EP1740935A1 - Field effect transistor for measuring biocomponents - Google Patents

Field effect transistor for measuring biocomponents

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Publication number
EP1740935A1
EP1740935A1 EP05715622A EP05715622A EP1740935A1 EP 1740935 A1 EP1740935 A1 EP 1740935A1 EP 05715622 A EP05715622 A EP 05715622A EP 05715622 A EP05715622 A EP 05715622A EP 1740935 A1 EP1740935 A1 EP 1740935A1
Authority
EP
European Patent Office
Prior art keywords
electrode
θate
layer
source
drain
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP05715622A
Other languages
German (de)
French (fr)
Inventor
Ingo Freund
Mirko Lehmann
Hans-Jurgen Gahle
Werner Dr. Baumann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TDK Micronas GmbH
Original Assignee
TDK Micronas 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 TDK Micronas GmbH filed Critical TDK Micronas GmbH
Publication of EP1740935A1 publication Critical patent/EP1740935A1/en
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/48707—Physical analysis of biological material of liquid biological material by electrical means
    • G01N33/48728—Investigating individual cells, e.g. by patch clamp, voltage clamp
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/403—Cells and electrode assemblies
    • G01N27/414—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS
    • G01N27/4145—Ion-sensitive or chemical field-effect transistors, i.e. ISFETS or CHEMFETS specially adapted for biomolecules, e.g. gate electrode with immobilised receptors

Definitions

  • the invention relates to a device for carrying out measurements on biocomponents, in particular on living cells, with at least one field effect transistor which has a source, a drain and a channel region connecting them on a substrate, on which a ⁇ ate electrode is arranged, which is electrically isolated from the channel area by a thin insulating layer.
  • Such a device is known from DE 196 23 517 Cl. It has a field effect transistor; in which the ⁇ ate electrode is connected in an electrically conductive manner via a conductor track to a contact area (pad) bounded by an electrical insulator and which is dimensioned for connection to a living biological cell in a nutrient solution.
  • the field effect transistor has a substrate made of silicon, into which a trough-shaped semiconductor layer of a first charge carrier type is embedded. Doped drain and source regions, between which a channel region is formed, are arranged in this semiconductor layer.
  • the ⁇ ate electrode consists of polysilicon and covers the entire channel area and the adjacent edges of the drain and source.
  • the ⁇ ate electrode forms an equipotential surface which distributes an electrical potential applied to it over the entire channel length extending from the drain to the source, so that the potential also in the saturation mode of the field effect transistor if there is an asymmetrical, one-sided distribution along the channel length sets the free charge carriers in the channel area, to the places where the channel area is most sensitive.
  • the device has the disadvantage that its measuring sensitivity is greatly reduced if the contact area connected to the ⁇ ate is only partially covered by the cell, so that the nutrient solution in which the cell is arranged comes into contact with the other areas of the contact area ,
  • the decrease in measuring sensitivity is mainly caused by the fact that the biological cell enters the contact area and thus the ⁇ ate electrode, which is essentially capacitively coupled in, corresponds to the output voltage of an equivalent voltage source with a high source resistance. Since the nutrient solution is relatively low-resistance due to the ions contained in it compared to the source resistance, the measurement signal applied to the ⁇ ate is reduced accordingly when the equivalent voltage source is loaded with the electrical resistance of the nutrient solution.
  • the cell signal to be measured is then practically short-circuited by the nutrient solution lying at a reference potential, ie the major part of the voltage is not present at the ⁇ ate but falls at the source resistance of the equivalent voltage source. It is also unfavorable that the arrangement formed from the ⁇ ate electrode, the conductor track and the contact area has a relatively large electrical capacitance to the nutrient solution, as a result of which the measurement signal is additionally weakened.
  • the ⁇ ate electrode has at least two electrode regions arranged laterally next to one another, which are spaced apart from one another and electrically insulated from one another transversely to the direction in which the channel region connects the source to the drain.
  • the ⁇ ate electrode is therefore advantageously divided into a plurality of electrode regions which are electrically insulated from one another and which are offset from one another transversely to a line which connects the source and drain directly to one another and approximately corresponds to the current flow direction in the channel region.
  • the ⁇ ate electrode is only partially covered in such a way that at least a first electrode area of the ⁇ ate electrode is in direct contact with the nutrient solution and at least a second electrode area is completely covered by the biocomponent and sealed by it against the nutrient solution, becomes a direct equipotential bonding between the first and the second
  • the divided ⁇ ate electrode reduces the capacitive load on the measurement signal due to parasitic capacitances compared to a device with a one-piece ⁇ ate electrode.
  • the device advantageously enables a relatively high sensitivity to measurement and detection even if the biocomponent only covers the ⁇ ate electrode in some areas.
  • the electrical potentials present at the individual electrode areas can be coupled into the sub-area of the channel area in which the channel area has its greatest sensitivity, in particular when the field effect transistor is operating in the saturation area.
  • the device is preferably designed such that the biocomponent to be measured can be immobilized directly on the ⁇ ate electrode. The device enables high-resistance signal tapping at the biocomponent.
  • the device has at least three, in particular at least five and preferably at least seven, of the electrode regions in a row next to one another. If the biocomponent only partially covers the ⁇ ate electrode, this can result in an even greater overall measurement sensitivity and measurement reliability with different arrangements of the biocomponent relative to the ⁇ ate electrode.
  • the edges of the drain and the source adjoining the channel region run approximately parallel to one another, with mutually facing electrode edges of mutually adjacent electrode regions each running approximately at right angles to the edges of the drain and / or the source adjoining the channel region.
  • the dividing lines between mutually adjacent electrode regions then run approximately in the direction in which the electrical current flows in the channel region.
  • an electrical insulator preferably designed as an oxide layer, is in each case on the drain and the source.
  • Layer is arranged, the thickness of which is a factor of at least 10, optionally 30 and preferably 50 greater than the thickness of the insulating layer, the electrode regions and optionally the insulating layer laterally directly adjoining the edge of the insulator layer facing the channel region.
  • the area that covers the individual electrode areas on the channel area is less than or equal to the area covered by a focal contact of a biological cell that can be immobilized on the ⁇ ate electrode, and if the area that covers the individual electrode areas on the Channel areas cover in particular between 0.5 ⁇ m 2 . and 5 ⁇ m 2 . is.
  • the insulating layer is designed as a silicon oxide layer, in particular as a silicon dioxide layer
  • the ⁇ ate electrode is designed as a noble metal layer, in particular as a palladium layer, with a between the insulating layer and the ⁇ ate electrode
  • Poly-silicon layer is arranged, which in the between adjacent electrode areas
  • the ⁇ ate electrode can then be structured during the manufacture of the device by the intermediary of the intermediate layer.
  • the channel region on the doped semiconductor layer (this can be formed by the substrate or a trough-shaped region on the substrate), in order to subsequently produce the electrically insulating silicon oxide layer ( ⁇ ateoxide) on the channel region.
  • a poly-silicon layer is then applied over the entire surface and then structured in such a way that it only adheres to the
  • the ⁇ ate electrode is later to be arranged. Structured layers to form conductor tracks are now applied to the substrate. Electrically insulating layers are arranged between the individual layers of the conductor track layers. A passivation layer is applied as the top layer. Then, depressions are etched over the locations at which the polysilicon is located, which extend as far as the polysilicon layer serving as an etching stop. If the ⁇ ate electrode should only partially cover the bottom of the wells, the poly-silicon layer is structured in the wells. Then a metallization made of a precious metal is applied over the entire surface.
  • silicon diffuses from the poly-silicon layer into the noble metal layer and forms a noble metal silicide in a region of the noble metal layer that is spaced from the surface of the noble metal layer.
  • the noble metal adheres better to the poly-silicon layer than to the rest of the surface, so that it can be structured mechanically, for example with the aid of ultrasound waves, in accordance with the structure of the poly-silicon layer.
  • the precious metal only comes off at those points that are not in contact with the poly-silicon layer.
  • the device according to the invention is preferably designed such that the biocomponent can be brought into direct contact with the ⁇ ate electrode arranged on the channel area, i.e. the biocomponent is preferably located on the side of the ⁇ ate electrode facing away from the channel area directly above the channel area during the measurement. This results in a small parasitic capacitance at the ⁇ ate electrode.
  • the ⁇ ate electrode preferably adjoins a measuring chamber or a trough for receiving the biocomponent (s) and, if appropriate, a nutrient solution containing them.
  • the individual electrode regions are each connected via a conductor track to an electrical contact element (pad) which is arranged for contacting the biocomponent in a contact region for the biocomponent spaced from the ⁇ ate electrode.
  • an electrical contact element pad
  • the device has a plurality of the field effect transistors, these field effect transistors preferably being arranged next to one another on a common semiconductor substrate in the form of a matrix. The device then enables spatially resolved measurement signal detection on the biocomponents.
  • At least one electrode region of the ⁇ ate electrode and / or a stimulation electrode which is present in addition to the electrode regions and is adjacent to these is connected to an electrical stimulation device for the biocomponent.
  • the stimulation device has an electrical voltage source; which can be connected to the electrode area and / or stimulation electrode via an electrical switch.
  • the propagation of electrical signals and / or signal patterns within the cell culture can be examined on cell cultures which have a plurality of nerve cells networked with one another.
  • an electrical stimulation potential is first applied to the at least one electrode area and / or the stimulation electrode, then removed again in order to then measure the response of the cell (s) to the stimulation potential with the aid of the electrode areas.
  • FIG. 1 is a three-dimensional partial view of a device having a field effect transistor for carrying out measurements on biocomponents, the device being shown in cross section in the area of the field effect transistor,
  • FIG. 2 shows a plan view of the device shown in FIG. 1 in the region of the field effect transistor, a structured ⁇ ate coating being recognizable
  • Fig. 3 is a partial plan view of the device in the ⁇ use position, and 4 shows a cross section through the device, wherein parasitic capacitances are shown schematically.
  • a device for carrying out extracellular cell potential measurements on living biological cells has a semiconductor chip; in which at least one field effect transistor 1 is integrated, which is connected to a measuring amplifier not shown in the drawing.
  • the semiconductor chip has a doped semiconductor layer 2 of a first charge carrier type; which is formed by the substrate of the semiconductor chip.
  • the semiconductor layer 2 is embedded in the semiconductor substrate as a trough-shaped doped region (well).
  • Doped regions of a second charge carrier type are arranged on the semiconductor layer 2, one region of which forms the source 3a and the other region forms the drain 3b of the transistor 1 when the latter is connected to the measuring amplifier.
  • the source 3a and the drain 3b are embedded in the surface of the semiconductor layer 2 and are laterally spaced apart from one another by a channel region 4 located between them.
  • the source 3a is connected to a source contact 5a and the drain 3b is connected to a drain contact 5b, which are connected to the measuring amplifier. 1 that the source contact 5a is also connected to the semiconductor layer 2 (substrate).
  • An insulating layer 6 is arranged on the channel region 4, which is designed as a thin oxide layer and extends continuously over the channel region 4 and the border regions 7a, 7b of the source 3a and the drain 3b adjoining it on both sides.
  • a structured poly-silicon layer is applied to the insulating layer ⁇ , on which an ⁇ ate electrode, generally designated 8, is arranged, which is formed by a metallization.
  • the metallization consists of a corrosion-resistant noble metal, preferably palladium.
  • a metal silicide layer is formed in the transition region from the poly-silicon layer to the ⁇ ate electrode 8.
  • the ⁇ ate electrode 8 adheres well to the polysilicon layer or is firmly connected to it.
  • the ⁇ te electrode 8 borders directly on a receiving space 9 which is designed to receive living cells 14 located in a nutrient solution 15.
  • the ⁇ ate electrode 8 has a plurality of electrode regions 10 arranged laterally next to one another; the parallel to the
  • Double arrow 1 1 marked direction in which the channel area 4 the source 3a with the
  • Drain 3b connects, spaced apart and electrically isolated from each other.
  • the individual electrode regions 10 are each approximately rectangular in shape and extend in the direction 1 1 in which the channel region 4
  • Source 3a connects to the drain 3b, without interruption via the channel region 4.
  • electrode regions 10 each cover the edge region 7a of the source 3a adjoining the channel region 4 and the opposite end of the edge region 7b of the drain 3b adjoining the channel region 4.
  • Adjacent electrode regions 10 are each spaced apart from one another by a narrow space which, when viewed from the top of the semiconductor chip, runs approximately at right angles to the edges of the source 3a and the drain 3b adjacent to the channel region 4. Parallel to these edges, the electrode regions 10 are offset in a straight line from one another, so that overall there is an approximately rectangular elongated ⁇ ate electrode 8 consisting of several electrode regions 10 arranged in a row, the dimensions of which are adapted to those of a biological cell. It can be seen in FIG. 2 that the source 3a and the drain 3b each extend without interruption over all electrode regions 10 of the ⁇ ate electrode 8.
  • An electrical insulator layer 12a, 12b which is designed as a thick oxide layer (field oxide layer) and has a greater thickness than the insulating layer ⁇ , is arranged on the source 3a and the drain 3b at a distance from the channel region 4.
  • the electrode areas 10 and the insulating layer ⁇ laterally adjoin at one end to the insulator layer 12a located on the source 3a and at the other end to the insulator layer 12b located on the drain 3b.
  • Fig. 3 shows a plan view of the device in the ⁇ use position. It can be clearly seen that a biological cell 14 is immobilized on the surface of the semiconductor chip, which is arranged in a nutrient solution 15 (FIG. 4), which is at an electrical reference potential, for example that at which, via a reference electrode not shown in the drawing Source contact 5a applied potential.
  • the cell 14 is positioned relative to the ⁇ ate electrode 8 such that it completely covers some of the electrode regions 10.
  • the cell adheres to these electrode areas 10 and to the surface areas of the semiconductor chip that delimit them and are electrically insulated from the electrode areas 10 such that the cell 14 seals these electrode areas 10 against the nutrient solution 15.
  • the remaining electrode regions 10 have contact with the nutrient solution 15 at least in regions and are therefore at the reference potential applied to the nutrient solution 15. Since the ⁇ ate electrode 8 is subdivided into several electrode regions 10, it is avoided that the cell potential coupled from the cell 1 via the cell membrane into the electrode regions 10 sealed by the cell 14 against the nutrient solution 15 is drawn to the comparatively low-resistance reference potential. The device therefore enables an accurate measurement of cell potential changes even when the ⁇ ate electrode 8 is only partially covered by the cell 14.
  • the device therefore enables a high measurement sensitivity and broadband, largely distortion-free measurement signal acquisition.
  • FIG 4 also shows an ohmic equivalent resistance R Sea ⁇ , which simulates the seal resistance via which the area of the cell membrane, which is arranged within the contact area of the cell and is spaced from the edge of the contact area, is connected to the electrical capacitance, that is formed between the area of the passivation layer 1 3 and the semiconductor layer 2 located outside the contact area of the cell.
  • the cell 14 seals against the surface of the passivation layer 13 when it is attached to it.
  • the distance between the cell membrane and the passivation layer 13 is greatly enlarged for reasons of clarity.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
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  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)
  • Insulated Gate Type Field-Effect Transistor (AREA)

Abstract

The invention relates to a device for measuring living cells or similar biocomponents comprising a field effect transistor (1) which is provided with a source, a drain and a channel area (4) placed on a substrate. Said channel area (4) connects said source and drain and is provided with a gate-electrode (8) mounted thereon. The gate electrode (8) has at least two laterally disposed parallel electrode areas (10) which are perpendicular to a direction in which the channel area (4) connects the source (3a) to the drain (3b) in such a way that they are distant and electrically insulated from each other.

Description

FELDEFFEKTTRANSISTOR FÜR MESSUNGEN ÄH BIOKOMPONEWTEN FIELD EFFECT TRANSISTOR FOR MEASUREMENTS UH BIOKOMPONEWTEN
Die Erfindung betrifft eine Vorrichtung zur Durchführung von Messungen an Biokomponenten, insbesondere an lebenden Zellen, mit mindestens einem Feldeffekf- transistor, der auf einem Substrat eine Source, eine Drain und ein diese miteinander verbindendes Kanalgebiet aufweist, auf dem eine Θate-Elektrode angeordnet ist, die durch eine dünne Isolierschicht gegen das Kanalgebiet elektrisch isoliert ist.The invention relates to a device for carrying out measurements on biocomponents, in particular on living cells, with at least one field effect transistor which has a source, a drain and a channel region connecting them on a substrate, on which a Θate electrode is arranged, which is electrically isolated from the channel area by a thin insulating layer.
Eine derartige Vorrichtung ist aus DE 196 23 517 Cl bekannt. Sie weist einen Feldeffekttransistor auf; bei dem die Θate-Elektrode über eine Leiterbahn mit einer von einem elektrischen Isolator umgrenzten, f eigelassenen Kontaktfläche (Pad) elektrisch leitend verbunden ist, die für eine Verbindung mit einer in einer Nährlösung befindlichen lebenden biologischen Zelle dimensioniert ist. Mit einer derartigen Vorrichtung kann das Aktionspotential einer an die Kontaktfläche angelager- ten Zelle, insbesondere einer Nerven- oder Muskelzelle, extrazellulär gemessen werden. Der Feldeffekttransistor hat ein Substrat aus Silizium, in das eine wannen- formige Halbleiterschicht eines ersten Ladungsträgertyps eingelassen ist. In dieser Halbleiterschicht sind dotierte Drain- und Source-Bereiche angeordnet, zwischen denen ein Kanalgebiet gebildet ist. Auf dem Kanalgebiet ist eine dünne Isolier- schicht und auf dieser die Θate-Elektrode angeordnet. Die Θate-Elektrode besteht aus Poly-Silizium und überdeckt das gesamten Kanalgebiet sowie die daran angrenzenden Ränder der Drain und der Source. Die βate-Elektrode bildet eine Äquipotentialfläche, die ein an ihr anliegendes elektrisches Potential über die gesamte, sich von der Drain zu der Source erstreckende Kanallänge verteilt, so dass das Potential auch im Sättigungsbetrieb des Feldeffekttransistors, wenn sich entlang der Kanallänge eine asymmetrische, einseitige Verteilung der freien Ladungsträger in dem Kanalgebiet einstellt, an die Stellen gelangt, an denen das Kanalgebiet seine größte Empfindlichkeit aufweist. Die Vorrichtung hat jedoch den Nachteil, dass ihre Messempfindlichkeit stark reduziert ist, wenn die mit dem θate verbundene Kontaktfläche nur teilweise von der Zelle überdeckt wird, so dass die Nährlösung, in der die Zelle angeordnet ist, mit den übrigen Bereichen der Kontaktfläche in Berührung gerät. Die Abnahme der Messempfindlichkeit wird vor allem dadurch bewirkt, dass die von der biologischen Zelle in die Kontaktfläche und somit auch die Θate-Elektrode im Wesentlichen kapazitiv eingekoppelte elektr i- sche Spannung der Ausgangsspannung einer Ersatzspannungsquelle mit hohem Quellenwiderstand entspricht. Da die Nährlösung aufgrund der darin enthaltenen Ionen im Vergleich zu dem Quellenwiderstand relativ niederohmig ist, reduziert sich 5 das an dem θate anliegende Messsignal entsprechend, wenn die Ersatzspannungsquelle mit dem elektrischen Widerstand der Nährlösung belastet wird. Das zu messende Zellsignal wird dann durch die auf einem Referenzpotential liegende Nährlösung praktisch kurzgeschlossen, d.h. der überwiegende Teil der Spannung liegt nicht an dem θate an sondern fällt an dem Quellenwiderstand der Ersatz- l o spannungsquelle ab. Ungünstig ist außerdem, dass die aus der Θate-Elektrode, der Leiterbahn und der Kontaktfläche gebildete Anordnung eine relativ große elektrische Kapazität zu der Nährlösung aufweist, wodurch das Messsignal zusätzlich abgeschwächt wird.Such a device is known from DE 196 23 517 Cl. It has a field effect transistor; in which the Θate electrode is connected in an electrically conductive manner via a conductor track to a contact area (pad) bounded by an electrical insulator and which is dimensioned for connection to a living biological cell in a nutrient solution. With such a device, the action potential of a cell attached to the contact surface, in particular a nerve or muscle cell, can be measured extracellularly. The field effect transistor has a substrate made of silicon, into which a trough-shaped semiconductor layer of a first charge carrier type is embedded. Doped drain and source regions, between which a channel region is formed, are arranged in this semiconductor layer. There is a thin insulating layer on the channel area and the Θate electrode on top of it. The Θate electrode consists of polysilicon and covers the entire channel area and the adjacent edges of the drain and source. The βate electrode forms an equipotential surface which distributes an electrical potential applied to it over the entire channel length extending from the drain to the source, so that the potential also in the saturation mode of the field effect transistor if there is an asymmetrical, one-sided distribution along the channel length sets the free charge carriers in the channel area, to the places where the channel area is most sensitive. However, the device has the disadvantage that its measuring sensitivity is greatly reduced if the contact area connected to the θate is only partially covered by the cell, so that the nutrient solution in which the cell is arranged comes into contact with the other areas of the contact area , The decrease in measuring sensitivity is mainly caused by the fact that the biological cell enters the contact area and thus the Θate electrode, which is essentially capacitively coupled in, corresponds to the output voltage of an equivalent voltage source with a high source resistance. Since the nutrient solution is relatively low-resistance due to the ions contained in it compared to the source resistance, the measurement signal applied to the θate is reduced accordingly when the equivalent voltage source is loaded with the electrical resistance of the nutrient solution. The cell signal to be measured is then practically short-circuited by the nutrient solution lying at a reference potential, ie the major part of the voltage is not present at the θate but falls at the source resistance of the equivalent voltage source. It is also unfavorable that the arrangement formed from the Θate electrode, the conductor track and the contact area has a relatively large electrical capacitance to the nutrient solution, as a result of which the measurement signal is additionally weakened.
15 Es besteht deshalb die Aufgabe, eine Vorrichtung der eingangs genannten Art zu schaffen, bei der die θefahr, dass das Messsignal durch einen Kontakt der Θate- Elektrode mit einer Nährlösung, in der die zu messende Biokomponente(n) angeordnet ist (sind), reduziert ist.15 It is therefore the task of creating a device of the type mentioned at the beginning, in which the risk that the measurement signal is caused by contact of the Θate electrode with a nutrient solution in which the biocomponent (s) to be measured is (are) arranged, is reduced.
20 Diese Aufgabe wird dadurch gelöst, dass die Θate-Elektrode mindestens zwei seitlich nebeneinander angeordnete Elektrodenbereiche aufweist, die quer zu der Richtung, in der das Kanalgebiet die Source mit der Drain verbindet, voneinander beabstandet und elektrisch gegeneinander isoliert sind.This object is achieved in that the Θate electrode has at least two electrode regions arranged laterally next to one another, which are spaced apart from one another and electrically insulated from one another transversely to the direction in which the channel region connects the source to the drain.
25 In vorteilhafter Weise ist also die Θate-Elektrode in mehrere elektrisch gegeneinander isolierte Elektrodenbereiche unterteilt, die quer zu einer die Source und Drain direkt miteinander verbindenden, etwa der Stromflussrichtung in dem Kanalgebiet entsprechenden Linie zueinander versetzt sind. Wenn eine in einer Nährlösung angeordnete Biokomponente, an der mit Hilfe des Feldeffekttransistors eineThe Θate electrode is therefore advantageously divided into a plurality of electrode regions which are electrically insulated from one another and which are offset from one another transversely to a line which connects the source and drain directly to one another and approximately corresponds to the current flow direction in the channel region. If a biocomponent arranged in a nutrient solution, to which a
30 Messung durchgeführt wird, die Θate-Elektrode nur teilweise überdeckt, derart, dass mindestens ein erster Elektrodenbereich der Θate-Elektrode mit der Nährlösung direkt in Kontakt steht und mindestens ein zweiter Elektrodenbereich vollständig von der Biokomponente überdeckt und durch diese gegen die Nährlösung abgedichtet wird, wird ein direkter Potentialausgleich zwischen dem ersten und dem zweiten30 measurement is carried out, the Θate electrode is only partially covered in such a way that at least a first electrode area of the Θate electrode is in direct contact with the nutrient solution and at least a second electrode area is completely covered by the biocomponent and sealed by it against the nutrient solution, becomes a direct equipotential bonding between the first and the second
35 Elektrodenbereich und somit eine Belastung der an dem zweiten Elektrodenbe- reich anliegenden Messspannung mit dem elektrischen Widerstand der mit dem ersten Elektrodenbereich in Kontakt befindlichen, auf einem Referenzpotential liegenden Nährlösung vermieden. Außerdem ist durch die unterteilte θateelektro- de die kapazitive Belastung des Messsignals durch parasitäre Kapazitäten gegen- über einer Vorrichtung mit einteiliger θateelektrode reduziert. In vorteilhafter Weise ermöglicht die Vorrichtung dadurch auch dann eine relativ hohe Mess- und Detektionsempfindlichkeit, wenn die Biokomponente die Θate-Elektrode nur bereichsweise überdeckt. Die an den einzelnen Elektrodenbereichen anliegenden elektrischen Potentiale können insbesondere beim Betrieb des Feldeffekttransistors im Sättigungsbereich jeweils in den Teilbereich des Kanalgebiets eingekoppelt werden, in dem das Kanalgebiet seine größte Empfindlichkeit aufweist. Die Vorrichtung ist vorzugsweise derart ausgebildet, dass die zu messende Biokomponente direkt an der Θate-Elektrode immobilisiert sein kann. Die Vorrichtung ermöglicht einen hochohmigen Signalabgriff an der Biokomponente.35 electrode area and thus a load on the second electrode measurement voltage with the electrical resistance of the nutrient solution in contact with the first electrode region and lying at a reference potential is avoided. In addition, the divided θate electrode reduces the capacitive load on the measurement signal due to parasitic capacitances compared to a device with a one-piece θate electrode. In this way, the device advantageously enables a relatively high sensitivity to measurement and detection even if the biocomponent only covers the Θate electrode in some areas. The electrical potentials present at the individual electrode areas can be coupled into the sub-area of the channel area in which the channel area has its greatest sensitivity, in particular when the field effect transistor is operating in the saturation area. The device is preferably designed such that the biocomponent to be measured can be immobilized directly on the Θate electrode. The device enables high-resistance signal tapping at the biocomponent.
Vorteilhaft ist, wenn die Vorrichtung mindestens drei, insbesondere mindestens fünf und bevorzugt mindestens sieben der Elektrodenbereiche in einer Reihe nebeneinander aufweist. Wenn die Biokomponente die Θate-Elektrode nur teilweise überdeckt, kann dadurch bei unterschiedlichen Anordnungen der Biokomponente relativ zu der Θate-Elektrode insgesamt eine noch größere Messempfindlichkeit und Messsicherheit erreicht werden.It is advantageous if the device has at least three, in particular at least five and preferably at least seven, of the electrode regions in a row next to one another. If the biocomponent only partially covers the Θate electrode, this can result in an even greater overall measurement sensitivity and measurement reliability with different arrangements of the biocomponent relative to the Θate electrode.
Bei einer bevorzugten Ausführungsform der Erfindung verlaufen die an das Kanalgebiet angrenzenden Ränder der Drain und der Source etwa parallel zueinander, wobei einander zugewandte Elektrodenränder zueinander benachbarter Elektrodenbereiche jeweils etwa rechtwinklig zu den an das Kanalgebiet angrenzenden Rändern der Drain und/oder der Source verlaufen. Die Trennlinien zwischen zueinander benachbart nebeneinander angeordneten Elektrodenbereichen verlaufen dann etwa in der Richtung, in welcher der elektrische Stromfluss in dem Kanalgebiet erfolgt. Dadurch wird eine gegenseitige Beeinflussung der an den einzelnen Elektrodenbereichen anliegenden elektrischen Potentiale noch wirkungsvoller vermieden.In a preferred embodiment of the invention, the edges of the drain and the source adjoining the channel region run approximately parallel to one another, with mutually facing electrode edges of mutually adjacent electrode regions each running approximately at right angles to the edges of the drain and / or the source adjoining the channel region. The dividing lines between mutually adjacent electrode regions then run approximately in the direction in which the electrical current flows in the channel region. As a result, a mutual influence of the electrical potentials present at the individual electrode areas is avoided even more effectively.
Bei einer vorteilhaften Ausführungsform der Erfindung ist auf der Drain und der Source jeweils eine vorzugsweise als Oxidschicht ausgebildete elektrische Isolator- Schicht angeordnet ist, deren Dicke um einen Faktor von mindestens 10, gegebenenfalls 30 und bevorzugt 50 größer ist als die Dicke der Isolierschicht, wobei die Elektrodenbereiche und gegebenenfalls die Isolierschicht seitlich jeweils direkt an den dem Kanalgebiet zugewandten Rand der Isolatorschicht angrenzen. Durch 5 diese Maßnahme wird eine noch geringe parasitäre Kapazität zwischen der bei der Messung mit der Nährlösung in Kontakt befindlichen Oberfläche der Vorrichtung und den von dieser Oberfläche beabstandeten Source- und Drain-Bereichen ermöglicht.In an advantageous embodiment of the invention, an electrical insulator, preferably designed as an oxide layer, is in each case on the drain and the source. Layer is arranged, the thickness of which is a factor of at least 10, optionally 30 and preferably 50 greater than the thickness of the insulating layer, the electrode regions and optionally the insulating layer laterally directly adjoining the edge of the insulator layer facing the channel region. This measure enables a still low parasitic capacitance between the surface of the device which is in contact with the nutrient solution during the measurement and the source and drain regions spaced from this surface.
l o Vorteilhaft ist, wenn die Fläche, welche die einzelnen Elektrodenbereiche jeweils auf dem Kanalgebiet überdecken, kleiner oder gleich der Fläche ist, die ein Fokalkontakt einer auf der Θate-Elektrode immobilisierbaren biologischen Zelle abdeckt und wenn die Fläche, welche die einzelnen Elektrodenbereiche jeweils auf dem Kanalgebiet überdecken insbesondere zwischen 0,5 μm2. und 5 μm2. beträgt.It is advantageous if the area that covers the individual electrode areas on the channel area is less than or equal to the area covered by a focal contact of a biological cell that can be immobilized on the Θate electrode, and if the area that covers the individual electrode areas on the Channel areas cover in particular between 0.5 μm 2 . and 5 μm 2 . is.
15 Dadurch wird eine noch größere Messempfindlichkeit und Zuverlässigkeit bei der Messsignalgewinnung an lebenden Zellen, die unterschiedliche Abmessungen aufweisen und/oder in unterschiedlichen Lagen relativ zu der Θate-Elektrode angeordnet sind, ermöglicht.15 This enables an even greater measurement sensitivity and reliability in the measurement signal acquisition on living cells which have different dimensions and / or are arranged in different positions relative to the Θate electrode.
20 Bei einer zweckmäßigen Ausgestaltung der Erfindung sind die Isolierschicht als Siliziumoxid-Schicht, insbesondere als Siliziumdioxid-Schicht, und die Θate-Elektrode als Edelmetall-Schicht, insbesondere als Palladium-Schicht, ausgebildet sind, wobei zwischen der Isolierschicht und der Θate-Elektrode eine Poly-Silizium-Schicht angeordnet ist, die in den zwischen zueinander benachbarten Elektrodenberei-In an expedient embodiment of the invention, the insulating layer is designed as a silicon oxide layer, in particular as a silicon dioxide layer, and the Θate electrode is designed as a noble metal layer, in particular as a palladium layer, with a between the insulating layer and the Θate electrode Poly-silicon layer is arranged, which in the between adjacent electrode areas
25 chen befindlichen Zwischenräumen jeweils unterbrochen ist, und dass zwischen der Poly-Silizium-Schicht und der Edelmetall-Schicht eine diese miteinander verbindende Edelmetall-Silizid-Schicht angeordnet ist. Die Θate-Elektrode kann dann bei der Fertigung der Vorrichtung durch die Vermittlung der Zwischenschicht strukturiert werden. Dazu werden bei dem Feldeffekttransistor zunächst die Source- und Drain-25 interstices located in each case is interrupted, and that between the poly-silicon layer and the noble metal layer a noble metal silicide layer connecting them is arranged. The Θate electrode can then be structured during the manufacture of the device by the intermediary of the intermediate layer. For this purpose, the source and drain
30 Bereiche sowie das Kanalgebiet auf der dotierten Halbleiterschicht (diese kann durch das Substrat oder einen wannenförmigen Bereich auf dem Substrat gebildet sein) erzeugt, um danach auf dem Kanalgebiet die elektrisch isolierende Siliziumoxid-Schicht (θateoxid) zu erzeugen. Auf diese wird dann eine Poly-Silizium-Schicht ganzflächig aufgebracht und danach derart strukturiert, dass sie nur noch an den30 regions as well as the channel region on the doped semiconductor layer (this can be formed by the substrate or a trough-shaped region on the substrate), in order to subsequently produce the electrically insulating silicon oxide layer (θateoxide) on the channel region. A poly-silicon layer is then applied over the entire surface and then structured in such a way that it only adheres to the
35 Stellen vorhanden ist, auf denen später die Θate-Elektrode angeordnet sein soll. Nun werden auf das Substrat strukturierte Schichten zur Bildung von Leiterbahnen aufgebracht. Zwischen den einzelnen Lagen der Leiterbahnschichten werden elektrisch isolierende Schichten angeordnet. Als Deckschicht wird eine Passivie- rungsschicht aufgebracht. Dann werden über den Stellen, an denen sich das Poly- Silizium befindet, Vertiefungen eingeätzt, die sich bis zu der als Ätzstopp dienenden Poly-Silizium-Schicht erstrecken. Falls die Θate-Elektrode den Boden der Vertiefungen nur teilweise bedecken soll, Wird die Poly-Silizium-Schicht in den Vertiefungen strukturiert. Anschließend wird ganzflächig eine Metallisierung aus einem Edelmetall aufgetragen. In einer nachfolgenden Wärmebehandlung diffundiert Silizium aus der Poly-Silizium-Schicht in die Edelmetall-Schicht und bildet in einem von der Oberfläche der Edelmetall-Schicht beabstandeten Bereich der Edelmetall-Schicht ein Edelmetall-Silizid. Das Edelmetall haftet dadurch besser an der Poly-Silizium- Schicht als an der übrigen Oberfläche, so dass es mechanisch, beispielsweise mit Hilfe von Ultraschallwellen, entsprechend der Struktur Poly-Silizium-Schicht strukturiert werden kann. Dabei löst sich das Edelmetall nur an den Stellen, die nicht mit der Poly-Silizium-Schicht in Kontaktstehen, ab.There are 35 locations on which the Θate electrode is later to be arranged. Structured layers to form conductor tracks are now applied to the substrate. Electrically insulating layers are arranged between the individual layers of the conductor track layers. A passivation layer is applied as the top layer. Then, depressions are etched over the locations at which the polysilicon is located, which extend as far as the polysilicon layer serving as an etching stop. If the Θate electrode should only partially cover the bottom of the wells, the poly-silicon layer is structured in the wells. Then a metallization made of a precious metal is applied over the entire surface. In a subsequent heat treatment, silicon diffuses from the poly-silicon layer into the noble metal layer and forms a noble metal silicide in a region of the noble metal layer that is spaced from the surface of the noble metal layer. As a result, the noble metal adheres better to the poly-silicon layer than to the rest of the surface, so that it can be structured mechanically, for example with the aid of ultrasound waves, in accordance with the structure of the poly-silicon layer. The precious metal only comes off at those points that are not in contact with the poly-silicon layer.
Die erfindungsgemäße Vorrichtung ist vorzugsweise derart ausgestaltet, dass die Biokomponente direkt mit der auf dem Kanalgebiet angeordneten Θate-Elektrode in Kontakt bringbar ist, d.h. die Biokomponente befindet sich während der Messung bevorzugt an der dem Kanalgebiet abgewandten Seite der Θate-Elektrode direkt über dem Kanalgebiet. Dadurch ergibt sich an der Θate-Elektrode eine kleine parasitäre Kapazität. Die Θate-Elektrode grenzt zu diesem Zweck bevorzugt an eine Messkammer oder einen Trog zur Aufnahme der Biokomponente(n) und gegebenenfalls einer diese enthaltende(n) Nährlösung an.The device according to the invention is preferably designed such that the biocomponent can be brought into direct contact with the Θate electrode arranged on the channel area, i.e. the biocomponent is preferably located on the side of the Θate electrode facing away from the channel area directly above the channel area during the measurement. This results in a small parasitic capacitance at the Θate electrode. For this purpose, the Θate electrode preferably adjoins a measuring chamber or a trough for receiving the biocomponent (s) and, if appropriate, a nutrient solution containing them.
Im Rahmen der Erfindung liegen aber auch Lösungen, bei denen die einzelnen Elektrodenbereiche jeweils über eine Leiterbahn mit einem elektrischen Kontaktelement (Pad) verbunden ist, das zum Kontaktieren der Biokomponente in einem von der Θate-Elektrode beabstandeten Anlagebereich für die Biokomponente angeordnet ist. Diese Ausführungsform wird bevorzugt, wenn eine räumliche Trennung zwischen dem eigentlichen Feldeffekttransistor und der (den) Biokompo- nente(n) vorteilhaft ist. Bei einer zweckmäßigen Ausführungsform der Erfindung weist die Vorrichtung mehrere der Feldeffekttransistoren auf, wobei diese Feldeffekttransistoren auf einem gemeinsamen Halbleitersubstrat vorzugsweise matrixförmig nebeneinander angeordnet sind. Die Vorrichtung ermöglicht dann eine ortsaufgelöste Messsignal- erfdssung an den Biokomponenten.However, solutions are also within the scope of the invention in which the individual electrode regions are each connected via a conductor track to an electrical contact element (pad) which is arranged for contacting the biocomponent in a contact region for the biocomponent spaced from the Θate electrode. This embodiment is preferred if a spatial separation between the actual field effect transistor and the biocomponent (s) is advantageous. In an expedient embodiment of the invention, the device has a plurality of the field effect transistors, these field effect transistors preferably being arranged next to one another on a common semiconductor substrate in the form of a matrix. The device then enables spatially resolved measurement signal detection on the biocomponents.
Bei einer vorteilhaften Ausführungsförm der Erfindung ist mindestens ein Elektrodenbereich der Θate-Elektrode und/oder eine zusätzlich zu den Elektrodenbereichen vorhandene und zu diesen benachbarte Stimulationselektrode mit einer elektri- sehen Stimulationseinrichtung für die Biokomponente verbunden. Die Stimulationseinrichtung weist eine elektrische Spannungsquelle auf; die über einen elektrischen Schalter mit dem Elektrodenbereich und/oder Stimulationselektrode verbindbar ist. Mit Hilfe der Vorrichtung kann an Zellkulturen, die mehrere miteinander vernetzte Nervenzellen aufweisen, die Ausbreitung von elektrischen Signalen und/oder Signalmustern innerhalb der Zellkultur untersucht werden. Dazu wird zunächst ein elektrisches Stimulationspotential an den mindestens einen Elektrodenbereich und/oder die Stimulationselektrode angelegt, anschließend wieder entfernt, um danach mit Hilfe der Elektrodenbereiche die Antwort der Zelle(n) auf das Stimulationspotential zu messen.In an advantageous embodiment of the invention, at least one electrode region of the Θate electrode and / or a stimulation electrode which is present in addition to the electrode regions and is adjacent to these is connected to an electrical stimulation device for the biocomponent. The stimulation device has an electrical voltage source; which can be connected to the electrode area and / or stimulation electrode via an electrical switch. With the aid of the device, the propagation of electrical signals and / or signal patterns within the cell culture can be examined on cell cultures which have a plurality of nerve cells networked with one another. For this purpose, an electrical stimulation potential is first applied to the at least one electrode area and / or the stimulation electrode, then removed again in order to then measure the response of the cell (s) to the stimulation potential with the aid of the electrode areas.
Nachfolgend ist ein Ausführungsbeispiel der Erfindung anhand der Zeichnung näher erläutert. Es zeigen:An exemplary embodiment of the invention is explained in more detail below with reference to the drawing. Show it:
Fig. 1 eine dreidimensionale Teilansicht einer einen Feldeffekttransistor aufweisenden Vorrichtung zur Durchführung von Messungen an Biokomponenten, wobei die Vorrichtung im Bereich des Feldeffekttransistors im Querschnitt dargestellt ist,1 is a three-dimensional partial view of a device having a field effect transistor for carrying out measurements on biocomponents, the device being shown in cross section in the area of the field effect transistor,
Fig.2 eine Aufsicht auf die in Fig. 1 gezeigte Vorrichtung im Bereich des Feldeffekttransistors, wobei eine strukturierte θatebeschichtung erkennbar ist,2 shows a plan view of the device shown in FIG. 1 in the region of the field effect transistor, a structured θate coating being recognizable,
Fig. 3 eine Teilaufsicht auf die Vorrichtung in θebrauchsstellung, und Fig.4 einen Querschnitt durch die Vorrichtung, wobei parasitäre Kapazitäten schematisch dargestellt sind.Fig. 3 is a partial plan view of the device in the θ use position, and 4 shows a cross section through the device, wherein parasitic capacitances are shown schematically.
Eine Vorrichtung zur Durchführung von extrazellulären Zellpotentialmessungen an lebenden biologischen Zellen weist einen Halbleiterchip auf; in den mindestens ein Feldeffekttransistor 1 integriert ist, der mit einem in der Zeichnung nicht näher dargestellten Messverstärker verbunden ist. Bei dem in Fig. 1 gezeigten Ausführungsbeispiel weist der Halbleiterchip eine dotierte Halbleiterschicht 2 eines ersten Ladungsträgeryps auf; die durch das Substrat des Halbleiterchips gebildet ist. Es sind aber auch andere Ausführungsbeispiele denkbar, bei denen die Halbleiterschicht 2 als wannenförmiger dotierter Bereich (Well) in das Halbleiter-Substrat eingelassen ist.A device for carrying out extracellular cell potential measurements on living biological cells has a semiconductor chip; in which at least one field effect transistor 1 is integrated, which is connected to a measuring amplifier not shown in the drawing. In the exemplary embodiment shown in FIG. 1, the semiconductor chip has a doped semiconductor layer 2 of a first charge carrier type; which is formed by the substrate of the semiconductor chip. However, other exemplary embodiments are also conceivable in which the semiconductor layer 2 is embedded in the semiconductor substrate as a trough-shaped doped region (well).
Auf der Halbleiterschicht 2 sind dotierte Bereiche eines zweiten Ladungsträgertyps angeordnet, von denen der eine Bereich die Source 3a und der andere Bereich die Drain 3b des Transistors 1 bildet, wenn dieser an dem Messverstärker angeschlossen ist. In Fig. 1 ist erkennbar, dass die Source 3a und die Drain 3b in die Oberfläche der Halbleiterschicht 2 eingelassen und durch ein zwischen ihnen befindliches Kanalgebiet 4 seitlich voneinander beabstandet sind. An einer von dem Kanalgebiet 4 entfernten Stelle ist die Source 3a mit einem Source-Kontakt 5a und die Drain 3b mit einem Drain-Kontakt 5b verbunden, die an dem Messverstärker angeschlossen sind. In Fig. 1 rechts ist erkennbar, dass der Source-Kontakt 5a außerdem an der Halbleiterschicht 2 (Substrat) angeschlossen ist.Doped regions of a second charge carrier type are arranged on the semiconductor layer 2, one region of which forms the source 3a and the other region forms the drain 3b of the transistor 1 when the latter is connected to the measuring amplifier. It can be seen in FIG. 1 that the source 3a and the drain 3b are embedded in the surface of the semiconductor layer 2 and are laterally spaced apart from one another by a channel region 4 located between them. At a location remote from the channel region 4, the source 3a is connected to a source contact 5a and the drain 3b is connected to a drain contact 5b, which are connected to the measuring amplifier. 1 that the source contact 5a is also connected to the semiconductor layer 2 (substrate).
Auf dem Kanalgebiet 4 ist eine Isolierschicht 6 angeordnet, die als dünne Oxidschicht ausgebildet ist und sich durchgängig über das Kanalgebiet 4 und die beidseits daran angrenzenden Randbereiche 7a, 7b der Source 3a und der Drain 3b erstreckt. Auf die Isolierschicht ό ist eine in der Zeichnung nicht näher dargestellte strukturierte Poly-Silizium-Schicht aufgebracht, auf der eine im θanzen mit 8 bezeichnete Θate-Elektrode angeordnet ist, die durch eine Metallisierung gebildet ist. Die Metallisierung besteht aus einem korrosionsbeständigen Edelmetall, vorzugsweise aus Palladium. Im Übergangsbereich von der Poly-Silizium-Schicht zu der Θate-Elektrode 8 ist eine Metall-Silizid-Schicht gebildet. Die Θate-Elektrode 8 haftet dadurch gut an der Poly-Silizium-Schicht an bzw. ist fest mit dieser verbunden. Die Θαte-Elektrode 8 grenzt direkt an einen Aufhahmeraum 9 an, der zur Aufnahme von in einer Nährlösung 15 befindlichen lebenden Zellen 14 ausgebildet ist.An insulating layer 6 is arranged on the channel region 4, which is designed as a thin oxide layer and extends continuously over the channel region 4 and the border regions 7a, 7b of the source 3a and the drain 3b adjoining it on both sides. A structured poly-silicon layer, not shown in the drawing, is applied to the insulating layer ό, on which an Θate electrode, generally designated 8, is arranged, which is formed by a metallization. The metallization consists of a corrosion-resistant noble metal, preferably palladium. A metal silicide layer is formed in the transition region from the poly-silicon layer to the Θate electrode 8. The Θate electrode 8 adheres well to the polysilicon layer or is firmly connected to it. The Θαte electrode 8 borders directly on a receiving space 9 which is designed to receive living cells 14 located in a nutrient solution 15.
Wie in Fig. 1 besonders gut erkennbar ist, weist die Θate-Elektrode 8 mehrere seitlich nebeneinander angeordnete Elektrodenbereiche 10 auf; die parallel zu derAs can be seen particularly well in FIG. 1, the Θate electrode 8 has a plurality of electrode regions 10 arranged laterally next to one another; the parallel to the
Erstreckungsebene des Halbleiterchips etwa rechtwinklig zu der in Fig. 1 durch denExtension plane of the semiconductor chip approximately at right angles to that in Fig. 1 by the
Doppelpfeil 1 1 markierten Richtung, in der das Kanalgebiet 4 die Source 3a mit derDouble arrow 1 1 marked direction in which the channel area 4 the source 3a with the
Drain 3b verbindet, voneinander beabstandet und elektrisch gegeneinander isoliert sind. Die einzelnen Elektrodenbereiche 10 sind jeweils etwa rechteckförmig ausgebildet und erstrecken sich in der Richtung 1 1, in der das Kanalgebiet 4 dieDrain 3b connects, spaced apart and electrically isolated from each other. The individual electrode regions 10 are each approximately rectangular in shape and extend in the direction 1 1 in which the channel region 4
Source 3a mit der Drain 3b verbindet, unterbrechungsfrei über das Kanalgebiet 4.Source 3a connects to the drain 3b, without interruption via the channel region 4.
In Fig. 2 ist erkennbar, dass die Elektrodenbereiche 10 jeweils mit ihrem einen Ende den an das Kanalgebiet 4 angrenzenden Randbereich 7a der Source 3a und mit ihrem gegenüberliegenden anderen Ende den an das Kanalgebiet 4 angrenzen- den Randbereich 7b der Drain 3b überdecken.2 that the electrode regions 10 each cover the edge region 7a of the source 3a adjoining the channel region 4 and the opposite end of the edge region 7b of the drain 3b adjoining the channel region 4.
Zueinander benachbarte Elektrodenbereiche 10 sind jeweils durch einen schmalen Zwischenraum voneinander beabstandet, der in der Aufsicht auf den Halbleiterchip jeweils etwa rechtwinklig zu den an das Kanalgebiet 4 angrenzenden Rändern der Source 3a und der Drain 3b verläuft. Parallel zu diesen Rändern sind die Elektrodenbereiche 10 in gerader Linie zueinander versetzt, so dass sich insgesamt eine etwa rechteckige, aus mehreren in einer Reihe angeordneten Elektrodenbereichen 10 bestehende, längliche Θate-Elektrode 8 ergibt, den Abmessungen an die einer biologischen Zelle angepasst sind. In Fig. 2 ist erkenn- bar, dass sich die Source 3a und die Drain 3b jeweils unterbrechungsfrei über sämtliche Elektrodenbereiche 10 der Θate-Elektrode 8 erstrecken.Adjacent electrode regions 10 are each spaced apart from one another by a narrow space which, when viewed from the top of the semiconductor chip, runs approximately at right angles to the edges of the source 3a and the drain 3b adjacent to the channel region 4. Parallel to these edges, the electrode regions 10 are offset in a straight line from one another, so that overall there is an approximately rectangular elongated Θate electrode 8 consisting of several electrode regions 10 arranged in a row, the dimensions of which are adapted to those of a biological cell. It can be seen in FIG. 2 that the source 3a and the drain 3b each extend without interruption over all electrode regions 10 of the Θate electrode 8.
Auf der Source 3a und der Drain 3b ist mit Abstand zu dem Kanalgebiet 4 jeweils eine elektrische Isolatorschicht 12a, 12b angeordnet, die als Dickoxidschicht (Feldoxidschicht) ausgebildet ist und eine größere Dicke aufweist als die Isolierschicht ό. Die Elektrodenbereiche 10 und die Isolierschicht ό grenzen seitlich jeweils mit ihrem einen Ende an die auf der Source 3a befindliche Isolatorschicht 12a und mir ihrem anderen Ende an die auf der Drain 3b befindliche Isolatorschicht 12b an. Auf den Isolatorschichten 12a, 12b ist als Decklage eine Passivierungsschicht 1 3 angeordnet, die mit Abstand zu der Θate-Elektrode 8 endet, so dass diese zugänglich ist.An electrical insulator layer 12a, 12b, which is designed as a thick oxide layer (field oxide layer) and has a greater thickness than the insulating layer ό, is arranged on the source 3a and the drain 3b at a distance from the channel region 4. The electrode areas 10 and the insulating layer ό laterally adjoin at one end to the insulator layer 12a located on the source 3a and at the other end to the insulator layer 12b located on the drain 3b. On the insulator layers 12a, 12b there is a passivation layer 13 as a cover layer arranged, which ends at a distance from the Θate electrode 8, so that it is accessible.
Fig. 3 zeigt eine Aufsicht auf die Vorrichtung in θebrauchsstellung. Deutlich ist erkennbar, dass an der Oberfläche des Halbleiterchips eine biologische Zelle 14 immobilisiert ist, die in einer Nährlösung 15 (Fig. 4) angeordnet ist, die über eine in der Zeichnung nicht näher dargestellte Referenzelektrode auf einem elektrischen Referenzpotential liegt, beispielsweise dem an dem Source-Kontakt 5a anliegenden Potential. Die Zelle 14 ist derart relativ zu der Θate-Elektrode 8 positioniert, dass sie einige der Elektrodenbereiche 10 vollständig überdeckt. Dabei haftet die Zelle derart an diesen Elektrodenbereichen 10 und den diese umgrenzenden, elektrisch gegen die Elektrodenbereiche 10 isolierten Oberflächenbereichen des Halbleiterchips an, dass die Zelle 14 diese Elektrodenbereiche 10 gegen die Nährlösung 15 abdichtet. Die übrigen Elektrodenbereiche 10 haben zumindest bereichsweise Kontakt zu der Nährlösung 15 und liegen somit auf dem an der Nährlösung 15 anliegenden Referenzpotential. Da die Θate-Elektrode 8 in mehrere Elektrodenbereiche 10 unterteilt ist, wird vermieden, dass das von der Zelle 1 über die Zellmembran in die durch die Zelle 14 gegen die Nährlösung 15 abgedichteten Elektrodenbereiche 10 eingekoppelte Zellpotential auf das vergleichsweise niederohmige Referenzpotential gezogen werden. Die Vorrichtung ermöglicht deshalb auch dann, Wenn die Θate-Elektrode 8 nur teilweise von der Zelle 14 überdeckt ist, eine genaue Messung von Zellpotentialänderungen.Fig. 3 shows a plan view of the device in the θ use position. It can be clearly seen that a biological cell 14 is immobilized on the surface of the semiconductor chip, which is arranged in a nutrient solution 15 (FIG. 4), which is at an electrical reference potential, for example that at which, via a reference electrode not shown in the drawing Source contact 5a applied potential. The cell 14 is positioned relative to the Θate electrode 8 such that it completely covers some of the electrode regions 10. The cell adheres to these electrode areas 10 and to the surface areas of the semiconductor chip that delimit them and are electrically insulated from the electrode areas 10 such that the cell 14 seals these electrode areas 10 against the nutrient solution 15. The remaining electrode regions 10 have contact with the nutrient solution 15 at least in regions and are therefore at the reference potential applied to the nutrient solution 15. Since the Θate electrode 8 is subdivided into several electrode regions 10, it is avoided that the cell potential coupled from the cell 1 via the cell membrane into the electrode regions 10 sealed by the cell 14 against the nutrient solution 15 is drawn to the comparatively low-resistance reference potential. The device therefore enables an accurate measurement of cell potential changes even when the Θate electrode 8 is only partially covered by the cell 14.
In Fig.4 sind die durch die Vorrichtung in dem von der Zelle 1 überdecken Bereich gebildeten elektrischen Kapazitäten schematisch in Form eines elektrischen4 the electrical capacitances formed by the device in the area covered by the cell 1 are schematically in the form of an electrical one
Ersatzschaltbilds eingezeichnet. Deutlich ist erkennbar, dass die Kondensatorplatten des Ersatzkondensators CFox für die durch die Isolatorschichten 12a, 12b gebildeten elektrischen Kapazitäten und die Kondensatorplatten des Ersatzkondensators CPasS für die durch den von der Zelle 14 überdecken Bereich der Passivierungsschicht 13 gebildeten elektrischen Kapazitäten jeweils wesentlich weiter voneinander beabstandet sind als die Kondensatorplatten des Ersatzkondensators Cox für die durch die Θate-Elektrode 8 gebildete elektrische Kapazität. Die Kapazitäten CFθχ und Cpass sind daher wesentlich kleiner als die Θesamtkapazität der Θate-ElektrodeEquivalent circuit diagram drawn. It can clearly be seen that the capacitor plates of the replacement capacitor C Fox for the electrical capacitances formed by the insulator layers 12a, 12b and the capacitor plates of the replacement capacitor C Pa s S for the electrical capacitances formed by the area of the passivation layer 13 covered by the cell 14 each significantly further are spaced apart from one another as the capacitor plates of the replacement capacitor C ox for the electrical capacitance formed by the Θate electrode 8. The capacitances C Fθ χ and Cp a ss are therefore significantly smaller than the total capacity of the Θate electrode
8. Da diese in mehrere, auf dem Halbleiterchip elektrisch gegeneinander isolierte Elektrodenbereiche unterteil ist, ist auch die durch die Kapazität Cox auf das Mess- signαl einwirkende kapazitive Last nur relativ klein. Die Vorrichtung ermöglicht deshalb insgesamt eine hohe Messempfindlichkeit und eine breitbandige, weitgehend verzerrungsfreie Messsignalgewinnung.8. Since this is subdivided into a plurality of electrode regions which are electrically insulated from one another on the semiconductor chip, the capacitance C ox on the measurement Significantly acting capacitive load only relatively small. Overall, the device therefore enables a high measurement sensitivity and broadband, largely distortion-free measurement signal acquisition.
In Fig. 4 ist außerdem ein ohmscher Ersatzwiderstand RSeaι erkennbar, der den Seal- Widerstand nachbildet, über den der Bereich der Zellmembrane, der innerhalb des Auflagebereichs der Zelle angeordnet und vom Rand des Auflagebereichs beabstandet ist, mit der elektrischen Kapazität verbunden ist, die zwischen dem außerhalb des Auflagebereichs der Zelle befindlichen Bereich der Passivierungs- schicht 1 3 und der Halbleiterschicht 2 gebildet ist. Die Zelle 14 dicht gegen die Oberfläche der Passivierungsschicht 1 3 ab, wenn sie an dieser angelagert ist. In Fig.4 ist der Abstand zwischen der Zellmembrane und der Passivierungsschicht 13 aus θründen der Übersichtlichkeit stark vergrößert dargestellt. 4 also shows an ohmic equivalent resistance R Sea ι, which simulates the seal resistance via which the area of the cell membrane, which is arranged within the contact area of the cell and is spaced from the edge of the contact area, is connected to the electrical capacitance, that is formed between the area of the passivation layer 1 3 and the semiconductor layer 2 located outside the contact area of the cell. The cell 14 seals against the surface of the passivation layer 13 when it is attached to it. In Figure 4, the distance between the cell membrane and the passivation layer 13 is greatly enlarged for reasons of clarity.

Claims

Patentansprüche claims
1. Vorrichtung zur Durchführung von Messungen an Biokomponenten, insbesondere an lebenden Zellen, mit mindestens einem Feldeffekttransistor (1), der auf einem Substrat eine Source, eine Drain und ein diese miteinander verbindendes Kanalgebiet (4) aufweist, auf dem eine Θate-Elektrode (8) angeordnet ist, die durch eine dünne Isolierschicht (ό) gegen das Kanalgebiet (4) elektrisch isoliert ist, dadurch gekennzeichnet, dass die Θate-Elektrode (8) mindestens zwei seitlich nebeneinander angeordnete Elektrodenbereiche (10) aufweist, die quer zu der Richtung, in der das Kanalgebiet (4) die Source (3a) mit der Drain (3b) verbindet, voneinander beabstandet und elektrisch gegeneinander isoliert sind.1. Device for carrying out measurements on biocomponents, in particular on living cells, with at least one field effect transistor (1) which has a source, a drain and a channel region (4) connecting them to one another on a substrate, on which a Θate electrode ( 8) which is electrically insulated from the channel region (4) by a thin insulating layer (ό), characterized in that the Θate electrode (8) has at least two electrode regions (10) arranged laterally next to one another, which are transverse to the direction , in which the channel region (4) connects the source (3a) to the drain (3b), is spaced apart and is electrically insulated from one another.
2. Vorrichtung nach Anspruch 1, dadurch gekennzeichnet, dass mindestens drei, insbesondere mindestens fünf und bevorzugt mindestens sieben der Elektrodenbereiche (10) in einer Reihe nebeneinander angeordnet sind.2. Device according to claim 1, characterized in that at least three, in particular at least five and preferably at least seven, of the electrode regions (10) are arranged in a row next to one another.
3. Vorrichtung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass an das Kanalgebiet (4) angrenzende Ränder der Drain (3a) und der Source (3b) et- wa parallel zueinander verlaufen und dass einander zugewandte Elektrodenränder zueinander benachbarter Elektrodenbereiche (1 0) jeweils etwa rechtwinklig zu den an das Kanalgebiet (4) angrenzenden Rändern der Drain (3a) und/oder der Source (3b) verlaufen.3. Device according to claim 1 or 2, characterized in that the edges of the drain (3a) and the source (3b) adjoining the channel region (4) run approximately parallel to one another and that mutually facing electrode edges of mutually adjacent electrode regions (1 0) each run approximately at right angles to the edges of the drain (3a) and / or the source (3b) adjacent to the channel region (4).
4. Vorrichtung nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass auf der Drain (3a) und der Source (3b) jeweils eine vorzugsweise als Oxidschicht ausgebildete elektrische Isolatorschicht (12a, 12b) angeordnet ist, deren Dicke um einen Faktor von mindestens 1 0, gegebenenfalls 30 und bevorzugt 50 größer ist als die Dicke der Isolierschicht (ό), und dass die Elekt- rodenbereiche (1 0) und gegebenenfalls die Isolierschicht (ό) seitlich jeweils direkt an den dem Kanalbereich (4) zugewandten Rand der Isolatorschicht (12a, 12b) angrenzen.4. Device according to one of claims 1 to 3, characterized in that on the drain (3a) and the source (3b) in each case a preferably formed as an oxide layer electrical insulator layer (12a, 12b) is arranged, whose thickness by a factor of at least 1 0, possibly 30 and preferably 50 is greater than the thickness of the insulating layer (ό), and that the electrode regions (1 0) and optionally the insulating layer (ό) laterally each directly to the edge of the insulator layer facing the channel region (4) (12a, 12b).
5. Vorrichtung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass die Fläche, welche die einzelnen Elektrodenbereiche (1 0) jeweils auf dem Kanalgebiet (4) überdecken, kleiner oder gleich der Fläche ist, die ein Fokalkontakt einer auf der Θate-Elektrode immobilisierbaren biologischen Zelle (14) abdeckt und vorzugsweise zwischen 0,5 μm2. und 5 μm2. beträgt.5. Device according to one of claims 1 to 4, characterized in that the area which the individual electrode areas (1 0) each on cover the channel area (4), is less than or equal to the area covered by a focal contact of a biological cell (14) immobilizable on the Θate electrode, and preferably between 0.5 μm 2 . and 5 μm 2 . is.
ό. Vorrichtung nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass die Isolierschicht (ό) als Siliziumoxid-Schicht, insbesondere als Siliziumdioxid-Schicht, und die Θate-Elektrode (8) als Edelmetall-Schicht, insbesondere als Palladium-Schicht, ausgebildet sind, dass zwischen der Isolierschicht (ό) und der Θate-Elektrode (8) eine Poly-Silizium-Schicht (8) angeordnet ist, die in den zwischen zueinander benachbarten Elektrodenbereichen (10) befindlichen Zwischenräumen jeweils unterbrochen ist, und dass zwischen der Poly- Silizium-Schicht (8) und der Edelmetall-Schicht eine diese miteinander verbindende Edelmetall-Silizid-Schicht angeordnet ist.ό. Device according to one of claims 1 to 5, characterized in that the insulating layer (ό) as a silicon oxide layer, in particular as a silicon dioxide layer, and the Θate electrode (8) as a noble metal layer, in particular as a palladium layer that between the insulating layer (ό) and the Θate electrode (8) a poly-silicon layer (8) is arranged, which is interrupted in the interstices between adjacent electrode areas (10), and that between the poly Silicon layer (8) and the noble metal layer, a noble metal silicide layer connecting them to one another is arranged.
7. Vorrichtung nach einem der Ansprüche 1 bis ό, dadurch gekennzeichnet, dass die Θate-Elektrode direkt an eine Messkammer oder einen Trog zur Aufnahme der Biokomponente(n) und gegebenenfalls einer diese enthaltende^) Nährlösung angrenzt.7. Device according to one of claims 1 to ό, characterized in that the Θate electrode directly adjoins a measuring chamber or a trough for receiving the biocomponent (s) and optionally a ^) nutrient solution containing them.
8. Vorrichtung nach einem der Ansprüche 1 bis 7, dadurch gekennzeichnet, dass die einzelnen Elektrodenbereiche (10) jeweils über eine Leiterbahn mit einem elektrischen Kontaktelement verbunden ist, das zum Kontaktieren der Biokomponente in einem von der Θate-Elektrode (8) beabstandeten Anlagebereich für die Biokomponente angeordnet ist.8. Device according to one of claims 1 to 7, characterized in that the individual electrode regions (10) are each connected via a conductor track to an electrical contact element which for contacting the biocomponent in a contact area spaced from the Θate electrode (8) the biocomponent is arranged.
9. Vorrichtung nach einem der Ansprüche 1 bis 8, dadurch gekennzeichnet, dass sie mehrere der Feldeffekttransistoren (1) aufweist, und dass diese Feldeffekttransistoren (1) auf einem gemeinsamen Halbleitersubstrat vorzugsweise matrixförmig nebeneinander angeordnet sind.9. Device according to one of claims 1 to 8, characterized in that it has a plurality of the field effect transistors (1), and that these field effect transistors (1) are arranged on a common semiconductor substrate, preferably in a matrix next to one another.
1 0. Vorrichtung nach einem der Ansprüche 1 bis 9, dadurch gekennzeichnet, dass mindestens ein Elektrodenbereich (1 0) Θate-Elektrode (8) und/oder eine zusätzlich zu den Elektrodenbereichen vorhandene und zu diesen benachbarte Stimulationselektrode mit einer elektrischen Stimulationseinrich- tung für die Biokomponente verbunden ist. 1 0. Device according to one of claims 1 to 9, characterized in that at least one electrode region (1 0) Θate electrode (8) and / or a stimulation electrode present and adjacent to the electrode regions with an electrical stimulation device for the biocomponent is connected.
1. Verwendung einer Vorrichtung nach einem der Ansprüche 1 bis 10 zur extrazellulären Messung eines Signals an einer biologischen Zelle, insbesondere einer Zellpotentialänderung. 1. Use of a device according to one of claims 1 to 10 for extracellular measurement of a signal on a biological cell, in particular a change in cell potential.
EP05715622A 2004-03-02 2005-03-01 Field effect transistor for measuring biocomponents Withdrawn EP1740935A1 (en)

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