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WO2006048351A1 - Detecteur servant a realiser des analyses chimiques et comportant un element micromecanique pouvant subir une deviation - Google Patents

Detecteur servant a realiser des analyses chimiques et comportant un element micromecanique pouvant subir une deviation Download PDF

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Publication number
WO2006048351A1
WO2006048351A1 PCT/EP2005/054462 EP2005054462W WO2006048351A1 WO 2006048351 A1 WO2006048351 A1 WO 2006048351A1 EP 2005054462 W EP2005054462 W EP 2005054462W WO 2006048351 A1 WO2006048351 A1 WO 2006048351A1
Authority
WO
WIPO (PCT)
Prior art keywords
micromechanical
deflection part
electric field
deflection
sensor according
Prior art date
Application number
PCT/EP2005/054462
Other languages
German (de)
English (en)
Inventor
Christoph Schelling
Julian Gonska
Original Assignee
Robert Bosch Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Robert Bosch Gmbh filed Critical Robert Bosch Gmbh
Publication of WO2006048351A1 publication Critical patent/WO2006048351A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/02—Analysing fluids
    • G01N29/036—Analysing fluids by measuring frequency or resonance of acoustic waves
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/02—Indexing codes associated with the analysed material
    • G01N2291/025—Change of phase or condition
    • G01N2291/0256—Adsorption, desorption, surface mass change, e.g. on biosensors

Definitions

  • the invention is based on a micromechanical sensor for chemical, in particular biochemical, analysis with at least one micromechanical deflection part, wherein the micromechanical deflection part has receptors for binding at least one analyte on at least one surface.
  • DNA fragments In many molecular biology applications, substances are analyzed that are not electrically neutral towards the outside. Examples include proteins or DNA fragments. The possibility of using a piezoresistive bending beam sensor with high sensitivity is explained here using the example of the analysis of DNA fragments. DNA fragments have a negative charge proportional to their length. However, the principle of operation can be transferred to all analysates (ligands) with electrical charge, for which specific binding receptor molecules exist.
  • the goal of DNA analysis is to demonstrate the presence of a particular sequence of bases in a section of DNA.
  • this section may have typical sequences of bases for certain hereditary diseases.
  • DNA extracted from cells purified and duplicated. Subsequently, the fragment to be analyzed is "excised” from the DNA strand using a special procedure.
  • One possible method for DNA analysis utilizes the specific juxtaposition (hybridization) of matching (complementary) DNA single strands.
  • DNA is usually present as a double strand, which can be decomposed by heating in 2 single strands. Exactly one complementary base sequence exists for each base sequence. If single strands are immobilized on a surface
  • DNA probes hybridization in the presence captures the complementary single strands from an analyte.
  • the analyte is usually labeled with a fluorescent dye, so that after hybridization, an evaluation can be carried out by fluorescence microscopy. If the searched base sequence is present in the analysate, it occurs after a rinsing step
  • Fluorescence while in analyzes without the desired sequence after a rinse step no fluorescence occurs.
  • the invention is based on a micromechanical sensor for chemical, in particular biochemical, analysis with at least one micromechanical deflection part, the micromechanical deflection part having receptors for binding at least one analyte on at least one surface.
  • the core of the invention is that the sensor has means for generating an electric field, wherein the micromechanical deflection part is deflectable under the influence of the analyte and the electric field.
  • the invention provides a simple and sensitive micromechanical sensor for detecting in particular chemical or biochemical analyzes.
  • the deflection of the micromechanical deflection part of the sensor according to the invention is advantageously much higher as the deflection of the bending beam of a sensor in the prior art with sole change of the surface tension during the immobilization of the receptors or the analysis would be.
  • the sensor has a higher sensitivity compared to a detection principle based purely on changing the surface electric voltage on one side of a bending beam.
  • the analyte should only be immobilized on one side of the flexbeam.
  • the avoidance of immobilization on the other hand requires a great deal of effort (see “Label-free protein assay based on a nanomechanical cantilever array", Nanotechnology 14, pp. 86-90 (2003), Y. Arntz, JD Selig, HP Lang, J. Zhang, P. Hunziker, JP Ramseyer, E. Meyer, M. Hegner, Ch. Gerber)
  • the sensor presented in this invention does not lose its functionality if the analyte is immobilized on both sides.
  • An advantageous embodiment provides that the means for generating an electric field are designed as at least two electrodes. Between two
  • Electrodes can be created in the simplest way an electric field.
  • the micromechanical deflection part constitutes an electrode.
  • the analyte is attracted to the deflection part and bound faster to the receptors.
  • the micromechanical deflection part is arranged between two electrodes.
  • the micromechanical deflection part occupied by an electrically charged analyte is deflected particularly effectively in the electric field between the electrodes.
  • micromechanical deflection part is a bending beam. This is a very easy-to-manufacture embodiment of a micromechanical deflection part.
  • the micromechanical deflection part has a piezoresistive resistance region whose resistance is variable depending on the deflection.
  • the deflection of the deflection part can be determined easily piezoresistive.
  • the senor has means for optical measurement of the deflection of the micromechanical deflection part.
  • the deflection can be measured without contact and without electrical connection to the deflection part.
  • a further advantage is that the analyte to be examined is electrically charged. Since the deflecting force acting on the micromechanical deflection part is proportional to
  • Micromechanical sensor characterized in that the means for generating an electric field are designed such that different electric field strengths can be generated. Since the deflecting force acting on the micromechanical deflection part is proportional to the electric field strength, by varying the applied voltage it is advantageously possible to vary the possible measuring range over a few orders of magnitude.
  • the immobilization time can be shortened advantageous.
  • the immobilization of non-fluorescently labeled receptor molecules e.g., DNA probes
  • Receptor or ligand molecule can be determined, how high the immobilization or hybridization density.
  • the senor can also be used for mass flow measurement or by applying an electrical voltage to the piezoresistive resistance regions of the
  • Bending bars are operated as a heater, if this requires any operating conditions to be envisaged.
  • FIG. 1 shows a bending beam as a micromechanical deflection part of a micromechanical sensor according to the invention.
  • FIG. 2 schematically shows a first embodiment of a micromechanical sensor according to the invention.
  • FIG. 3 shows the operating principle of a micromechanical sensor according to the invention with an electric field between the deflection part and the electrode.
  • FIG. 4 shows the operating principle of a micromechanical sensor according to the invention with deflection part in the electric field between two electrodes.
  • FIG. 5 shows schematically a second embodiment of a micromechanical sensor according to the invention.
  • a bending beam 6 of a sensor element may have the shape shown here in cross section. Shown is a main body 1 of the bending beam 6, which consists of conductive material such as n-doped silicon.
  • the base body 1 has on the surface of an insulating jacket 2 made of non-conductive material such as silicon dioxide.
  • a functional layer with receptors 3 is arranged, to which the analyte molecules can bind.
  • the functional layer with Receptors 3 may be located not only on one but also on a plurality of surfaces of the bending beam 6, in particular on opposite sides.
  • the bending beam 6 has piezoresistive resistance regions 4 within a bending region.
  • the piezoresistive resistance regions 4 are preferably located at the point with the highest stress coupling in deflection of the bending beam 6 and consist in this example of p-doped silicon.
  • p-doped regions 5 can be introduced into the bending beam 6.
  • FIG. 2 schematically shows a first embodiment of a micromechanical sensor according to the invention with a deflection part. Shown is a bending beam 6, whose base body 1 is structured out of a silicon substrate 100. The silicon substrate 100 is arranged in a housing 9. Above and below the bending beam 6 are 2 electrodes 7 and 8, which may be attached to the housing 9 by means of an adhesive bond or other connection, for example.
  • the attachment to an outside of the housing 9 prevents an electrolysis reaction during the analysis.
  • the housing 9 has inlet and outlet ports 10 and 11 for supplying and discharging an analyte, i. a liquid containing the analyte.
  • the inlet and outlet openings 10 and 11 open accesses to a cavity 200 in which the bending beam 6 is arranged accessible for the analysis.
  • Housing 9 also has electrically conductive connections 12 and 13 (e.g., metallic bonds on bonding regions of substrate 100) for electrically contacting piezoresistive resistor region 4 of bending beam 6.
  • electrically conductive connections 12 and 13 e.g., metallic bonds on bonding regions of substrate 100
  • FIG. 3 shows the operating principle of a micromechanical sensor according to the invention with an electric field between the deflection part and the electrode. Between an electrode 7 and a bending beam 6, an electric field 15 is generated by means of a connected voltage source 300.
  • a possible application example of the micromechanical sensor is the DNS analysis.
  • DNA fragments 14 are introduced into the cavity 200 of the sensor. The DNA fragments 14 adhere to the receptors 3 on the
  • the DNA fragments 14 have one surplus electron per base and thus a proportional to the length negative electric charge.
  • the electric field 15 can be used to increase the concentration of the DNA fragments on the surface of the bending beam 6. This increases the speed of Analysis, since without electrical field, the DNA fragments reach the surface exclusively by diffusion.
  • FIG. 4 shows the operating principle of a micromechanical sensor according to the invention with deflection part in the electric field between two electrodes. Shown is a
  • a voltage source 400 By means of a voltage source 400, a voltage is applied between the electrodes 7 and 8, resulting in an electric field 17 between the electrodes 7 and 8.
  • immobilization or hybridization as described, for example, in FIG. 3, it can be demonstrated that DNA probes reach the surface or DNA fragments to be analyzed.
  • Fragments 16 are attached to the DNA probes.
  • the electric field 17 between the electrodes 7 and 8 serves this purpose.
  • the micromechanical deflection part, in this case the bending beam 6, which is occupied by the electrically charged analyte 16, is deflected in the electric field 17.
  • the deflection 18 of the bending beam 6 is detected piezoresistive. It is proportional to the charge on the surface of the
  • the analyte 16 is in a buffer solution 410 which is introduced into the cavity 200 for analysis.
  • the buffer solution 410 preferably has a high electrical resistance.
  • FIGS. 3 and 4 can also be combined with one another for the purpose of detection, that is to say they can be used successively, for example.
  • FIG. 5 shows schematically a second embodiment of a micromechanical sensor according to the invention with two deflection parts.
  • two electrically separated analysis chambers 510 and 520 with two electric fields of opposite polarity 19 and 20 are provided in a housing 9.
  • the resistance of the piezoresistive regions 4 of the bending beam 6 increases during analysis while it decreases in the other analysis chamber.
  • the measurement signals from the piezoresistive regions 4 can be evaluated.
  • external influences and disturbances which act equally on both bending beam 6, can be eliminated.
  • more bending beams can be provided, which can be deflected in a common or in opposite directions.
  • the micromechanical deflection part can also be designed differently than in the form of a bending beam and the detection of the deflection can not be piezoresistive but, for example, optical. This would be possible by means of simple light barriers or else with a light source which throws light directed at the deflection part. The light is reflected at a certain angle as a function of the deflection of the deflection part and can be detected spatially resolved with suitable sensors. From this, the deflection can be determined in retrospect.
  • the structure and mode of action of the micromechanical sensor can be described as follows. Shown is a sensor with at least one micromechanical deflection part, in particular with a bending beam 6 with piezoresistive areas 4, with at least two electrodes 7 and 8, which are located on two opposite sides of the bending beam.
  • the bending beam 6 has a receptor-coated surface on which analyte molecules can be immobilized. The analyte is electrically charged and there are binding sites that allow specific binding to the receptors.
  • the space 200 around the bending beam 6 and between the electrodes 7 and 8 can be filled with a buffer solution.
  • An electrical voltage 400 can be applied to the two electrodes 7 and 8.
  • an electric field 17 with a component perpendicular to the bending beam 6 is formed.
  • the deflection of the bending beam 6 is proportional to the applied electric field 17 and to the fixed amount of charge at the bending beam surface.
  • the deflection of the bending beam 6 can be detected by means of the piezoresistive resistance regions 4.
  • the ligand molecule concentration or, in the case of receptors with electrical charge, the receptor molecule concentration above the surface of the bending beam 6 can be increased during the receptor-ligand binding reaction or the receptor immobilization by applying an electric field 15 between the bending beam and an electrode.
  • the sensor may have an electrical circuit which, for example, interconnects the piezoresistive resistance regions 4 in the form of a Wheatstone bridge circuit.

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  • Physics & Mathematics (AREA)
  • Acoustics & Sound (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)

Abstract

L'invention concerne un détecteur micromécanique servant à réaliser des analyses chimiques, comportant au moins un élément micromécanique (6) pouvant subir une déviation, qui, sur au moins une surface, comporte des récepteurs (3) destinés à fixer au moins une substance à analyser (14). Ce détecteur présente des moyens servant à produire un champ électrique. L'élément micromécanique (6) peut subir une déviation sous l'effet de la substance à analyser (14) et du champ électrique (15, 17, 19, 20).
PCT/EP2005/054462 2004-11-04 2005-09-08 Detecteur servant a realiser des analyses chimiques et comportant un element micromecanique pouvant subir une deviation WO2006048351A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004053261.3 2004-11-04
DE200410053261 DE102004053261A1 (de) 2004-11-04 2004-11-04 Mikromechanischer Sensor zur chemischen Analyse

Publications (1)

Publication Number Publication Date
WO2006048351A1 true WO2006048351A1 (fr) 2006-05-11

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DE (1) DE102004053261A1 (fr)
WO (1) WO2006048351A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4549427A (en) * 1983-09-19 1985-10-29 The United States Of America As Represented By The Secretary Of The Air Force Electronic nerve agent detector
US5807758A (en) * 1995-07-21 1998-09-15 Lee; Gil U. Chemical and biological sensor using an ultra-sensitive force transducer
US6289717B1 (en) * 1999-03-30 2001-09-18 U. T. Battelle, Llc Micromechanical antibody sensor
US20030032293A1 (en) * 2001-08-07 2003-02-13 Korean Institute Of Science And Technology High sensitive micro-cantilever sensor and fabricating method thereof
WO2003098661A2 (fr) * 2001-10-26 2003-11-27 Integrated Nano-Technologies, Llc Systeme de detection de risques chimiques et biologiques et leurs procedes
WO2003104784A1 (fr) * 2002-06-07 2003-12-18 Cantion A/S Capteur cantilever a ecran de courant et son procede de production

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4549427A (en) * 1983-09-19 1985-10-29 The United States Of America As Represented By The Secretary Of The Air Force Electronic nerve agent detector
US5807758A (en) * 1995-07-21 1998-09-15 Lee; Gil U. Chemical and biological sensor using an ultra-sensitive force transducer
US6289717B1 (en) * 1999-03-30 2001-09-18 U. T. Battelle, Llc Micromechanical antibody sensor
US20030032293A1 (en) * 2001-08-07 2003-02-13 Korean Institute Of Science And Technology High sensitive micro-cantilever sensor and fabricating method thereof
WO2003098661A2 (fr) * 2001-10-26 2003-11-27 Integrated Nano-Technologies, Llc Systeme de detection de risques chimiques et biologiques et leurs procedes
WO2003104784A1 (fr) * 2002-06-07 2003-12-18 Cantion A/S Capteur cantilever a ecran de courant et son procede de production

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