EP2291647A1

EP2291647A1 - Multichannel saw-sensor chip

Info

Publication number: EP2291647A1
Application number: EP09769114A
Authority: EP
Inventors: Markus Perpeet; Ulrich Schlecht
Original assignee: Saw Instruments GmbH; Biosensor GmbH
Current assignee: Saw Instruments GmbH
Priority date: 2008-06-25
Filing date: 2009-06-08
Publication date: 2011-03-09
Also published as: DE102008029843A1; US20110104824A1; WO2009156265A1

Abstract

Sensor chip for specific determination of analytes in a liquid, said sensor chip having a plurality of sensor elements based on the SAW principle, said sensor elements are applied as layer structures onto the surface of a substrate, wherein the surface of each sensor element is coated with a sensitive substrate ("Coating"), which has receptors specifically binding one analyte, wherein during operation, the surface of the sensor chip rests against and seals the half-open covering part, wherein the covering part and the sensor chip form a flow cell to be flushed by the liquid, wherein conductor structures are created for contacting of the sensor elements from the flow cell, wherein more than six sensor elements are present which can each be triggered and read out separately via a trigger- and measuring electronics, wherein at least two of the sensor elements, in particular all sensor elements, are each populated with a differently sensitive substrate, wherein the sensitive substrate is applied to the surface before the attachment of the cover part.

Description

Multi-channel SAW sensor chip

The invention relates to a sensor chip for the specific determination of analytes in a liquid comprising a plurality of sensor elements based on the SAW principle, which are applied as layer structures on the surface of a substrate, wherein the surface of the sensor elements is coated with a sensitive substrate ("coating") in that the surface of the sensor chip bears sealingly against a half-open cover part during operation, the cover part and the sensor chip forming a flow cell to be flushed by the liquid, conductor structures leading out of the flow cell for contacting the sensor elements. The invention also relates to a method for driving and reading such a sensor chip and a handleable unit with such a sensor chip.

Nowadays relatively compact systems are known as laboratory devices, with which biomolecules in low concentration can be conveniently detected without the use of markers. These are based in particular on sensor chips that use the physical principle of "surface acoustic wave", or SAW for short, with which SAW sensors can detect the smallest mass changes on the sensor surface occupied by receptor molecules sensitive to the analyte to be detected requires the operation of these systems and in particular the analysis of the analyte molecules dissolved in liquid using the receptor molecules a considerable amount of technical experience and (bio) chemical and physical knowledge the field use and for operation by inexperienced in handling staff, the known systems are not suitable.

Such a sensor for installation in a laboratory device is sold, for example, under the name "K5" by the Applicant.This sensor chip has five separately controllable sensor elements in a parallel arrangement, so that it is possible to perform the same measurement on the liquid loaded with analyte in one pass The contacting of the sensor chip in the device is relatively complicated, since four connections are provided per sensor element, with ground connections for the shielding layer still being added, an increase in the number of individual sensors is not useful because of the small benefit that results from even better coverage of the measurement.

In addition, in the known sensor chips the application of the coating takes place in the built-in "operating state" in which the sensor chip is covered by the cover part and forms a flow cell together with the cover part Before a measurement on the surface of the individual sensors in a first flushing receptors eg anft-thrombin aptamers immobilized by carbodiimite chemistry, ready for actual measurement on the analyte-loaded fluid, and because of these preparatory steps, the operating effort for the measurement is relatively high, so that the measurements are essentially reserved for laboratory use. Miniaturization with regard to fast measurements with manageable units is not possible.

The object of the present invention is now to provide a sensor chip, which nevertheless can be handled easily and safely with an increased number of individual sensors, which allows simultaneous measurements of different analytes in the liquid and which, above all, can be used conveniently in a mobile system , In addition, it is an object of the invention to provide a method for the readout of such a sensor chip and a manageable unit with such a sensor chip. These objects are achieved by the sensor chip having the features of claim 1, the method of claim 11 and the handleable unit of claim 12. Advantageous embodiments are mentioned in the respective subclaims.

One of the fundamental principles of the invention is to equip the sensor chip with a plurality of, namely with more than six simultaneously operating sensor elements, each of which enables SAW measurements, wherein each individual sensor element responds specifically to a specific substance. For other substances, the respective sensor element remains "blind." According to the invention, at least two of the sensor elements, but in particular all sensor elements, are each occupied by a substrate sensitive to another analyte.This sensitivity is realized by special receptor molecules on the sensitive regions of the sensor elements Such a sensor chip is therefore immediately ready for operation and can be distributed in bulk as an easily handled component for manageable systems. and measuring electronics excitable and readable.

With such a sensor chip, several different ingredients of a liquid sample can be detected and evaluated for their concentration in a single test procedure. In addition, it is possible to test a fluid sample differentiated to a single or multiple substances from a spectrum of different potentially possible substances. The SAW-based sensor chip supplies as test result a signal which can be clearly assigned to the substances and can be evaluated electronically.

Sensor chips of the type according to the invention can be integrated into special modules ("cartridges") and serve as consumables in connection with the manageable devices. <br/> These systems can identify and quantify, in particular, illegal drugs, explosives, toxins and / or hazardous substances by electronic-biochemical means. With regard to easy handling and reliable operation within particular of manageable units, it is particularly advantageous if the sensor elements have rectangular and in particular similar sensor strips, which are applied to each other in isolation in a parallel arrangement on a corresponding carrier. It has proven to be advantageous to provide the sensor chip with more than ten, in particular with twelve sensor elements in the form of parallel arranged sensor strips.

The carrier can be formed by a monocrystalline piezoelectric. For contacting, the sensor strips each have two conductor structures on each end face. The sensor strips are advantageously made of a metal layer, in particular a gold or aluminum layer, with less than 500 nm thickness. This is applied in a structured manner to the carrier and covered by a common guide layer which guides the mechanical waves, for example by a layer of SiO 2. The thickness of the guide layer is of the order of a few micrometers, with the cover part sealing against this guide layer. In addition, it is advantageous to cover the sensor strips by means of the guide layer in each case with a shielding the shielding shielding, which in turn is formed in particular by a about 100 nm thick gold layer. These shielding strips then carry the biologically sensitive substrate applied before use.

In order to control the sensor chip with the large number of SAW-based individual sensors, each of which has typically four to six electrical contacts, correspondingly robust possibilities of contacting are required. This should be reversible and possible without technical effort. On the side of the sensor chip, a robustness of the contacts is achieved in particular via the contact surface of the individual contacts ("contact pads") .The size of these contact pads, however, in conjunction with the required number, represents a decisive limiting factor with regard to miniaturization. A size reduction of the sensor chips is always desirable in terms of cost, as the cost increases proportionally with the size of the chip. Another essential aspect of the invention is therefore the special way of contacting the individual sensor elements, in particular the sensor strips. Since these should each be excitable separately via the control and measurement electronics, a large number of contacts are necessary, which, as explained, mean a particularly complex layout for the sensor chip and a complex contacting. The contacting according to the invention assumes that the number of contacts is reduced by merging different contact pads. According to the invention, individual contact pads are shared by a plurality of individual sensors. This idea contributes to a significant reduction in the size of the sensor chip. The differentiated reading of the signals requires a special "intelligent" control, which also includes an essential idea of the invention.

In order to be able to control two parallel sensor elements via a common contact pad, it is advantageous if the number of N sensor elements is assigned in each case on each end face (N-1) + 2 contact means. This number is due to the fact that N sensor elements lie side by side in series, of which those N - 1, each having two neighbors, are to be contacted via a common contact pad. The outer 2 sensor elements each need an additional contact pad, which is assigned to them alone. Thus, the N - 1 contact means each contact two adjacent individual sensors, wherein the remaining two contact means each contact the two individual sensors located on the edge. About such an arrangement of contact pads, the individual sensors can be sequentially controlled separately and read.

It is advantageous if the N-1 contact means in alternating sequence each serve as a phase connection and adjacent as a ground terminal, wherein each of the phase terminals and each of the ground terminals each contact two adjacent individual sensors. During the control and readout, the phase connections arranged on one side of the sensor chip serve for the input of exciter signals and those on the opposite side of the sensor chip arranged phase terminals for tapping the resulting measurement signals.

The single sensor can thus indicate the presence of a single substance to which it reacts specifically. From the intensity of the measurement signal, it is also possible to make a statement about the amount of substance present, that is, about the concentration. The sensor chip in its entirety, with its multiple individual sensor elements, thus forms a detector with which a large number of different substances can be simultaneously identified during a single test procedure and also quantified in terms of their concentration. Sensor chips of the type described can be integrated in special cartridges. In particular, they can be designed as consumables and can be used in devices that can identify and quantify illicit drugs, explosives and other toxic and hazardous substances electronically and biochemically. It is advantageous in terms of consumables to make such cartridges cost. As the most expensive component of such a cartridge, a cost-reduced sensor chip can significantly reduce the overall cost.

Another essential aspect of the invention thus lies in the cartridge, which forms a suitable manageable unit together with the sensor chip according to the invention. This advantageously forms, in conjunction with the sensor chip, a flow cell for guiding a liquid, wherein in the flow cell the liquid loaded with analyte is guided over the sensitive sensor surfaces. According to the invention, the flow cell has a cover part which bears sealingly against the surface of the sensor chip and encloses the sensitive sensor surfaces. For sealing, the edge of the cover part applies by means of a seal sealingly against the sensor surface, wherein means for clamping the cover part against the seal are present and wherein the sensor chip has conductor tracks for contacting the sensor surface, which lead out of the flow cell.

The invention will be explained in more detail with reference to Figures 1 and 2. Show it: Figure 1 is a plan view of a 12-channel sensor chip and

Figure 2: a cartridge.

FIG. 1 shows a 12-channel sensor chip which has a first side 1 for the signal input and a second side 2 for the signal output. The sensor chip has 12 sensor elements which are designed as rectangular and similar sensor strips 3. The sensor strips 3 are applied in a parallel arrangement and by a joint 4 against each other isolated on a carrier, not shown, of monocrystalline piezoelectric. At the end faces of the sensor strips 3 conductor structures for contacting are present, each sensor strip 3 are assigned at each end face two conductor structures.

In this case, a number of (N-1) + 2 = 13 contact pads 5 are assigned to the number of N = 12 sensor strips 3 at each end face, respectively. In addition, four ground connections 6 arranged at the corners are provided for the entire sensor chip, which are shown hatched and contact the shielding layer respectively the shielding strip. On the shielding strips selectively binding haptens are applied, wherein after drying of the respective hapten a firm hapten binding is present on the surface of the shielding strip.

Each of the 13 contact pads 5 contacts two adjacent sensor strips 3 and bridges the respective joints 4. Two outer contact means 5a respectively contact the two sensor strips 3 located at the edge. With the combination of two mass contacts respectively two phase contacts of two adjacent sensor strips 3 each a common contact pad, the number of contacts on a sensor chip can be significantly reduced. In addition, the earth of all sensor elements is summarized centrally and contacted only a few electrical connections, namely the ground terminals 6.

The contact pads 5 realize in alternating sequence each have a phase connection P and a ground terminal M. Here are the Phase terminals P on the first side of the sensor chip for feeding the high-frequency excitation signals and the staggered phase terminals P provided on the second side of the sensor chip for tapping the resulting measurement signals. The phase connection P1 contacts the sensor strips A and B in this case.

When the contact pads are combined in the manner according to the invention, two sensor elements are always excited simultaneously when an RF signal is fed into a phase pad on the input side. Analogously applies to the output, that also always two sensor elements are read out simultaneously. In order to ensure unambiguousness, that is to be able to clearly detect the signal of only a single sensor element, it is necessary to make the signal feed and the corresponding signal readout offset.

The process steps are represented on the basis of the sensor strips A, B and C. The two adjacent sensor strips A and B are excited simultaneously via the common phase connection P1. On the output side both P3 and P4 can be used for readout. A readout of the measurement signal generated by the first sensor element A takes place via the opposite phase connection P3, which is assigned to the first sensor element A and to the sensor element adjacent to the second sensor element B. With a time delay, the measurement signal generated by the second sensor element B can be read out via the opposite phase connection P4, which is assigned to the second sensor element B and to the sensor element C adjacent to the side opposite the first sensor element. In this case, an electronic or software-based control is required to realize the illustrated concept for differentiated signal acquisition, which makes the staggered excitation and readout process.

A complete manageable unit ("cartridge") is shown in Figure 2, as it may be used in a particular mobile system, based on the SAW based multi-channel sensor chip, whose surface is provided with biochemical receptor molecules. From the sensor chip here only the contact strip 10 can be seen. Such a (not shown) mobile system advantageously has a task module for easy task of the analyte. For fast and uncomplicated analyzes, it is particularly useful to have wipers which in particular absorb samples of body fluids such as sweat. In addition, a fluidic module should be present, where the analyte is introduced into a serving as a transport fluid. The fluidic module is provided with corresponding channels for the administration of the analyte-loaded fluid. In addition, a drive and analysis unit for automatically performing the measurement is available. This has in particular a microcomputer, which controls the sensor chip with signal frequencies and evaluates the measurement results. Via output means, such as a display and / or a printer, the measurement results are output to the user.

Evident are the two housing parts 11 and 12 of the cartridge, which lie on support surfaces against each other, wherein the support surface 13 of the first housing part 11 is larger and serves as an abutment of the outstanding under the seal strip conductors 10. The interconnects form a comb-like conductor structure, which rests on the support surface 13 of the housing part 11 and is freely accessible for electrical contact. This can interact with appropriately provided in the mobile system mating contacts. Overall, the geometry of the housing parts is dimensioned so that the housing can be positively inserted into a corresponding receptacle in the mobile system. In the present case, the two housing parts 11 and 12 are connected by means of pin-like snap fasteners 14.

Via connections 15, which form an inlet and a drain, the flow cell formed by the sensor chip and by the cover part, not shown, is supplied with the liquid to be examined.

Claims

claims

1. Sensor chip for the specific determination of analytes in a liquid comprising a plurality of sensor elements based on the SAW principle, which are applied as layer structures on the surface of a substrate, wherein the surface of the sensor elements each with a sensitive substrate ("coating") is occupied an analyte-specific binding receptors, wherein in operation the surface of the sensor chip sealingly abuts against a half-open lid part, the cover part and the sensor chip form a flushed by the liquid flow cell, wherein conductor structures (5) are led out for contacting the sensor elements from the flow cell , characterized in that more than six sensor elements are present, which are each separately excitable and readable via a control and measurement electronics, wherein at least two of the sensor elements, in particular all sensor elements, each occupied with a different sensitive substrate sin d, wherein the sensitive substrate is brought to the surface before being subjected to the cover part.

2. Sensor chip according to claim 1, characterized in that the sensor elements have rectangular and in particular similar sensor strips (3) which are in a parallel arrangement against each other isolated on a support, in particular a monocrystalline piezoelectric, are applied, wherein the conductor structures (5) on the end faces contact the sensor strip (3) and wherein each sensor strip (3) are associated with two conductor structures (5) on each end face.

3. Sensor chip according to claim 2, characterized in that the sensor strips (3) are formed by a less than 500 nm thick metal layer, in particular gold or aluminum, which are applied in a structured manner on the carrier, wherein over all sensor strips a common guide layer in particular SiO2 is applied, whose thickness is of the order of a few microns, wherein the cover member seals against the guide layer.

4. Sensor chip according to claim 3, characterized in that the sensor strip is covered by means of the guide layer in each case with a Abschirmstreifen, which is in particular formed by a about 100 nm thick gold layer, wherein the Abschirmstreifen carry the biological sensitive substrate.

5. Sensor chip according to one of the preceding claims, characterized in that more than ten, in particular twelve, sensor elements with parallel sensor strips (3) are present.

6. Sensor chip according to one of the preceding claims, characterized in that the number of N sensor elements is assigned in each case at each end face a number of (N - 1) + 2 contact means (5).

7. Sensor chip according to claim 6, characterized in that the N-1 contact means each two adjacent individual sensors (A ₁ B) contact, wherein the remaining two contact means each contact the two lying on the edge of individual sensors.

8. Sensor chip according to claim 7, characterized in that the N-1 contact means in each case a phase connection (P) and a ground terminal (M) realize, each of the phase terminals (P) and each of the ground terminals (M) each two adjacent Single sensors (A, B) contacted, wherein the phase terminals on one side (1) of the sensor chip for supplying excitation signals and the phase terminals on one side (2) of the sensor chip for tapping the resulting measurement signals are used.

9. Sensor chip according to one of the preceding claims, characterized in that at least one contact means (6) is provided on each end face, which is connected as a ground terminal the shielding strip.

10. Sensor chip according to one of the preceding claims, characterized in that on the Abschirmstreifen selectively binding haptens are applied, wherein after drying of the respective hapten a fixed hapten binding is present on the surface of the Abschirmstreifens.

11. A method for driving and reading a sensor chip according to one of the preceding claims 6 to 10, characterized in that on the common phase connection two adjacent

Sensor elements are excited, that the measurement signal generated by the first sensor element is read out at the opposite phase terminal, the first

Sensor element and the adjacent to the second sensor element adjacent side sensor element is assigned, that time-offset the measurement signal generated by the second sensor element is read out via the opposite phase connection, which is associated with the second sensor element and the sensor element adjacent to the opposite side of the first sensor element.

12. A handleable unit comprising a sensor chip according to one of the preceding claims and a flow cell for guiding a fluid over the analyte-sensitive sensor surfaces of the sensor chip, characterized in that the flow cell has a lid part which is placed on the sensitive sensor surface, wherein the edge the cover part by means of a seal sealingly applied to the sensor surface, wherein means for clamping the lid part against the seal are present and wherein the sensor chip has conductor tracks for contacting the sensor surface, which lead out of the flow cell.