or biochemical structures.

When using at least one optical semiconductor sensor, the present device is optimized, for example, for an analysis of biological, chemical and / or biochemical samples by measuring an absorbance, for example a light absorption. This includes a number of advantages: Filters are required for fluorescence-based analyzes in order to filter or attenuate the excitation light with a defined wavelength. No filters are required when measuring light absorption, since a signal change due to light attenuation is measured by the incident light.

In contrast to fluorescence-based analyzes, no light filtering of the excitation light is required for a light absorption measurement with the device, so that furthermore no parallel beam path and thus no collimators are required to generate one.

Another limiting factor is the radiation source in fluorescence measurements, since high-energy radiation in the short-wave ultraviolet to blue range of light is often required to excite the fluorescence molecules. To generate these wavelengths, expensive radiation sources, such as xenon or halogen sources, are used, on the one hand, and, as a result, additional and expensive optical components, such as monochromators, are used to separate the excitation radiation with desired wavelengths from undesired wavelengths. Alternatives are lasers, laser diodes, light-emitting diodes or organic light-emitting diodes, which can generate radiation in a very narrow-band wavelength range. Lasers and laser diodes in particular work with a high radiation power and are characterized by high costs in a high-energy wavelength range. Light-emitting diodes and organic light-emitting diodes mostly work with lower radiation powers, but this can restrict the usability of different fluorophores and thus a diagnostic or analytical application, since certain types of fluorophore require a minimum energy of the excitation radiation for the emission of fluorescent light. The absorption measurement with the present device, on the other hand, can be carried out in the entire spectral range of light, that is to say in the ultraviolet, in the visual spectrum, in the near infrared spectrum and in the infrared spectrum, since signal changes to be measured are due to intrinsic radiation attenuation properties of the structures to be analyzed in the analysis sample, for example the analyte itself and / or bound markers.

Due to the high sensitivity of the device, even small changes in irradiance of the radiation source in the analysis sample can be detected with low emitted irradiance. For example, inexpensive light-emitting diodes with low radiation power and any wavelength can be used individually and / or in combination as a radiation source, depending on the analytical application.

Because of the high sensitivity with variable signal resolution and adjustable dynamic range of the device, it is also possible to dispense with the use of markers. By dispensing with markers, additional consumables, such as the markers themselves, liquids and additional process steps of the marking process when preparing analytical samples, and consequently time and costs, can be saved.

Due to the high sensitivity of the device, so-called analyte multiplication steps, such as so-called polymerase chain reactions (PCR) in the preparation for analysis and the materials required for this, can at least be reduced or completely saved. This in turn leads to a reduction in costs and time savings.

In addition, the device enables analytical applications to be carried out with a large number of different analytes and analyte concentrations. Analytical applications with analysis platforms with different types of analytes can be carried out on an atomic, molecular, gene-based, protein-based, cell-based or other level using various optical methods, such as fluorescence, luminescence and in particular extinction and absorption measurements of electromagnetic radiation, and other methods be used.

Thus, the device for integration as a technology platform in diagnostic systems for fast, inexpensive, user-friendly but above all precise, reliable and possibly continuous and personalized on-site analyzes, in point-of-care testing and in vitro -Diagnostic applications suitable.

In one possible embodiment of the device, the setting device comprises at least one amplifier circuit arranged between the semiconductor sensor and the application-specific integrated circuit or between a component of the setting device and the application-specific integrated circuit, which is set up to amplify the electrical signal generated by the semiconductor sensor.

The amplifier circuit can be used to carry out an adjustable amplification of the electrical signal generated by the semiconductor sensor as an input signal for the application-specific integrated circuit. If an integrator circuit is used to integrate the generated electrical signal, it is still possible to set the dynamic range by means of the amplification of the generated electrical signal, since the set amplification defines a size of the amplified electrical signal to be integrated. Furthermore, due to the definition of the size of the amplified electrical signal to be integrated, the amplification can influence the integration time of the generated electrical signal and the integration capacity. A signal resolution can also be influenced by means of the amplification. The term signal resolution refers to a measurable value of a signal or a signal change and / or a fineness or step size of a sampling of a signal or the signal change for converting the analog signal into a digital signal. A signal-to-noise ratio, that is to say a ratio of a useful signal or a signal change to an interference signal, for example noise, can be a measure for assessing a quality of the signal resolution. Furthermore, a sensitivity of the device can be set by means of the amplifier circuit.

A high gain leads, for example, to the ability to detect small signals or signal changes and to focus on a section of the dynamic range, to increased sensitivity, to less material of analysis samples required for a detection reaction, to less sample material and / or fewer additional substances for the detection reaction fewer and / or shorter necessary preparatory steps to shorten the detection time and / or a duration of the entire analysis process.

A small amplification leads, for example, to the detection of larger signals or signal changes and to the observation of a larger section or the entire dynamic range and thus enables use for optical detection methods with a large dynamic range, such as, for example, kinetic measurements, such as a measurement of enzyme kinetics.

By adjusting the gain and the consequent adjustment of the dynamic range and influencing the sensitivity, a field of application of the device is enlarged and the microelectronic sensor system can be used with different optical detection principles for different analysis methods, for example with end point determinations or kinetic measurements.

Furthermore, the adjustable amplification enables only a few optical components to be required depending on an optical detection principle used and on an analysis method used, such as extinction or luminescence.

In a further possible embodiment of the device, the setting device comprises at least one current-digital-to-analog converter which is arranged between the semiconductor sensor and the application-specific integrated circuit and which is set up to add electrical currents with different signs to the electrical signal generated by the semiconductor sensor .

The current-digital-to-analog converter can be used to adapt the dynamic range by adding electrical currents with different signs to the generated electrical signal. When using an integrator circuit for integrating the generated electrical signal, the addition of electrical currents to the generated electrical signal further enables the dynamic range to be set, since the total signal generated defines a size of the amplified electrical signal to be integrated and has an influence on an integration time . Furthermore, an influence on the signal resolution and the sensitivity of the device can be realized. Thus, the addition of electrical currents with different signs to the generated electrical signal leads to less necessary material of analysis samples for a detection reaction, to less sample material and / or fewer additional substances for the detection reaction, to fewer and / or shorter necessary preparation steps, to shorten the Detection time and / or a duration of the entire analysis process. Furthermore, the addition of electrical currents with different signs to the generated electrical signal makes it possible that, depending on an optical detection principle used and on an analysis method used, such as extinction or luminescence, only a few optical components are required.

In one possible development of the device, the setting device comprises at least one integrator circuit which is arranged between the semiconductor sensor and the application-specific integrated circuit and which comprises an adjustable electrical capacitance which can be acted upon by the electrical signal generated by the semiconductor sensor.

The integrator circuit can be used to influence the signal-noise in a simple manner. Ratio through natural low-pass characteristics and consequently suppression of high-frequency noise can be realized. The adjustable size of the capacitance for integration leads to a changeable low-pass characteristic and thus to a changeable filter characteristic of noise as well as to the adjustment of the dynamic range, since among other things the size of the capacitance defines how much electrical current can be integrated into the capacitance. Furthermore, the integration time for integrating the electrical signal generated by the semiconductor sensor is dependent on the adjustable size of the capacitance. Furthermore, the signal resolution can be influenced by means of the integrator circuit. If the integrator circuit comprises a switch, this can be used to implement a reset function which prevents accumulation of charge on the integration capacity, which would falsify an actual measured value of the integrated electrical signal when the sensor is selected. Furthermore, an influence on the sensitivity of the device can be realized. Thus, the use of the integrator circuit leads to less necessary material of analysis samples for a detection reaction, to less sample material and / or fewer additional substances for the detection reaction, to fewer and / or shorter necessary preparation steps, to a shortening of the detection time and / or a time duration of the entire analysis method . Furthermore, the addition of electrical currents with different signs to the generated electrical signal makes it possible that, depending on an optical detection principle used and on an analysis method used, such as extinction or luminescence, only a few optical components are required.

In a possible embodiment of the device it is provided that the integrator circuit is followed by a comparator circuit which is set up to detect a rise in an electrical integration voltage resulting from charging the adjustable electrical capacitance of the integrator circuit and a value of the resulting electrical integration voltage with at least two different signal thresholds to compare. With knowledge of a past time between reaching the two signal thresholds, an increase in the electrical integration voltage above the capacitance can be determined in a simple and reliable manner.

In a further possible embodiment of the device, it is provided that a counter circuit is coupled to the comparator circuit, which is set up to start a time counting process at a defined frequency as a function of a clock fed into the microelectronic sensor system and when a first signal threshold of the resulting electrical integration voltage is reached Stop reaching a higher second signal threshold to count the time. It is thus possible to output information to a user about an end of a signal processing process for a semiconductor sensor. In this way, an overlapping of two successive sensor reading processes and a mutual and signal-distorting influence can be prevented.

In one possible development of the device, the microelectronic sensor system comprises at least one heating structure for heating the technical interface. The integrated heating structure enables thermal energy to be supplied to the analyte, which, if necessary, promotes compound reactions of individual constituents in the analyte and thus accelerates reaction rates. As a result, the analysis process can be significantly accelerated, which shortens analysis times and enables the device to be used in fast point-of-care testing and in-vitro diagnostic applications. In this case, an integrated temperature sensor provided in one possible development of the device can be used both for temperature monitoring of the analyte directly on the technical interface and for regulating a temperature of the heating structure and any cooling elements provided.

According to a possible embodiment of the device, the technical interface comprises at least one ion-sensitive layer which, for example, silicon oxide (SiO ₂ ), silicon nitride (Si ₃ N ₄ ), aluminum oxide (Al ₂ O ₃ ), tantalum (V) oxide (Ta ₂ O ₅ ), zirconium (IV) oxide (ZrO ₂ ), hafnium (IV) oxide (HfO ₂ ), ruthenium (IV) oxide (RuO ₂ ), iridium (IV) oxide (IrO ₂ ), titanium (IV ) oxide (TiO ₂ ), titanium nitride (TiN), titanium oxynitride (TiON) and / or at least one other layer suitable as a technical interface.

In the method according to the invention for analyzing biological, chemical and biochemical substances by means of a microelectronic sensor system, at least one biological, chemical or biochemical substance is applied to a technical interface arranged in a detection area of at least one semiconductor sensor. By means of the at least one semiconductor sensor, substance information formed as a function of the substance is detected and an electrical signal corresponding to the substance information is generated. The electrical signal is fed to an adjusting device, by means of which a dynamic range and / or a signal resolution of the electrical signal is or is set and a modified electrical signal is generated. The modified electrical signal becomes one application-specific integrated circuit for signal processing supplied.

The method enables analyzes of biological, chemical and biochemical substances with the aid of optical and non-optical methods, such as, for example, electromagnetic, electrical, magnetic and / or electrochemical methods, in order to detect pathogenic changes in biological, chemical and / or biochemical substances. Due to the setting of the dynamic range and / or the signal resolution, the method enables a large number of optical, electromagnetic, electrical, magnetic, electrochemical and biochemical analysis methods to be carried out, with a number of necessary preparation steps, material consumption for sample preparation and a number of technical, for example optical, components being significant can be reduced. The setting options have an impact, for example, on a structure, a sequence and a function of the detection method and an entire biochemical analysis method, that is to say on technical components, such as optics of a detection / diagnosis system or a technical interface of the microelectronic sensor system, on a quantity of Samples, for a lot of additionally required substances, a number and duration of preparation steps and thus for a duration of the entire analysis process as well as for a pure detection time.

According to a possible development of the method, the technical interface is arranged between at least one semiconductor sensor designed as an optical semiconductor sensor and at least one radiation source, light being emitted in the direction of the substance and the at least one semiconductor sensor by means of the radiation source and an in as substance information by means of the at least one semiconductor sensor Dependence of the substance formed differential light is detected and an electrical signal corresponding to the differential light is generated.

In one possible embodiment of the method, the setting device is used to amplify the electrical signal generated by means of the semiconductor sensor, add electric currents with different signs to the electrical signal generated by means of the semiconductor sensor, and / or to set an adjustable electrical capacitance of an integrator circuit with that by means of the semiconductor sensor Generated electrical signal is applied, an increase in an electrical integration voltage resulting from charging the adjustable electrical capacitance of the integrator circuit is detected, a value of the resulting electrical integration voltage is compared with signal thresholds, and when a first signal threshold is reached, a time counting process as a function of a clock fed into the microelectronic sensor system with a defined clock Frequency started and the time counting process stopped when a higher second signal threshold was reached. This makes it possible to set the dynamic range and / or the signal resolution of the electrical signal in a particularly reliable and simple manner.

Exemplary embodiments of the invention are explained in more detail below with reference to drawings.

• 1 schematisch einen Ausschnitt eines mikroelektronischen Sensorsystems mit einer Analysenprobe,
• 2 schematisch einen Ablauf zur Vorbereitung des mikroelektronischen Sensorsystems und der Analysenprobe,
• 3 schematisch einen Ablauf eines Verfahrens zum biologischen, chemischen und/oder biochemischen Nachweis in einer genbasierten Substanz,
• 4 schematisch einen Ablauf eines Verfahrens zum biologischen, chemischen und/oder biochemischen Nachweis in einer proteinbasierten Substanz,
• 5 schematisch einen Ablauf eines Verfahrens zum biologischen, chemischen und/oder biochemischen Nachweis in einer zellbasierten Substanz,
• 6 schematisch einen Ausschnitt einer Vorrichtung zur Analyse biologischer, chemischer und biochemischer Substanzen,
• 7 schematisch ein Blockschaltbild eines mikroelektronischen Sensorsystems mit Grundkomponenten,
• 8 schematisch ein Blockschaltbild eines mikroelektronischen Sensorsystems,
• 9 schematisch ein Blockschaltbild eines Signalpfads eines mikroelektronischen Sensorsystems und
• 10 schematisch zeitliche Signalverläufe von in dem Signalpfad gemäß 9 vorhandenen Signalen.

In it show:

• 1 schematically a section of a microelectronic sensor system with an analysis sample,
• 2nd schematically a sequence for the preparation of the microelectronic sensor system and the analysis sample,
• 3rd schematically a sequence of a method for biological, chemical and / or biochemical detection in a gene-based substance,
• 4th schematically a sequence of a method for biological, chemical and / or biochemical detection in a protein-based substance,
• 5 schematically a sequence of a method for biological, chemical and / or biochemical detection in a cell-based substance,
• 6 schematically a section of a device for the analysis of biological, chemical and biochemical substances,
• 7 schematically a block diagram of a microelectronic sensor system with basic components,
• 8th schematically a block diagram of a microelectronic sensor system,
• 9 schematically shows a block diagram of a signal path of a microelectronic sensor system and
• 10th schematically temporal waveforms of in the signal path according to 9 existing signals.

Corresponding parts are provided with the same reference symbols in all figures.

1 shows a section of a possible embodiment of a microelectronic sensor system 1 with an analytical sample 2nd , the microelectronic sensor system 1 to a biological, chemical and / or biochemical analysis of the analytical sample 2nd is trained.

The analytical sample 2nd comprises a biological, chemical and / or biochemical structure 2.1 with analyte and a biochemical interface 2.2 . Under the term "biological, chemical and / or biochemical structure 2.1 with analyte “all structures 2.1 understand that under the conceptual analysis sample 2nd are described, with the exception of a functional structure 2.1 . The functional structure 2.1 comprises at least essentially a structure or a structure complex with the analytes necessary and to be evaluated for the analysis.

In order to be able to evaluate the analyte, a biotechnological detection method may be required to prepare the analysis sample 2nd necessary.

The core element of a possible detection method can, for example, be an interaction between a capture structure and a target structure, which is, for example, a binding reaction. The catcher structure is designed in such a way that, according to the key-lock principle, it specifically connects only to structures of the target structure as a result of a biological, chemical and / or biochemical reaction that have pathogenic characteristics. This can cause diseases and / or pathogenic changes in biological, chemical and / or biochemical structures 2.1 be clearly identified.

Furthermore, the “biological, chemical and / or biochemical structure 2.1 with analyte ”contain a marking structure that includes, for example, so-called markers, tags and / or label dyes and, if appropriate, are bound to the target structure and / or to a structure additionally connected to it. In the following, for the sake of simplicity, we will only speak of markers with biological, chemical, biochemical and / or physical properties that are important for the analysis.

Markers can be, for example, fluorophores, nanoparticles, dyes, etc. First of all, because of their intrinsic properties, markers serve to improve a detection method, for example by amplifying a signal to be measured and / or a signal change and / or for example to improve a specific binding reaction. The properties of such markers are explained in the following in terms of their importance for optical detection methods in medical diagnostics.

In possible optical detection methods using markers, one or more markers with the same, similar or different biological, chemical and / or biochemical structure are used 2.1 , with these having a similar or different structural structure can also have different properties, bound to the target structure and / or to an intermediate structure additionally connected to it. The markers can have the property that they absorb electromagnetic radiation, for example light, with one or more wavelengths, convert a supplied energy, for example thermally, and / or get into an energetically excited state and, upon leaving this state, energy in the form of electromagnetic radiation, for example Emit light at a wavelength corresponding to the properties of the marker.

The possible optical detection methods include, but are not limited to, measurements of a so-called extinction, in particular light absorption, but also luminescence. The latter can include measurement of chemiluminescent, bioluminescent, phosphorescent and / or fluorescent light.

For example, if a target structure with a marker has been specifically linked to a capture structure as a result of a biological, chemical and / or biochemical reaction, this connection can be detected directly by measuring the light emitted and / or absorbed by the marker or markers. Direct detection of pathogenic changes in biological, chemical and / or biochemical structures 2.1 is thus possible, whereby a conclusion can be drawn about the presence or absence of a disease.

For binding between marker and target structure or marker, intermediate and target structure as well as between target and catcher structure, binding forces are required, which can be, among other things, electrostatic and / or hydrogen bonds and / or on Van der Waals forces and / or Dipole interactions are based.

In addition to marking the target structure, immobilization of the catcher structure on microelectronic sensor systems is required 1 an additional step of a microelectronic-based detection principle described below for a catcher / target structure interaction. The capture structure is immobilized at a so-called biochemical interface 2.2 . This is a locally defined binding of the catcher structure to at least one functional structure 2.1 that are part of the biochemical interface 2.2 is.

The biochemical interface 2.2 can contain structures that have decisive biological, chemical and / or biochemical properties for the binding of functional structures 2.1 on a microelectronic surface and / or for adequate binding of the capture structure. In addition, it can optionally have properties influencing the analysis, such as a weakening and / or emitting light in the case of an optical analysis.

For binding the functional structures 2.1 There may be biological, chemical and / or biochemical structures that directly link to a technical interface 3rd of the microelectronic sensor system 1 are connected. The technical interface 3rd can be a surface structure of the microelectronic sensor system consisting of one or more chemical elements 1 and / or one from the microelectronic sensor system 1 be separate surface structure, which is the result of a standardized process in a semiconductor production and / or in a subsequent process on the microelectronic sensor system 1 and / or as additional and from the microelectronic sensor system 1 independent structure is generated in a separate manufacturing process.

The technical interface 3rd can have the following properties: bio-compatibility, protective function of the microelectronic sensor system 1 against destructive media, such as electrically conductive liquids, as well as properties that convert a signal into an electrical signal in the semiconductor sensor 4th of the microelectronic sensor system 1 enabled and improved if necessary.

A semiconductor material of the semiconductor sensor 4th is silicon, for example. The semiconductor sensor 4th is designed, for example, as a so-called CMOS component.

• Ein optischer Halbleitersensor 4, der beispielsweise eine in 9 näher dargestellte Photodiode PD ist, besitzt eine oder mehrere speziell erstellte Schichten, beispielsweise gebildet aus Siliziumoxid (SiO₂) und/oder Siliziumnitrid (Si₃N₄) und/oder anderen Materialien und/oder Materialkombinationen, die seine optischen Eigenschaften hinsichtlich seines optischen Signalübertragungsverhaltens, wie beispielsweise eine spektrale Sensitivität und/oder Selektivität, Signal-Störgrößen-Eigenschaften, eine Signalverstärkung usw. verbessert.

The semiconductor sensor 4th realized together with the technical interface 3rd defined sensory properties. The following examples are mentioned:

• An optical semiconductor sensor 4th who, for example, one in 9 Photodiode shown in more detail PD is, has one or more specially created layers, for example formed from silicon oxide (SiO ₂ ) and / or silicon nitride (Si ₃ N ₄ ) and / or other materials and / or material combinations, which its optical properties with regard to its optical signal transmission behavior, such as one spectral sensitivity and / or selectivity, signal-disturbance properties, signal amplification, etc. improved.

An ion-sensitive field effect transistor, ISFET for short, comprises a typical semiconductor component, for example a so-called MOSFET, and one or more ion-sensitive layers, for example formed from silicon oxide (SiO ₂ ), silicon nitride (Si ₃ N ₄ ), aluminum oxide (Al ₂ O ₃ ), Tantalum (V) oxide (Ta ₂ O ₅ ), zirconium (IV) oxide (ZrO ₂ ), hafnium (IV) oxide (HfO ₂ ), ruthenium (IV) oxide (RuO ₂ ), iridium (IV) -oxide (IrO ₂ ), titanium (IV) -oxid (TiO ₂ ), titanium nitride (TiN), titanium oxynitride (TiON) and / or other as a technical interface 3rd suitable layers. Due to their technical interface, ISFETs have 3rd the property of converting changes in ion quantities into an electrical signal in a medium on an ion-specific basis on their sensor surface. That is why they are suitable, among other things, as pH sensors in which they have sensitivity and, if appropriate, selectivity for hydrogen ions.

Electrochemical sensors, such as oxygen sensors, integrated in the semiconductor have one or more electrodes, the material of which is a metal used in the semiconductor, and their technical interface 3rd for example, precious metals such as gold, silver, platinum, iridium and others, and / or other materials. By refining the electrode material in this way, they can, for example, have a particularly high electrochemical stability, for example in the case of redox reactions, and do not adulterate an actual detection reaction due to their electrode material properties.

Other types of technical interfaces 3rd can also be produced in a semiconductor process and / or in post-processes in a separate process by the microelectronic sensor system 1 independent structures, for example made of glass and / or plastic. These structures can have the biological, chemical and / or biochemical properties for an optimized application of components of the analysis sample 2nd on the structures and the optical analysis influencing optical properties, such as absorption, reflection, scattering, diffraction, wavelength-generating, -separating, -focusing, -guiding (e.g. collimation) and / or -filtering characteristics. You may be in direct contact with the technical interface 3rd of the microelectronic sensor system 1 , but mandatory in direct contact with structures 2.1 the analytical sample 2nd .

The step of immobilizing catcher structures on the technical interface 3rd of the semiconductor sensor 4th of the microelectronic sensor system 1 therefore possibly requires steps of activation and functionalization of a sensor surface. Biochemically induced signals or Signal changes on a sensor surface can be made using the semiconductor sensor 4th converted into electrical signals and through an application-specific integrated circuit 5 , also called ASIC for short.

• - Multiparametrische Signalverarbeitung: Diese beinhaltet die Messung verschiedener analytischer Parameter mit unterschiedlichen Nachweisreaktionen, wie z.B. pH-Wert-Messung, Sauerstoffmessung, Impedanzmessung usw. mittels verschiedener Arten von Halbleitersensoren 4 mit für den jeweiligen Parameter individuellen technischen Schnittstellen 3, wie beispielsweise ein ISFET mit pHsensitiver Schicht für eine pH-Wertmessung, Clark-Elektrodenkonfiguration mit Edelmetallbeschichtung für eine Sauerstoff-Messung oder Interdigitalelektroden für eine Impedanzmessung. Dadurch können über die Messung mehrerer Parameter Rückschlüsse auf die Eigenschaften der zu analysierenden Strukturen 2.1 in der Analysenprobe 2 gezogen werden.
• - Durch eine größere Anzahl an Halbleitersensoren 4 einer bestimmten Art erhöht sich eine Messdatenvalidität des jeweilig zu messenden Parameters. Die Messdatenvalidität verbessert sich nochmals, wenn mehrere Halbleitersensoren 4 verschiedener Art für dieselbe Nachweisreaktion verwendet werden können.
• - Eine größere Anzahl an Halbleitersensoren 4 ermöglicht außerdem verschiedene Analyten mit derselben Nachweisreaktion zu untersuchen.
• - Durch die Verwendung mehrerer Halbleitersensoren 4 ist es möglich, ein oder mehrere Analyten parallel zu untersuchen.

The microelectronic sensor system 1 can, depending on the biological, chemical and / or biochemical analysis application, one or more semiconductor sensors 4th in a defined arrangement, for example a matrix and / or row arrangement. The integration of multiple semiconductor sensors 4th can implement the following functions and advantages individually or in combination, but these are not mentioned here conclusively:

• - Multiparametric signal processing: This includes the measurement of various analytical parameters with different detection reactions, such as pH measurement, oxygen measurement, impedance measurement, etc. using different types of semiconductor sensors 4th with individual technical interfaces for the respective parameter 3rd , such as an ISFET with a pH sensitive layer for a pH measurement, Clark electrode configuration with a noble metal coating for an oxygen measurement or interdigital electrodes for an impedance measurement. This allows conclusions to be drawn about the properties of the structures to be analyzed by measuring several parameters 2.1 in the analytical sample 2nd to be pulled.
• - By a larger number of semiconductor sensors 4th of a certain type increases the measurement data validity of the respective parameter to be measured. The measurement data validity improves again if several semiconductor sensors 4th different types can be used for the same detection reaction.
• - A larger number of semiconductor sensors 4th also enables different analytes to be examined with the same detection reaction.
• - By using several semiconductor sensors 4th it is possible to examine one or more analytes in parallel.

2nd shows schematically a possible sequence for preparing the microelectronic sensor system 1 and the analytical sample 2nd .

An analysis sample preparation, in particular of the target structure, does not necessarily involve the microelectronic sensor system 1 directly, but possibly includes the microelectronic sensor system 1 independent and external processes and measures. In particular, the steps of duplication and marking require resource-based, in particular time-consuming and costly, processes which are based on the microelectronic sensor system described here 1 can be reduced or even omitted. In addition, it is not excluded that depending on the biological, chemical and / or biochemical detection principle and the structures used 2.1 the analytical sample 2nd Preparation and implementation steps of the illustrated process can be summarized, expanded, exchanged and / or reduced.

In a first step V1 first cleaning the microelectronic sensor system 1 . In a second step V2 activation, functionalization and immobilization of the catcher structure as well as extraction, duplication and marking of the target structure take place. In a third step V3 there is a detection reaction and in a fourth step V4 the corresponding detection.

• - genbasierten Strukturen 2.1, beispielsweise eine Hybridisierung von Einzelstrang- mit Komplementärstrang-DNA oder -RNA, mit und ohne Marker, katalysiert oder nicht-katalysiert usw.,
• - proteinbasierten Strukturen 2.1, beispielsweise Antigen-Antikörper-Bindungsreaktion, mit und ohne Marker, katalysiert oder nicht-katalysiert usw. und
• - zellbasierten Strukturen 2.1, beispielsweise Bindungsreaktionen, mit und ohne Marker, katalysiert oder nicht-katalysiert usw.

nach einem Schlüssel-Schloss-Prinzip inklusive Analysenprobenvorbereitung der Fängerstruktur, die für die optische Detektionsmethode durch Messung von Extinktion am Beispiel der Lichtabsorption und/oder Lumineszenz mit dem hier beschriebenen mikroelektronischen Sensorsystem 1 möglich ist, dargestellt.In the 3rd to 5 are examples of possible biological, chemical and / or biochemical detection principles of bioanalytics with

• - gene-based structures 2.1 , for example a hybridization of single-stranded with complementary stranded DNA or RNA, with and without markers, catalyzed or uncatalyzed, etc.,
• - protein-based structures 2.1 , for example antigen-antibody binding reaction, with and without marker, catalyzed or non-catalyzed etc. and
• - cell-based structures 2.1 , for example binding reactions, with and without markers, catalyzed or non-catalyzed, etc.

According to a lock and key principle including sample preparation of the catcher structure, which is used for the optical detection method by measuring extinction using the example of light absorption and / or luminescence with the microelectronic sensor system described here 1 is possible.

• Ausgehend von einem gereinigten mikroelektronischen Sensorsystem 1 in einer ersten Stufe S1 erfolgt eine Aktivierung und Funktionalisierung der Sensoroberfläche in einer zweiten Stufe S2. Daraufhin wird die Immobilisierung der Analysenprobe 2 durchgeführt, insbesondere jedoch einer eine Fängerstruktur beinhaltenden Analysekomponente inklusive der alleinigen Fängerstruktur selbst in einer dritten Stufe S3.

Independent of the analytical sample to be examined 2nd can the biological, chemical and / or biochemical detection principle with the microelectronic sensor system described here 1 be structured as follows:

• Starting from a cleaned microelectronic sensor system 1 in a first stage S1 the sensor surface is activated and functionalized in a second stage S2 . Thereupon the immobilization of the analytical sample 2nd carried out, in particular, however, an analysis component including a catcher structure including the sole catcher structure itself in a third stage S3 .

Then follows in a fourth stage S4 the connection between the catcher and target structure or between the catcher and target structure and a marking structure located on the target structure, which shows the optical properties of the analysis sample 2nd changed. This change in the optical properties can be due to the fact that, for example, light at one and / or more wavelengths is more or less strongly absorbed by an additional presence of the target structure (see the step S4 appropriate lower level a)). Another possibility is that the marking structure located on the target structure, which can consist of one or more components and is bound to the target structure in one or more process steps of the analysis sample preparation, has additional properties or properties dominating the absorption at one and / or several wavelengths of light (see level S4 appropriate lower level b)). Furthermore, there is the possibility that the marking structure emits light that differentiates the excitation light with respect to the wavelength by excitation of light of a defined wavelength and / or the target structure and / or catcher-target structure and / or other components of the analysis sample 2nd stimulates luminescence (see step S4 appropriate lower level c)). In another case, according to the level S4 associated sub-stage d), the combination of the compound catcher-target-marking structure requires the addition of one or more biologically, chemically and / or biochemically reactive components in accordance with a fifth stage S5 to change the optical properties of the analytical sample 2nd by changing the light absorption (see level S6 associated sub-stage a)) and / or generation of luminescence (see for stage S6 associated sub-stage b)) by possibly a catalytic process.

The additional reactive component can be used to change the optical properties with the marking and / or the target and / or catcher structure and / or the combination of individual or the entire structures 2.1 to interact. This change in the optical properties can be a time-consuming process, for example until an equilibrium state is reached, which may exist in time beyond the interaction between catcher, target, marking structure and / or additional reactive structures.

Or it is a state change that takes place directly through the interaction between catcher, target, marker structure and / or additional reactive structures.

There is also the possibility that only a partial change in the optical properties of the analysis sample 2nd due to, for example, only a partial connection reaction of the components of the analysis sample 2nd he follows.

In all cases described using an optical semiconductor sensor 4th is the use of a radiation source suitable for optical analysis 7 Basic requirement. It may be necessary to use optical components such as light-guiding, light-guiding, light-focusing, light-filtering, light-reflecting components and other components.

The microelectronic sensor system described here 1 enables analyzes of biological, chemical and / or biochemical substances or structures 2.1 using optical detection methods directly on the at least one semiconductor sensor 4th of the microelectronic sensor system 1 .

How the microelectronic sensor system works 1 and methods for the optical analysis of biological, chemical and biochemical substances are described below on the basis of the principle of light absorption. It is based on the principle of determining the extinction or the optical density, which can include the absorption, scattering, reflection and / or diffraction of electromagnetic waves, for example of light with one and / or more wavelengths. The absorbance and the optical density are determined directly by the capture structure (s) and / or target structure (s) and / or marking structure (s) and / or in the analysis sample 2nd existing and possibly interacting structure (s) 2.1 and / or by a combination or interaction of the named biological, chemical and / or biochemical structures 2.1 caused.

For the sake of simplicity, the description of the microelectronic sensor system described here 1 and method further assumed light absorption as the dominant opto-physical effect without the functionality of the microelectronic sensor system 1 and to restrict the described method to the use of this special effect.

mit:

A:

Absorbanz/Extinktion,

OD:

optische Dichte,

E_e:

von einer Strahlungsquelle 7 emittierte Bestrahlungsstärke,

Er:

empfangene Bestrahlungsstärke,

ε:

stoffspezifischer molarer Extinktionskoeffizient der vom Licht durchdrungenen Analysenprobe 2,

c:

Konzentration ein oder mehrerer Bestandteile der Analysenprobe 2 und

d:

Länge eines Lichtwegs durch die Analysenprobe 2.

The absorption of light by a biological, chemical and / or biochemical structure 2.1 is based on the basic Bouguer-Lambert-Beer law of photometry: $$A=OD=lOG\left(\frac{E_e}{E_r}\right)=\epsilon \ast c\ast d$$

With:

A:

Absorbance / absorbance,

OD:

optical density,

E _e :

from a radiation source 7 emitted irradiance,

He:

received irradiance,

ε:

substance-specific molar extinction coefficient of the analytical sample penetrated by light 2nd ,

c:

Concentration of one or more components of the analytical sample 2nd and

d:

Length of a light path through the analysis sample 2nd .

The Bouguer-Lambert-Beer law gives a statement about a received and measurable irradiance and an incident irradiance of the radiation in one 6 Radiation source shown in more detail 7 which is a light absorbing analytical sample 2nd penetrates. In addition, the law provides a direct connection between light absorption and analytically relevant chemical parameters, such as the concentration of one or more components of the analysis sample 2nd and their light-absorbing properties via the extinction coefficient.

The known path length of the light and the light attenuation capacity of a substance to be analyzed can be used to infer the concentration of a specific substance from the absorption of light. The substance to be analyzed can have atomic, molecular, gene, protein and / or cell-based structures 2.1 and have wavelength-dependent absorbance properties with regard to their specific structural structure.

• - Der zu analysierenden Bestandteile der Analysenprobe 2, die für den Nachweis nicht ausschlaggebende aber gegebenenfalls interagierende Komponenten in der Analysenprobe 2 sind.
• - Mindestens der Strukturen 2.1 der Analysenprobe 2, die maßgebend für die Änderung der optischen Eigenschaften der Analysenprobe 2, z. B. der Lichtschwächung, eindeutig von weiteren und gegebenenfalls interagierenden Komponenten der Analysenprobe 2 unterscheidbar sowie für die biologische, chemische und/oder biochemische Nachweisreaktion ausschlaggebend sind.

The optical analysis of a biological, chemical and / or biochemical analysis sample 2nd By measuring light absorption, knowledge of the light-attenuating properties of the following components is required:

• - The components of the analytical sample to be analyzed 2nd , the components in the analytical sample that are not decisive for the detection but which may interact 2nd are.
• - At least the structures 2.1 the analytical sample 2nd , which are decisive for the change in the optical properties of the analysis sample 2nd , e.g. B. the attenuation of light, clearly from further and possibly interacting components of the analysis sample 2nd are distinguishable and decisive for the biological, chemical and / or biochemical detection reaction.

In 6 are a section of a device 6 for the analysis of biological, chemical and biochemical substances and the analysis sample 2nd shown.

In addition to the microelectronic sensor system 1 comprises the device 6 a radiation source 7 which electromagnetic radiation of defined wavelength and radiation power in the direction of the analysis sample 2nd emitted, the radiation with the at least one semiconductor sensor 4th interacts.

Type, structure and properties of the analysis sample 2nd determine the selection and setting of a suitable radiation source 7 and thus the definition of the wavelength and radiation power of the electromagnetic radiation for biological, chemical and / or biochemical analysis and therefore depend on the diagnostic application.

There may be additional optical components 8th , such as lenses, mirrors, filters, diffusers, monochromators, collimators and / or other components are provided which have optical properties influencing the optical analysis, such as, for example, influencing absorption, reflection, scattering and / or diffraction and / or wavelength-generating, separating , -focusing, -guiding and / or -filtering characteristics. These optical components 8th are possibly between the radiation source 7 and the microelectronic sensor system 1 arranged and are in direct contact with the analysis sample in the analysis in a possible embodiment 2nd and / or the radiation source 7 .

A spatial orientation of the radiation source 7 and a solid angle of the radiation in relation to the described components of the microelectronic sensor system 1 as well as possible optical components 8th are defined according to the biological, chemical and / or biochemical analysis application in terms of optimal signal acquisition, conversion and / or processing.

The following are basic components of a microelectronic sensor system 1 for the analysis of biological, chemical and / or biochemical analysis samples 2nd based on 7 generally named and exemplified.

The microelectronic sensor system 1 consists of one or more microelectronic blocks. The blocks of the semiconductor sensor form an essential component 4th and a signal processing path 9 .

The block of the semiconductor sensor 4th comprises at least one light-sensitive optical semiconductor sensor 4th , for example a photodiode PD , an avalanche photodiode, a single-photon avalanche diode, a silicon photomultiplier, a charge coupled device, a phototransistor, a photomultiplier tube and / or a special type of photodiode PD , for example a multi-transistor pixel architecture, etc., or a combination of these.

The optical semiconductor sensor 4th has the property of reaching light of defined irradiance and wavelength according to its optical properties into an electrical current, the so-called photocurrent I _PD which in 9 is shown in detail to convert. The change in the electrical signal generated by it is proportional to the change in the irradiance of the incident light, in accordance with its optical properties.

The block “semiconductor sensor 4th “Can next to the semiconductor sensor 4th even additional signal processors, such as signal amplifiers, for example an in 9 amplifier circuit shown in more detail 16 , signal converting and / or signal filtering components in a signal processing path 9 include. These can be one or more transistors in the case of an optical semiconductor sensor 4th Signal processing properties of a passive transistor pixel (PPS), an active transistor pixel (APS) or a digital pixel sensor (DPS), which are known as transistor pixel architectures from the development of CMOS image sensors. Alternatively or additionally, the components can be used as an amplifier circuit 16 one or more current mirrors that represent a current, in the case of the optical semiconductor sensor 4th the photocurrent I _PD , with a defined ratio and sign, and / or one or more microelectronic amplifier topologies and / or further signal processing topologies, such as, for example, transimpedance amplifier (TIA), chopper amplifier, lock-in amplifier, etc., and / or Signal processing concepts such as correlated double sampling (CDS), double delta sampling (DDS), correlated multiple sampling (CMS), signal-integrating circuits (integrator circuit 10.1 ), Comparator circuits 10.2 and counter circuits 10.4 , Analog-to-digital converters, digital-to-analog converters, active and / or passive filters, etc., include.

The one for the semiconductor sensor 4th The signal processing structures listed can also be used individually and in combination in the additional signal processing path 9 after the semiconductor sensor 4th of the microelectronic sensor system 1 additional signal processing structures 10th his. This is particularly advantageous if the microelectronic sensor system 1 due to the analytical application a large number of semiconductor sensors 4th must have.

An example of this is DNA sequencing with, for example, ISFET sensors. The higher the number of sensors, the more DNA or DNA sequences can be analyzed. The number of semiconductor sensors 4th but also requires dimensions of the microelectronic sensor system 1 . Because the size of the microelectronic sensor system 1 is a crucial cost factor when you have a large number of semiconductor sensors 4th is careful to keep the sensor size as small as possible, accordingly reducing signal processing structures, see example transistor pixel architecture, to a minimum and large-area signal processing components outside the sensor matrix in the microelectronic sensor system 1 outsource.

However, a large number of sensors also have a number of disadvantages for signal processing. A high number of sensors usually means and depending on the circuit complexity of the semiconductor sensor 4th also a large number of signal-carrying lines. Since these also often carry digital signals, interference can occur and signal crosstalk to the semiconductor sensor 4th as well as among the semiconductor sensors 4th come that negatively affect the signal processing. In addition, inequalities in the sensor and subsequent signal processing components, for example due to process fluctuations in the technological manufacturing process, lead to intrinsic non-linearities of the components used, non-ideal systemic structure and / or placement of the components, etc. and to further problems in signal processing. These can in turn be made by a suitable signal processing method inside and / or outside the microelectronic sensor system 1 partially solved, but also require increased systemic complexity inside and / or outside the microelectronic sensor system 1 . This is mostly reflected in the costs.

The microelectronic sensor system described here 1 with application-specific integrated circuits 5 for processing analog and / or digital signals (mixed signal) offers the possibility of a compromise between the necessary systemic complexity and optimal signal processing in the sense of biological, chemical and / or biochemical analytical application.

Other signal processing structures 10th can volatile and / or non-volatile memory elements, such as a capacity, ROM memory, RAM memory, etc., in the microelectronic sensor system 1 integrated microprocessor architectures as well as microelectronic structures that are the microelectronic sensor system 1 capable of wireless communication, for example via RFID, NFC, Bluetooth, ZigBEE, WiFi, IR etc., with system components external to microelectronics.

An additional system component is a digital interface 11 , for example an IC, SPI, etc., which provide communication between the microelectronic sensor system 1 and system components external to microelectronics. Among other things, this includes a configuration of the microelectronic sensor system 1 to defined properties and functions of the microelectronic sensor system 1 adjust. This can include, for example, a selection of a type and a sequence of signal processing, generation, forwarding and storage of analog and / or digital signals, amplifications, filters, differential and / or reference-point-related signal processing, AD conversion and / or reverse DA -Conversion, storage of signals in volatile and / or non-volatile memory elements, continuing signal processing in the microelectronic sensor system 1 Integrated microprocessor architectures, microelectronic structures for wireless communication, for example via RFID, NFC, Bluetooth, ZigBEE, WiFi, IR etc., a selection of the signal-converting semiconductor sensor 4th and / or selection and connection of signal-converting semiconductor sensors 4th , internal and / or external electrical supplies 12th and include other functions. On the other hand, the microelectronic sensor system 1 Processed analog and / or digital signals to system components external to microelectronics.

Another important component is an electrical supply 12th , which is formed, for example, by a so-called bias block. In this block, electrical currents and / or voltages are generated that are used for the electrical supply 12th serve other microelectronic structures and / or provide reference signals, for example for signal processing.

The following is an example of a microelectronic sensor system 1 and a method for the optical analysis of biological, chemical and / or biochemical analysis samples 2nd described. The hybridization of DNA / RNA, specifically for the in 3rd , third step 3rd to fourth stage 4th , Sub-stage a) described, forms an example and not limited to the outgoing detection reaction for the description of the functionality and the structure of the system in the sense of an analytically relevant application.

The biochemical detection method based on the lock and key principle is designed in such a way that the biochemical detection reaction takes place through the hybridization of DNA / RNA (connection of two single strands to the double strand) in such a way that this process affects the optical properties of the analysis sample 2nd provable, ie optically or opto-electronically measurable and specifically influenced.

The following information is important: DNA and RNA absorb light in the ultraviolet wavelength range at approx. 260 nm, whereby each base of the DNA / RNA has a specific UV absorption spectrum and maximum. This characteristic absorption spectrum makes it possible, with a suitable optical measuring principle in the UV wavelength range, to use any base type (DNA: adenine (A), thymine (T); for RNA uracil (U), guanine (G), cytosine (C) ) to identify based on their molecular structure. This also makes it possible to sequence DNA or RNA.

• - Vollständig hybridisiert und 90° zur Sensoroberfläche ausgerichtet;
• - vollständig hybridisiert und 90° zur Sensoroberfläche ausgerichtet und nichthybridisierter Einzelstrang, Überstand der Ziel-DNA;
• - teilweise hybridisiert, die gesamte DNA liegt auf der Sensorberfläche und Einzelstrang-Bereiche der Ziel-DNA sind willkürlich im Raum zum Halbleitersensor 4 ausgerichtet;
• - teilweise hybridisiert, 90° zur Sensoroberfläche ausgerichtet und sehr langer Überstand der Ziel-DNA, der willkürlich im Raum angeordnet ist („Knäuel“);
• - Mischzustände der beispielhaft benannten Hybridisierungsformen sowie der Arten der Anordnung und Orientierung der DNA/RNA.

It is also possible to distinguish between single and double stranded DNA / RNA by measuring the absorbance, for example light absorption, in the UV wavelength range at approximately 260 nm. Due to the effect of hypochromicity, there is a decrease in absorbance, for example light absorption, in the UV wavelength range at approximately 260 nm when two complementary DNA / RNA single strands combine to form a DNA / RNA double strand as a result of hybridization. For example, depending on partial hybridizations of complementary DNA / RNA regions and / or DNA / RNA base chains that, for example, survive over complementary DNA / RNA regions, this effect can be neutralized or even reversed. In addition, the spatial orientation and arrangement of the DNA / RNA in relation to the semiconductor sensor 4 can represent influences on the measurement conditions. Possible forms of hybridization as well as types of spatial orientation and arrangements can be:

• - Fully hybridized and aligned 90 ° to the sensor surface;
• - fully hybridized and aligned at 90 ° to the sensor surface and non-hybridized single strand, supernatant of the target DNA;
• - partially hybridized, the entire DNA lies on the sensor surface and single-stranded areas of the target DNA are arbitrarily in the space to the semiconductor sensor 4th aligned;
• - partially hybridized, aligned 90 ° to the sensor surface and very long overhang Target DNA, which is randomly arranged in the room ("ball");
• - Mixed states of the hybridization forms named by way of example and the types of arrangement and orientation of the DNA / RNA.

Regardless, the principle of hybridization of DNA / RNA is an important diagnostic technique in molecular genetics to diagnose diseases. Conversely, the detection of hybridization of DNA / RNA by measuring the absorbance, for example light absorption, in the UV wavelength range of light offers the possibility of diagnosing diseases. It is also possible to use any type of detection reaction according to the key-lock principle of any biological, chemical and / or biochemical analysis sample 2nd with atomic, molecular, gene, protein and / or cell-based structures 2.1 which, for example as a result of a connection reaction, cause an absorbance of light in the UV, visible (VIS), near-infrared (NIR) and infrared (IR) wavelength range to be detected by measuring the same pathogenic changes and, if appropriate, diagnosing diseases. Reference is made here to the possible forms of the biological, chemical and / or biochemical detection principles already described without claiming to be complete, for which the application and functioning of the microelectronic sensor system described 1 Have validity.

In addition, the effects and influencing factors described for the DNA / RNA on the measurement conditions also apply to these examples, for example with regard to the spatial arrangement and orientation as well as the type and quality of connection processes and reactions in the biological, chemical and / or biochemical analysis samples 2nd .

The structural construction from microelectronic blocks of an example of the microelectronic sensor system described here 1 for optical analysis of biological, chemical and / or biochemical substances is in 8th shown.

The microelectronic sensor system 1 comprises one or more each as a photodiode PD trained semiconductor sensors 4th .

One in the at least one photodiode PD generated photocurrent I _PD is in one or more amplifier circuits designed as a current mirror (CM) 16 mirrored in proportions of defined size and sign and thus preprocessed. The photodiode PD and the amplifier circuit designed as a current mirror 16 together form the block semiconductor sensor 4th .

The pre-processed photocurrent I _PD is then used in other signal processing structures 10th processed further. The signal processing structures 10th form together with the amplifier circuit 16 an adjusting device 17th for setting a dynamic range and / or a signal resolution of the by means of the at least one semiconductor sensor 4th generated electrical signal, especially the photocurrent I _PD , and include an integrator circuit 10.1 , comprising one or more in 9 Capacities CINT of a defined size and a reference potential, as well as a comparator circuit 10.2 with at least one threshold comparator. A current digital to analog converter 10.3 (IDAC) is with a signal node (summation point) between, for example, amplifier circuits designed as current mirrors 16 and the integrator circuit 10.1 connected.

There is also a counter circuit 10.4 intended. The counter circuit 10.4 is again with the digital interface 11 , designed as a so-called I ² C interface, coupled. Additional blocks of the microelectronic sensor system 1 are an identification block 13 , a temperature sensor 14 who have favourited Electrical Supply 12th as well as a heating structure 15 .

According to one in 9 illustrated embodiment of a signal path of the microelectronic sensor system 1 the function of the in 8th shown microelectronic sensor system 1 described below. In 10th are temporal waveforms according to in the signal path 9 represented existing signals.

Incident light with the received irradiance It is used as a photodiode PD trained semiconductor sensor 4th according to its properties in a defined photocurrent I _PD converted. The at least one subsequent amplifier circuit 16 , which is designed, for example, as a current mirror, amplifies the generated photocurrents I _PD in the defined ratio and the sign to the signal node. Mirror ratio 1: G with a gain factor G can via register of the digital interface 11 can be set by a user. This allows biochemically induced signals through the photodiode PD directly converted into an electrical signal and amplified if necessary.

A direct signal conversion and amplification improves the signal-to-noise ratio and makes signal processing more robust against interference coupling, which is a significant advantage over optical measuring systems in which the analysis samples are 2nd not directly or in close proximity to the sensor surface.

The at least one amplifier circuit designed as a current mirror 16 is dimensioned so that it has a particularly high linearity in both small and large signal behavior and also a very large dynamic range of the photocurrents I _PD allow. Any semiconductor sensor 4th can exist in the case of multiple existence in the row and / or matrix combination individually and / or coupled via the registers of the digital interface 11 selected by the user.

The pre-processed photocurrent I _PD is in the integrator circuit 10.1 which has a microelectronic capacity C _INT includes a defined size and has a defined reference potential. As long as no photocurrent I _PD on capacity C _INT is integrated, for example before reading out and / or switching between possibly several semiconductor sensors 4th , the capacity C _INT discharge via a microelectronic switch SDC. This prevents transmission of signal-distorting charge carriers when reading out the at least one semiconductor sensor 4th .

The integrating signal processing method with the capacity C _INT also favors the signal-to-noise ratio in that high-frequency noise can be reduced by the natural low-pass characteristic of the electronic circuit concept.

By charging the capacitance CINT with the photocurrent I _PD an integration tension increases V _INT at the signal node.

Two threshold value comparators with different threshold reference voltages of a defined size and sign evaluate this signal increase in the comparator circuit 10.2 out. When a first signal threshold is passed V _KS1 an output signal level of the first comparator with the signal CNTSTRT switched to active. At this point, the counter is activated, which starts a counting process depending on the microelectronic sensor system 1 fed clocks CLK defined frequency f _CLK with f _CLK = l / T _CLK (T _CLK - period of the cycle CLK ) starts. When crossing the second signal threshold V _KS2 the output signal level of the second comparator with the signal CNTSTP set active. With the signal CNTSTP the counter ends its counting process with a signal EOC (End of Conversion) in the register of the digital interface 11 is deposited.

The user can thus end a signal processing process for a semiconductor sensor 4th in the register of the digital interface 11 check. This is necessary to prevent, for example, an overlap of two successive sensor read-out processes and thus a mutual and signal-distorting influence.

A behavior over time S _SEL of the selected semiconductor sensor 4th visualizes the time in which a semiconductor sensor 4th is selected for the readout process. The counter circuit 10.4 registers the time of the increasing integration voltage V _INT between crossing the first signal threshold V _KS1 until crossing the second signal threshold V _KS2 . This counter value CNT is then displayed as a digital variable in a register of the digital interface 11 stored and is available to the user. The principle is also called analog value-to-time-to-digital value conversion (TDC - Time-to-Digital Conversion). The rise in the integration voltage VINT is a measure of the generated photocurrent I _PD the photodiode PD . Strikes more light of a defined wavelength, i.e. with higher intensity on the photodiode PD , more charge carriers are generated and there is a higher photocurrent I _PD , the capacity C _INT can be charged faster and the integration voltage V _INT rises steeply. The same principle applies to the reverse case. From the counter value obtained CNT can the generated photocurrent I _PD can be calculated as follows: $${\mathrm{I.}}_{PD}=\frac{{\mathrm{C.}}_{\mathrm{I.}NT}\times \left(V_{KS\mathrm{2nd}}-V_{KS1}\right)\times f_{\mathrm{C.}LK}}{G\times \mathrm{C.}NT}-\frac{{\mathrm{I.}}_{\mathrm{I.}DA\mathrm{C.}}}{G}$$

• Werden die optischen Eigenschaften einer Analysenprobe 2 infolge der Präsenz ihrer Strukturen 2.1 und/oder durch Veränderungen derselben und/oder Veränderung der strukturellen Zusammensetzung der Analysenproben 2 beeinflusst, ändert sich auch der generierte Photostrom I_PD und damit der ermittelte Zählerwert CNT. Erfolgt eine Beeinflussung der optischen Eigenschaften der Analysenprobe 2 so, dass die auf die Photodiode PD auftreffende Bestrahlungsstärke des Lichts verringert wird, werden weniger Ladungsträger generiert, der Photostrom I_PD nimmt ab und der Zählerwert CNT wird größer, da die Kapazität C_INT langsamer aufgeladen wird, der Anstieg der Integrationsspannung V_INT flacher wird und die Spannungsrampe mehr Zeit benötigt, um die beiden Signalschwellen V_KS1 , V_KS2 zu durchschreiten. Erfolgt eine Beeinflussung der optischen Eigenschaften der Analysenprobe 2 so, dass die auf die Photodiode PD auftreffende Bestrahlungsstärke des Lichtes erhöht wird, so nimmt der Photostrom I_PD zu und der Zählerwert CNT verringert sich nach demselben Prinzip in umgekehrter Funktionsweise.

The counter value CNT is therefore directly proportional to the generated photocurrent via the formula described I _PD . Related to the optical analysis of biological, chemical and / or biochemical analysis samples 2nd it means the following:

• Become the optical properties of an analytical sample 2nd due to the presence of their structures 2.1 and / or by changing the same and / or changing the structural composition of the analytical samples 2nd influenced, the generated photocurrent also changes I _PD and thus the determined counter value CNT . The optical properties of the analysis sample are influenced 2nd so that the on the photodiode PD incident light intensity is reduced, fewer charge carriers are generated, the photocurrent I _PD decreases and the counter value CNT gets bigger as the capacity C _INT charging slower, the increase in integration voltage V _INT becomes flatter and the voltage ramp takes more time to reach the two signal thresholds V _KS1 , V _KS2 to go through. The optical properties of the analysis sample are influenced 2nd so that the on the photodiode PD incident irradiance of the Light is increased, so the photocurrent decreases I _PD to and the counter value CNT decreases in the same way in reverse.

Using the example of measuring the absorbance, for example the light absorption, this means that the change in the irradiance on the photodiode PD incident light with the Bouguer-Lambert-Beer law, conclusions about the concentration of a structure to be analyzed 2.1 the analytical sample 2nd can be drawn provided the extinction properties of this structure 2.1 about the irradiance, the layer thickness of the light-absorbing structure and the irradiance of that from a radiation source 7 emitted light of a defined wavelength are known. It is not only possible to make a qualitative but also a quantitative statement about structures 2.1 the analytical sample 2nd and thus possibly via pathogenic structures 2.1 to meet in no time. This can be relevant for long-term patient monitoring in order to decide whether it is necessary to use stressful forms of therapy or whether gentle therapies and / or even the patient's self-healing powers have a regulating and healing effect.

In addition to the advantages of the concept described here with the direct conversion of biochemically induced signals in the analysis sample 2nd into usable electrical signals through the microelectronic sensor system 1 , signal processing via an integrative process and direct digitization of measured values by means of analog value-to-time-to-digital value conversion, there are further advantages in the variably adjustable signal resolution and the configurable dynamic range of the microelectronic sensor system 1 .

Because of the signals to be measured or signal changes due to existing optical properties or due to the change in the optical properties of the analysis samples 2nd Due to processes at the atomic, molecular, gene, protein and / or cell-based level, depending on the analytical application, different measurement conditions can arise, the signal resolution and dynamic range must be variable.

For example, there are measurement conditions for the analysis of biological, chemical and / or biochemical structures 2.1 which must enable the measurement of small or large signal changes in the received irradiance Er in relation to a basic signal in the irradiance.

In absolute terms, the basic signal of the irradiance can be a small or a large signal. The microelectronic sensor system 1 should nevertheless cover the entire measuring range (dynamic range of the microelectronic sensor system 1 ) with the necessary signal resolution. It is therefore relevant whether, with a very low or (as yet) not measurable relative irradiance, a small or large signal change in the received irradiance Er (received irradiance change) with a medium relative irradiance (for example due to the emission of light from a radiation source 7 ) a small or large received change in irradiance or, in the case of very high relative irradiations, a small or large received change in irradiance must be measured. In this regard, the microelectronic sensor system described here offers 1 a variety of options for the optimal setting of signal resolution and dynamic range.

The frequency f _CLK of the cycle defined and supplied by the user CLK determines the signal resolution. The higher the frequency f _CLK is, the finer the signal ramp of the integration voltage V _INT be scanned.

In addition, a suitable choice of signal resolution enables, among other things, real-time measurements of the analysis sample 2nd . Small differences in the voltage ramp increases due to small changes in the generated photocurrent I _PD which in turn result from small signal changes in the irradiance can thus be processed. On the other hand, it affects the frequency f _CLK the integration time of the signal.

Will the frequency f _CLK decreases, the integration time of the photocurrent increases I _PD and vice versa. Especially with small received irradiance Er or irradiance changes, this means that a few photons collected over a longer period and the resulting low photocurrent I _PD can be integrated.

On the choice of the size of the integration capacity C _INT the integration time and signal resolution can also be influenced and set.

• Mit hohen Verstärkungsfaktoren G können bereits sehr kleine Bestrahlungsstärkeänderungen hochaufgelöst verarbeitet werden. Sind die Bestrahlungsstärken oder Bestrahlungsstärkeänderungen relativ groß, kann der Dynamikbereich durch kleinere Verstärkungsfaktoren G im Halbleitersensor 4 erweitert und die Signalauflösung verringert werden. Die Kombination aus der unmittelbaren Umwandlung biochemisch induzierter Signale in der Analysenprobe 2 in elektrische verwertbare Signale durch das mikroelektronische Sensorsystem 1, dem integrativen Signalverarbeitungskonzept mit variabler Signalauflösung sowie einstellbarem Dynamikbereich und der Photodiode PD als Halbleitersensor 4 mit hoher spektralen Empfindlichkeit und geringem Dunkel-Rauschen resultieren in einer hohen Sensitivität des beschriebenen mikroelektronischen Sensorsystems 1.

Thanks to the variable setting options for the gain factors G in the semiconductor sensor 4th can different sections of the dynamic range of the microelectronic sensor system 1 be emphasized and expanded. With small relative irradiations or changes in irradiance, the gain factor can G in the semiconductor sensor 4th be increased, thereby increasing the dynamic range of the microelectronic sensor system 1 is set to the relevant area of signal processing. This also results in a Defined signal resolution in this signal range as follows:

• With high gain factors G Even very small changes in irradiance can be processed with high resolution. If the irradiance or changes in irradiance are relatively large, the dynamic range can be reduced by using smaller amplification factors G in the semiconductor sensor 4th expanded and the signal resolution reduced. The combination of the immediate conversion of biochemically induced signals in the analysis sample 2nd into usable electrical signals through the microelectronic sensor system 1 , the integrative signal processing concept with variable signal resolution as well as adjustable dynamic range and the photodiode PD as a semiconductor sensor 4th with high spectral sensitivity and low dark noise result in a high sensitivity of the microelectronic sensor system described 1 .

• Bei der Ermittlung einer Nachweisreaktion beispielsweise durch DNA-Hybridisierung mit Hilfe der Absorptionsmessung sei eine hohe absolute eingestrahlte Bestrahlungsstärke von Licht definierter Wellenlänge Ausgangspunkt für die Signalgröße eines generierten Photostroms I_PD des mikroelektronischen Sensorsystems 1. Infolge der Hybridisierung zweier komplementärer Einzelstränge kommt es beispielsweise zu einer sehr geringen Extinktion der Bestrahlungsstärke, so dass diese und die damit verbundene Signaländerung des generierten Photostroms I_PD im Vergleich zum hohen absoluten Ausgangssignal der Bestrahlungsstärke oder des generierten Photostroms I_PD sehr klein ist. Es muss also eine sehr geringe Signaländerung im Vergleich zu einem hohen Absolutwert ermittelt werden. Zum einen kann für diesen Fall der Strom I_IDAC genutzt werden, um den hohen Absolutwert in einen geeigneteren Wertebereich zu verschieben. Der Strom I_IDAC ist der durch den Anwender über die Register der digitalen Schnittstelle 11 eingestellte elektrische Strom definierter Größe und Vorzeichen des Strom-Digital-zu-Analog-Wandlers 10.3, der auf den Signalknotenpunkt addiert wird. Diese Funktionsmöglichkeit wurde im System implementiert, um die optimale Funktionsweise der Signalkonversion von Photostrom I_PD zu Zählerwert CNT im Signalpfad auch bei verschieden großen absoluten Bestrahlungsstärken zu ermöglichen und am Signalknotenpunkt einen optimalen Arbeitspunkt einstellen zu können. Damit kann beispielsweise eine Verkleinerung des Absolutwertes durch entsprechende Einstellung des Stroms I_IDAC ermöglicht werden, um kleine Signaländerungen besser herauszuheben.

The described properties of the microelectronic sensor system 1 for the analysis of analytical samples 2nd are explained below using the optical methods of absorbance and luminescence measurement of light as examples:

• When determining a detection reaction, for example by DNA hybridization using the absorption measurement, a high absolute irradiance of light of a defined wavelength is the starting point for the signal size of a generated photocurrent I _PD of the microelectronic sensor system 1 . As a result of the hybridization of two complementary single strands, there is, for example, a very low extinction of the irradiance, so that this and the associated signal change in the generated photocurrent I _PD compared to the high absolute output signal of the irradiance or the generated photocurrent I _PD is very small. A very small signal change compared to a high absolute value must therefore be determined. For one thing, the current can be used in this case I _IDAC be used to shift the high absolute value into a more suitable value range. The current I _IDAC is by the user via the register of the digital interface 11 set electrical current of defined size and sign of the current digital-to-analog converter 10.3 which is added to the signal node. This function was implemented in the system to ensure the optimal functioning of the signal conversion from Photostrom I _PD to counter value CNT To allow in the signal path even with different absolute irradiance levels and to be able to set an optimal working point at the signal node. This can, for example, reduce the absolute value by adjusting the current accordingly I _IDAC be made possible to better emphasize small signal changes.

In addition, the signal resolution can be selected by selecting the appropriate capacity C _INT and / or setting the frequency f _CLK selected by the user as high as possible to be able to resolve small signal changes.

In a further example, a detection reaction, for example of DNA hybridization, is such that after the binding reaction, light of a defined wavelength and intensity is emitted by the hybridized DNA (analyte). The emission of light can, for example, as a result of a biological, chemical and / or biochemical reaction and / or by excitation of the analyte and / or components bound to the analyte and / or structures interacting with the analyte and / or components bound to the analyte 2.1 the analytical sample 2nd with light of a defined wavelength.

The starting point is a very low absolute irradiance of light of a defined wavelength or no irradiation. The microelectronic sensor system 1 should process the emitted light of a defined wavelength or the very small change in irradiance. For example, by reducing the frequency f _CLK can be the integration time of the generated photocurrent I _PD due to the low irradiance or photons received. Thus, the photons can be collected over a longer period of time and the resulting photocurrent I _PD integrated as well as via the counter circuit 10.4 be evaluated. The choice and size of capacity CINT offers an additional manipulated variable to optimally configure integration time and signal resolution.

Another possibility is the direct signal amplification of the small signal change in the irradiance or the resulting photocurrent I _PD by setting an appropriate gain factor G in the sensor block, ie the semiconductor sensor 4th , the microelectronic sensor system 1 . This makes it possible to represent even a very small amount of light, as is common in luminescent detection methods such as fluorescence, phosphorescence, chemo- and bioluminescence measurements, etc., as a representation of a binding reaction to be detected with the microelectronic sensor system described here 1 to detect.

Regardless of examining the analytical sample 2nd by the named methods of extinction and luminescence measurement with the microelectronic sensor system 1 remains the basic principle of signal processing in the microelectronic sensor system 1 the same thing. The photons that make up the photodiode PD of the microelectronic sensor system 1 are achieved by the photodiode PD into a photocurrent I _PD converted that in the semiconductor sensor 4th if necessary, depending on the application. The photocurrent resulting from the sensor block I _PD then on the capacity C _INT integrated. The resulting integration tension V _INT again passes through the two signal thresholds V _KS1 , V _KS2 of the two threshold comparators. With the help of the counter circuit 10.4 the time can be determined and evaluated after passing through the first signal threshold V _KS1 up to the second signal threshold V _KS2 is needed. The resulting digital counter value CNT which is directly proportional to the generated photocurrent I _PD is, which in turn is directly proportional to the received irradiance Er or to the received photons, is available to the user for further processing in the register of the digital interface 11 of the microelectronic sensor system 1 to disposal.

The setting options described here and the adaptation of the microelectronic sensor system 1 for the analysis of analytical samples 2nd with the help of optical methods for absorbance and luminescence measurement are exemplary. Additional configuration options for the microelectronic sensor system 1 among other things, also allow - and not limited to - kinetic measurements with transient signal profiles as a result of biological, chemical and / or biochemical reactions of the analysis sample 2nd Real time.

Another microelectronic block, not shown in detail, forms a digital interface that enables communication between the microelectronic sensor system 1 and system components external to microelectronics. As already described in parts, this includes the configuration of the microelectronic sensor system 1 via the registers of the digital interface 11 to the properties and functions of the microelectronic sensor system 1 adjust. On the other hand, the microelectronic sensor system 1 processed digital signals are transmitted to system components external to microelectronics.

The identification block 13 realizes the possibility of the microelectronic sensor system 1 assign an identification number. In diagnostic applications, this enables a clear assignment and is used for quality assurance. The electrical supply 12th generates electrical currents and / or voltages that serve to supply electrical power to other microelectronic structures and / or to provide reference signals for microelectronic structures. The heating structure 15 is a structure integrated in the semiconductor from a metal used in the semiconductor process, with which it is possible to heat this structure in a controlled manner by feeding in voltages or currents. In some applications and implementation forms of biological, chemical and / or biochemical detection principles, a direct thermal influence on the structures can be 2.1 of the analytical samples 2nd be conducive to reaction quality and speed.

An example is the hybridization of DNA, which, depending on the protocol, takes place at temperatures well above room temperature (for example 40 ° C, 50 ° C, 60 ° C, 70 ° C, 80 ° C or other temperatures above room temperature) .

Another method, called polymerase chain reaction (PCR), enables the duplication of, as a rule, DNA / RNA and / or DNA / RNA components and / or biological, chemical and / or biochemical structures 2.1 to which DNA / RNA is bound. The PCR works in such a way that heating and, if necessary, cooling elements that hold the analysis sample 2nd direct thermal influence, controlled temperature cycles from a start temperature to a target temperature and back again in defined times. This makes it possible to analyze biological, chemical and / or biochemical structures 2.1 to reproduce.

Signal amplification with regard to detection, for example a binding reaction on the part of the biological, chemical and / or biochemical analysis application, can be achieved by increasing the number of biological, chemical and / or biochemical target structures to be examined by the PCR. By in the microelectronic sensor system 1 integrated heating structure 15 and an external control makes it possible to generate controlled temperatures up to 80 ° C. On the microelectronic sensor system 1 analysis samples located 2nd can be directly influenced thermally. The function of controlled cooling is not in the microelectronic sensor system 1 integrated, but can be done via an external control using the heating structure 15 or via an additional controlled and microelectronic element, for example a thermoelectric element. In the latter case, the cooling element would have to be in close proximity to the microelectronic sensor system 1 as well as the analytical sample 2nd be arranged and can influence both thermally directly. This would make it possible to use the microelectronic sensor system 1 to use for PCR applications, also to run fast PCR cycles and a duplication of searched biological, chemical and / or biochemical structures 2.1 to enable.

If no active cooling is used, PCR applications would still be possible, even if the cooling process passively via convection may take longer depending on the desired temperatures and would allow the ambient temperature as the lowest possible temperature.

The integrated temperature sensor 14 is used to monitor the temperature of the microelectronic sensor system 1 as well as in the immediate vicinity of the surface of the microelectronic sensor system 1 analysis sample located 2nd . It measures the temperature and makes it available to the user as an analog and / or digital value. Reading the values of the temperature sensor 14 can be done via settings in the register of the digital interface 11 be made by the user.

In addition, the complete and adequate use, ie with a setting of the microelectronic sensor system optimally adapted to the bioanalytical application 1 , additional requirements and systemic requirements result: Luminescent detection methods such as fluorescence measurements require optical filters in order to excite the radiation source 7 from the emitted light of the analysis sample 2nd or to separate or strongly attenuate the analyte. This can have a disruptive influence by the radiation source 7 be reduced. If necessary, the technical interface would have to be used 3rd of the microelectronic sensor system 1 have a corresponding filter characteristic with regard to the excitation light.

In the case of time-resolved luminescence measurements, such as the time-resolved fluorescence measurement of analysis samples 2nd , which emit light after the excitation for a defined period of time, is possible by appropriate control and adjustment of the microelectronic sensor system 1 and peripheral system components influences the afterglow of the exciting radiation source 7 after switching off and annoying background lighting by whatever technical system components, for example a construction and connection technology for the microelectronic sensor system 1 to reduce or even eliminate. The control and setting can be done by peripheral system components outside of the microelectronic sensor system 1 be initiated.

Through this overall system functionality of the microelectronic sensor system 1 in combination with other peripheral technical system components, a readout time for the readout process of the at least one semiconductor sensor 4th after switching off the radiation source 7 can be found so that the influences of afterglow of the radiation source 7 as well as background lighting can be minimized or even eliminated. The times for the afterglow of the radiation source 7 and for the backlighting may have to be determined experimentally with the system. If necessary, these properties are described in the corresponding data sheets for the named components.

A problem with absorbance measurement is fluctuations or transient processes of the radiation sources 7 . To solve this problem, peripheral technical system components, such as an additional photodiode PD and a driver circuit can be used to determine these influences, regulating the radiation source 7 to act and suitable times for reading processes with the microelectronic sensor system 1 to specify.

The advantages and disadvantages of implementing several sensors, sensor matrices, arrays etc. in the microelectronic sensor system have already been discussed in advance 1 described. At this point it should be pointed out that the integration of at least one reference sensor is essential for the analytical application. No analytical structures important for the detection reaction are allowed on this sensor 2.1 including the analyte itself. As a result, in addition to the actual detection reaction on the other sensors, additional influences of the analysis samples can be made 2nd , such as influences by different types of ions and ion concentrations or by other structures 2.1 the analytical sample 2nd , to the actual detection reaction, can be determined in parallel. This may result in subsequent correction or signal processing of the measurement data of the semiconductor sensors 4th on which the actual reaction took place, in the sense of the evidence to be provided.

Reference list

1

microelectronic sensor system

2nd

Analytical sample

2.1

structure

2.2

biochemical interface

3rd

technical interface

4th

Semiconductor sensor

5

circuit

6

contraption

7

Radiation source

8th

optical component

9

Signal processing path

10th

Signal processing structure

10.1

Integrator circuit

10.2

Comparator circuit

10.3

Current digital-to-analog converter

10.4

Counter circuit

11

digital interface

12th

connected to the electricity grid

13

Identification block

14

Temperature sensor

15

Heating structure

16

Amplifier circuit

17th

Adjusting device

1: G

Mirror ratio

a) to d)

Lower level

CINT

capacity

CNTSTP

signal

CNTSTRT

signal

EOC

signal

E _r

receive irradiance

f _CLK

frequency

G

Gain factor

I _PD

Photocurrent

PD

Photodiode

S1 to S6

step

S _DC

switch

S _SEL

temporal behavior

V1 to V4

step

V _INT

Integration tension

V _KS1

Signal threshold

V _KS2

Signal threshold

Claims (13)

Device (6) for analyzing biological, chemical and biochemical substances, comprising a microelectronic sensor system (1) with - at least one semiconductor sensor (4), at least one application-specific integrated circuit (5) coupled to the at least one semiconductor sensor (4) for signal processing of an electrical signal generated by means of the at least one semiconductor sensor (4), - At least one technical interface (3) for applying at least one biological, chemical or biochemical substance in a detection area of the at least one semiconductor sensor (4) and - At least one setting device (17) for setting a dynamic range and / or a signal resolution of the electrical signal generated by means of the at least one semiconductor sensor (4). Device (6) after Claim 1 , wherein the setting device (17) comprises at least one amplifier circuit (16) arranged between the at least one semiconductor sensor (4) and the application-specific integrated circuit (5) or between a component of the setting device (17) and the application-specific integrated circuit (5), which is set up to amplify the electrical signal generated by means of the at least one semiconductor sensor (4). Device (6) after Claim 1 or 2nd The setting device (17) comprises at least one current-digital-to-analog converter (10.3) arranged between the at least one semiconductor sensor (4) and the application-specific integrated circuit (5), which converts electrical currents with different signs the electrical signal generated by means of the at least one semiconductor sensor (4) is set up. Device (6) according to one of the preceding claims, wherein the setting device (17) comprises at least one integrator circuit (10.1) which is arranged between the at least one semiconductor sensor (4) and the application-specific integrated circuit (5) and which has an adjustable electrical capacitance (C _INT ) comprising the electrical signal generated by means of the at least one semiconductor sensor (4). Device (6) after Claim 4 The integrator circuit (10.1) is followed by a comparator circuit (10.2) which is set up to detect an increase in an electrical integration voltage (V _INT ) resulting from charging the adjustable electrical capacitance (C _INT ) of the integrator circuit (10.1) and a value to compare the resulting electrical integration _voltage (V _INT ) with at least two different signal _thresholds (V _KS1 , V _KS2 ). Device (6) after Claim 5 , A counter circuit (10.4), which is set up, is coupled to the comparator circuit (10.2) Reaching a first signal threshold (VKS1) of the resulting electrical integration voltage (V _INT ) to start a time counting process depending on a clock fed into the microelectronic sensor system (1) with a defined frequency (f _CLK ) and when reaching a higher second signal _threshold (V _KS2 ) Stop counting. Device (6) according to one of the preceding claims, wherein the microelectronic sensor system (1) comprises at least one heating structure (15) for heating the technical interface (3). Device (6) according to one of the preceding claims, wherein the technical interface (3) comprises at least one ion-sensitive layer. Device (6) according to one of the preceding claims, wherein - At least one semiconductor sensor (4) is designed as an optical semiconductor sensor and - A radiation source (7) for emitting light in the direction of the at least one semiconductor sensor (4) is provided. Device (6) according to one of the preceding claims, wherein - At least one semiconductor sensor (4) is designed as a non-optical semiconductor sensor. Method for analyzing biological, chemical and biochemical substances using a microelectronic sensor system (1), wherein at least one biological, chemical or biochemical substance is applied to a technical interface (3) arranged in a detection area of at least one semiconductor sensor (4), - by means of the at least one semiconductor sensor (4), substance information formed as a function of the substance is detected and an electrical signal corresponding to the substance information is generated, - The electrical signal is fed to an adjusting device (17), by means of which a dynamic range and / or a signal resolution of the electrical signal is or is set and a modified electrical signal is generated and - The modified electrical signal is supplied to an application-specific integrated circuit (5) for signal processing. Procedure according to Claim 11 , wherein - the technical interface (3) is arranged between at least one semiconductor sensor (4) designed as an optical semiconductor sensor and at least one radiation source (7), - by means of the radiation source (7) light in the direction of the substance and the at least one semiconductor sensor (4) is emitted, - by means of the at least one semiconductor sensor (4), as substance information, a differential light formed as a function of the substance is detected and an electrical signal corresponding to the differential light is generated. Procedure according to Claim 11 or 12th , wherein the adjusting device (17) - amplifies the electrical signal generated by the at least one semiconductor sensor (4), - adds electric currents with different signs to the electrical signal generated by the semiconductor sensor (4) and / or - an adjustable electrical signal Capacitance (C _INT ) of an integrator circuit (10.1) with which the electrical signal generated by the at least one semiconductor sensor (4) is applied, an increase in an electrical integration voltage (V.) Resulting from charging the adjustable electrical capacitance (C _INT ) of the integrator circuit (10.1) _INT ) is detected, a value of the resulting electrical integration _voltage (V _INT ) is compared with signal _thresholds (V _KS1 , VKS2), when a first signal _threshold (V _KS1 ) is reached, a time counting process is also dependent on a clock fed into the microelectronic sensor system (1) defined frequency (F _CLK ) is started and the time counting process is stopped when a higher second signal _threshold (V _KS2 ) is reached.

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