WO2009027896A1

WO2009027896A1 - Microelectronic sensor device with wetting detection

Info

Publication number: WO2009027896A1
Application number: PCT/IB2008/053308
Authority: WO
Inventors: Coen A. Verschuren
Original assignee: Koninklijke Philips Electronics N. V.
Priority date: 2007-08-24
Filing date: 2008-08-18
Publication date: 2009-03-05

Abstract

The invention relates to a wetting detector (100) for detecting which one of a first and a second medium is present at a contact surface (212) of a carrier (200). In a preferred embodiment, the wetting detector (100) comprises a light source (110) for emitting a primary light beam (L0) onto a test region (213) at the contact surface (212), from where a secondary light beam (LR) is reflected and then detected by a light detector (120). The angle (ϑ) of incidence of the primary light beam (L0) is chosen such that it is between the critical angles (ϑc,a, ϑc,f) of total internal reflection of the first and the second medium. The occurrence or the absence of total internal reflection, which can be detected in the amount of light in the secondary light beam (LR), can thus be used to infer if the first or the second medium is present at the contact surface (212). The wetting detector can particularly be used in a microelectronic sensor device to detect if the contact surface (212) is wetted with a liquid sample or if e.g. gas bubbles (3) are present.

Description

MICROELECTRONIC SENSOR DEVICE WITH WETTING DETECTION

The invention relates to a wetting detector and a method for detecting which one of a first and a second medium is present at a contact surface of a carrier. Moreover, it relates to a microelectronic sensor device comprising such a wetting detector and its use. A magnetic sensor device is known from the WO 2005/010543 Al and

WO 2005/010542 A2 (which are incorporated into the present application by reference) which may for example be used in a micro fluidic biosensor for the detection of molecules, e.g. biological molecules, labeled with magnetic beads. The magnetic sensor device is provided with an array of sensor units comprising wires for the generation of a magnetic field and Giant Magneto Resistances (GMR) for the detection of stray fields generated by magnetized beads. The signal of the GMRs is then indicative of the number of the beads near the sensor unit. A problem of this and similar sensor devices is that they require a sufficient contact of the sample to the contact surface where sensing takes place. Disturbances of this contact, for example by gas bubbles, can therefore severely deteriorate the measurements.

Based on this situation it was an object of the present invention to provide means for improving the reliability of examinations of a sample adjacent to a contact surface.

This object is achieved by a wetting detector according to claim 1, by a microelectronic sensor device according to claim 2, by a method according to claim 10, and by a use according to claim 11. Preferred embodiments are disclosed in the dependent claims.

According to its first aspect, the invention relates to a wetting detector for detecting which one of a first and a second medium is present at a contact surface of a carrier. The wetting detector comprises the following components: a) A light source for emitting a light beam, called "primary light beam" in the following for purposes of reference, onto a test region of the contact surface at an angle of incidence that has a value between the critical angles of total internal reflection (TIR) prevailing at the contact surface with respect to the first medium and the second medium, respectively. The light source may for example be a laser or a light emitting diode (LED), optionally provided with some optics for shaping and directing the primary light beam. b) A light detector for detecting a light beam, called "secondary light beam" in the following for purposes of reference, that originates from a reflection or a refraction of the primary light beam at the contact surface. The detector may comprise any suitable sensor or plurality of sensors by which light of a given spectrum can be detected, for example photodiodes, photo resistors, photocells, a CCD chip, or a photo multiplier tube.

The "carrier" that is mentioned in connection with the wetting detector may be a component of this wetting detector or not. It is often made from a transparent material, for example glass or polystyrene, to allow the propagation of light of a given (particularly visible, UV, and/or IR) spectrum. Moreover, the carrier will typically be a disposable component (synonymously called "cartridge").

The term "contact surface" is chosen primarily as a unique reference to a particular part of the surface of the carrier, and though a sample will in many applications actually contact said surface, this does not necessarily need to be the case.

The first and the second medium may be arbitrary materials, provided that they have different refractive indices (and therefore different critical angles of TIR at the contact surface with respect to the carrier material). In general, the refractive indices of the first and second medium may be smaller or larger than the refractive index of the carrier (including the case that one of them is smaller and the other is larger). Preferably, the refractive indices of both the first and the second medium are smaller than the refractive index of the carrier; a (primary) light beam impinging onto the contact surface from the side of the carrier can then experience total internal reflection provided that its angle of incidence is sufficiently large. The described wetting detector has the advantage that it provides a simple but reliable means for detecting if a first or a second medium is present at the contact surface of a carrier. A further advantage is that the detection is achieved with optical means and does not require a physical contact or the application of electricity to the carrier.

The invention further relates to a microelectronic sensor device for examining a sample, wherein the examination shall comprise any kind of manipulation and/or interaction with the sample. The examination may preferably comprise the qualitative or quantitative detection of target components comprising label particles, wherein the target components may for example be biological substances like biomolecules, complexes, cell fractions or cells. The microelectronic sensor device comprises the following components: a) A carrier with a sample chamber in which a sample to be examined can be provided and with a transparent light channel comprising the path of a light beam that propagates from an entrance window of the carrier to a test region at a contact surface of the sample chamber and that is reflected there, for example towards an exit window of the carrier or towards some region where it is absorbed. Typically the light channel will extend straight between the test region and the optical window(s) and will be made from a transparent material with homogeneous refractive index. The "sample chamber" is typically an empty cavity or a cavity filled with some substance like a gel that may absorb a sample substance; it may be an open cavity, a closed cavity, or a cavity connected to other cavities by fluid connection channels. b) A wetting detector of the kind described above for emitting a primary light beam through the entrance window onto the test region at an angle of incidence between the critical angles of total internal reflection with respect to a first and second medium, respectively, and for detecting a secondary light beam that originates from a reflection or a refraction of the primary light beam at the contact surface.

The microelectronic sensor device comprises as a principal component a wetting detector of the kind described above. For more details about the features, advantages and modifications of the microelectronic sensor device, reference is therefore made to the above description of the wetting detector.

The microelectronic sensor device preferably comprises a sensor element that is suited for sensing a parameter of interest from a sample and/or from target particles in a sample, for example an optical, magnetic, mechanical, acoustic, thermal and/or electrical sensor element. A magnetic sensor element may particularly comprise a coil, Hall sensor, planar Hall sensor, flux gate sensor, SQUID (Superconducting Quantum Interference Device), magnetic resonance sensor, magneto -restrictive sensor, or magneto -resistive sensor of the kind described in the WO 2005/010543 Al or

WO 2005/010542 A2, especially a GMR (Giant Magneto Resistance), a TMR (Tunnel Magneto Resistance), or an AMR (Anisotropic Magneto Resistance). An optical sensor element may particularly be adapted to detect variations in an output light beam that arise from a frustrated total internal reflection due to target particles at a sensing surface. Other optical, mechanical, acoustic, and thermal sensor concepts are described in the WO 93/22678, which is incorporated into the present text by reference. Moreover, it should be noted that the sensor element may (exclusively or in addition) be used as light detector of the wetting detector, i.e. for sensing the secondary light beam.

According to another embodiment, the microelectronic sensor device may comprise a fluid-mo vement-device for inducing a flow of a sample fluid within the sample chamber. Thus a sample to be examined can for example be transported into the reach of sensor elements, or a sample can be mixed to establish homogeneous conditions. The fluid-movement-device may optionally comprise microfluidic pumping elements, valves and the like. In the following, further developments of the invention will be described that relate both to the wetting detector and the microelectronic sensor device.

As the name "wetting detector" indicates, one of the first and the second medium is preferably a liquid and the other a gas. In this case it is possible to detect if the wetting of the contact surface with the liquid medium has taken place or not, which is a crucial precondition for the proper function of many biosensors that shall measure properties of a liquid sample (e.g. blood or saliva).

The wetting detector and/or the microelectronic sensor device may preferably comprise an evaluation unit for evaluating a detection signal that is provided by the light detector, wherein this evaluation takes place with respect to the presence of the first or the second medium at the contact surface. The evaluation unit may for example be realized by dedicated electronic hardware, digital data processing hardware with appropriate software, or a mixture of both. The detection signal provided by the light detector may particularly represent the amount of light that was detected in the secondary light beam coming from the contact surface, and the evaluation unit may be adapted to infer from this amount of light if the first or the second medium is present in the test region. As the angle of incidence of the primary light beam is between the critical angles of the first and the second medium, the presence of one of these media will be accompanied by the occurrence of total internal reflection while the presence of the other medium will not. Accordingly, the light of the primary light beam will completely be converted into a (totally internally) reflected beam or it will be subdivided between a reflected and a refracted beam. The presence or absence of total internal reflection, i.e. the presence of the first or the second medium at the contact surface, will therefore change the amount of light in the secondary light beam, a fact that can be exploited by the evaluation unit.

When the amount of light in the secondary light beam is evaluated, the amount of light in the primary light beam is preferably taken into account, for example in a normalization process, to make the result robust with respect to variations of the power of the light source.

In a further development of the invention, at least two spatially different test regions at the contact surface are examined or can be examined in the way the previously mentioned (first) test region is examined by the primary light beam. Thus the wetting detector may for example comprise a second light source for emitting a further primary light beam onto the second test region of the contact surface at an angle between the critical angles of total internal reflection with respect to the first and the second medium, respectively, and a second light detector for detecting a further secondary light beam that originates from a reflection or a refraction of the further primary light beam at the second test region. Alternatively, scanning may be applied to direct a single primary light beam from a single light source in succession to the first and the second test region and/or to direct secondary light beams coming from the first and the second test region, respectively, in succession onto a single light detector. The provision of two or more test regions at the contact surface allows to check for the presence of the first or second medium at more than one location, thus increasing the reliability of the detection result with respect to a generalization for the whole contact surface. In a further development of the aforementioned embodiment, the previously mentioned evaluation unit is adapted to infer which one of the first and the second medium is present at the contact surface in a zone between the two different test regions. Thus a statement is possible about a zone of the contact surface that is not directly measured, for example because it is not accessible for the optical measurements due to the presence of a sensor element integrated into the carrier. By a continuous observation of the first and second test region, the evaluation unit may for instance control which media have entered and left the zone between the test regions, which allows to infer which medium is currently in that zone. In case of a biosensor for a liquid sample that streams from the first to the second test region, the presence of a gas bubble in a sensor zone between the test regions may thus be detected even if no gas bubble is present in the test regions themselves.

According to another embodiment of the invention, the evaluation unit is adapted to detect a misalignment of the carrier with respect to the wetting detector. Such a detection may for example be based on the observation that no secondary light beam at all or only an extraordinarily small secondary light beam is observed, which indicates that the light path from the light source to the light detector is corrupted.

The invention further relates to a method for detecting which one of a first and a second medium is present at a contact surface of a carrier, the method comprising the following steps: a) Emitting a primary light beam onto a test region of the contact surface at an angle of incidence between the critical angles of total internal reflection with respect to the first and the second medium, respectively. b) Detecting a secondary light beam that originates from a reflection or a refraction of the primary light beam at the contact surface.

The method comprises in general form the steps that can be executed with a wetting detector of the kind described above. Therefore, reference is made to the preceding description for more information on the details, advantages and improvements of that method. The invention further relates to the use of the microelectronic device described above for molecular diagnostics, biological sample analysis, or chemical sample analysis, food analysis, and/or forensic analysis. Molecular diagnostics may for example be accomplished with the help of magnetic beads or fluorescent particles that are directly or indirectly attached to target molecules.

These and other aspects of the invention will be apparent from and elucidated with reference to the embodiment(s) described hereinafter. These embodiments will be described by way of example with the help of the accompanying drawings in which:

Figure 1 shows schematically a microelectronic sensor device with a wetting detector according to the present invention, wherein the drawing corresponds to a section along line I-I indicated in Figure 2; Figure 2 shows a top view of the microelectronic sensor device;

Figure 3 corresponds to a section through the microelectronic sensor device along line III-III of Figure 2.

Like reference numbers in the Figures refer to identical or similar components. The invention will in the following be explained with respect to magnetic biosensors, though it is not restricted these devices but can favorably be used in many different applications.

Figure 1 illustrates a microelectronic magnetic sensor device according to the present invention in the particular application as a biosensor for the detection of magnetically interactive particles 1, e.g. biomolecules labeled with super-paramagnetic beads, in a sample chamber 202. Magneto-resistive biochips or biosensors have promising properties for bio-molecular diagnostics, in terms of sensitivity, specificity, integration, ease of use, and costs. Examples of such biochips are described in the WO 2003/054566, WO 2003/054523, WO 2005/010542 A2, WO 2005/010543 Al, and WO 2005/038911 Al, which are incorporated into the present application by reference.

The microelectronic sensor device may for example be intended for roadside drugs of abuse testing in saliva. Drugs of abuse are generally small molecules that only possess one epitope and for this reason cannot be detected by a sandwich assay. A competitive or inhibition assay is the method to detect these molecules. A competitive assay setup can be realized by coupling the target molecules of interest onto a sensing surface 212' above a sensor element 220, and link antibodies to a detection tag (e.g. an enzyme, fluorophore, or, as assumed in Figure 1, a magnetic bead), yielding the target particles 1 of Figure 1. This system is used to perform a competitive assay between the target molecules from the sample and the target molecules on the surface, using the tagged antibodies. For road-side testing, the assay should be fast (~ 1 min) and robust. The superparamagnetic beads can be used in the magnetic biosensors both for detection as well as for actuation (attraction of the magnetic particles to the sensing surface 212' speeds up the binding process, and magnetic washing removes the unbound beads).

It should be noted that many other principles than magnetic detection can be used to detect the presence of the magnetic target particles in the sample chamber 202, for example the principle of frustrated total internal reflection of a light beam that is directed onto the sensing surface 212'.

For both magnetic and other types of detection, a reliable measurement requires that the fluid to be tested (saliva, blood, ...) is in complete contact with the sensing surface. During fluid injection, it may however be possible (e.g. due to a manufacturing error or some contamination) that an air bubble 3 gets trapped and prevents good "wetting" of the sensing surface. In order to prevent a false test result, it is therefore essential to confirm the wetting of the sensing surface. Such a wetting detection can be done electrically, for example by capacitive or resistive means with comb-like electrode structures near the sensor element (preferably on the same surface). This requires however electrical contacts to the cartridge. A more simple wetting detection is therefore desirable that should have little additional costs and be robust.

To address this issue, an optical, contactless wetting detection in a carrier or cartridge 200 (such as a disposable cartridge used for a biosensor) is proposed here that exploits the difference in refractive index between different media, particularly between air (empty cartridge) and the liquid to be tested (the latter being larger than 1 , typically 1.33). The principle used in this approach is to detect the amount of light that is reflected from the cartridge interface with the fluidics channel.

Figure 1 illustrates a corresponding "wetting detector" 100 that is added to the biosensor and that comprises the following components: a) A light source 110, e.g. a laser, for emitting a "primary light beam" LO via an entrance window 215 onto a test region 213 at the contact surface 212 of the cover 214 of the carrier 200. b) A light detector 120 behind a pinhole 121 (or a similar structure to shield light from other directions) for detecting a "secondary light beam" LR that originates from a reflection of the primary light beam LO at the contact surface 212. Obviously, the cover 214 of the cartridge should be transparent for the light of the light source 110 at least in a light channel along the paths of the light beams LO, LR. c) An evaluation module 130, e.g. a digital data processor with associated software, receiving the detection signals that encode the detection results of the light detector 120 and optionally also receiving an information from the light source 110 about the intensity of the primary light beam LO. When the incident primary light beam LO enters the cover 214 at an angle θ between the critical angle θ_{c a} for glass or plastic (n_g = 1.5 - 1.6) to air (n_a = 1) and the critical angle θ_C;f for glass or plastic to fluid (n_f = 1.33), i.e. between about θ_c,_a = 40.2° and θ_c>f= 59.1° (e.g. about 45°), its light will be totally internally reflected if the cartridge 200 is empty. When there is a fluid in the cartridge at the test region 213, the reflected intensity will drop because some of the light of the primary light beam LO branches into a refracted light beam LT that propagates into the sample chamber 202.

The intensity of the secondary light beam LR is sensed by the light detector 120, resulting in a high signal when the light source 120 is on and there is no liquid in the test region 213 and in a low signal if liquid is present (indicating good wetting). Even when the injected liquid is highly dispersive and/or absorbing, the intensity at the detector will still drop due to the presence of the liquid. In this way, wetting is still correctly detected. The differences in the intensity of the secondary light beam LR that are sensed by the light detector 120 are evaluated by the evaluation module 130 with respect to the presence of gas or liquid in the test region 213. As only (part of) the fluidics part of the cartridge 200 needs to be transparent, the method can easily be used in combination with a GMR-based biosensor platform as shown in the Figures.

To effectively couple the light into and out of the cartridge 200, a prism- like structure like that shown in Figure 1 can be used. Other possibilities may contain spherical or cylindrical surfaces, and even grating structures. Moreover, it is beneficial to position the optical windows 215, 216 in a recess to protect them from contamination e.g. by fingerprints. Finally, it should be noted that it would also be possible to use the refracted light beam LT (instead of LR) as a secondary light beam for detection purposes. This light beam LT could for instance be measured by an optical particle- sensor element 220 or by some optical sensor (e.g. a photodiode) added to a (non- optical, e.g. GMR-based) particle-sensor element 220.

Figure 2 shows a top view onto the microelectronic sensor device with the line I-I indicating the section shown in Figure 1. In this example, the sample chamber 202 is (part of) a fluidics channel through which sample fluid is pumped with a fluid-movement-device (not shown) in the direction indicated by the arrow. The lower part 211 of the cartridge 200 is non-transparent and contains a GMR chip 220 for sensing. A structure for optical detection might be used as well.

Figure 3 shows in a section through the microelectronic sensor device (along line HI-III of Figure 2) two electromagnets 231, 232 directly above and below the bio-detection area above the sensor element 220. As the magnet diameter is large compared to the cartridge height, wetting detection directly at this area, i.e. in the test region 213 above the GMR sensor 220, is not easy. It is therefore proposed to do detection in test regions 213a, 213b outside the bio-detection area. Thus continuous wetting detection in a first test region 213a directly in front (left in Figure 2) of the bio- detection area allows reliable detection. To improve reliability, this can especially be combined with wetting detection in a second test region 213b behind the bio-detection area. A drop in signal in the first test region 213a then indicates the successful injection of fluid, and a drop in signal in the second test region 213b indicates the arrival of fluid at the end of the channel 202. Normally this would mean that the bio-detection area is also filled with liquid. However, there is a small possibility that an air bubble may have entered the channel 202 and gets stuck in the bio-detection area. This situation can be detected by monitoring the signal of the first test region 213a: after injection, it should stay low until at least a short time after the fluid has reached the second test region 213b (end of channel, fluid stopped moving). If this is the case, no air bubble has passed the first test region 213a. In case an air bubble does pass, the signal from the first test region 213a will (briefly) go up again after the first detection.

A cartridge 200 provided with transparent windows 215, 216 coinciding with the light beams' nominal entrance and exit areas and being non-transparent outside these areas has the additional advantage that it can also be used to check and confirm correct insertion of the cartridge 200 into the reader: The reader expects to find an empty cartridge 200, which should give a "high" signal (secondary light beam LR hits detector 120 through pinhole). Misalignment of the cartridge 200 will however lead to a "low" signal, since the primary light beam can no longer reach the detector (blocked by one or both windows 215, 216).

While the invention was described above with reference to particular embodiments, various modifications and extensions are possible, for example:

The sensor element can be any suitable sensor to detect the presence of particles on or near to a sensor surface, based on any property of the particles, e.g. it can detect via magnetic methods, optical methods (e.g. imaging, fluorescence, chemiluminescence, absorption, scattering, surface plasmon resonance, Raman, etc.), sonic detection (e.g. surface acoustic wave, bulk acoustic wave, cantilever, quartz crystal etc), electrical detection (e.g. conduction, impedance, amperometric, redox cycling), etc.

A magnetic sensor can be any suitable sensor based on the detection of the magnetic properties of the particle on or near to a sensor surface, e.g. a coil, magneto -resistive sensor, magneto -restrictive sensor, Hall sensor, planar Hall sensor, flux gate sensor, SQUID, magnetic resonance sensor, etc. - In addition to molecular assays, also larger moieties can be detected with sensor devices according to the invention, e.g. cells, viruses, or fractions of cells or viruses, tissue extract, etc.

The detection can occur with or without scanning of the sensor element with respect to the sensor surface. - Measurement data can be derived as an end-point measurement, as well as by recording signals kinetically or intermittently.

The particles serving as labels can be detected directly by the sensing method. As well, the particles can be further processed prior to detection. An example of further processing is that materials are added or that the (bio)chemical or physical properties of the label are modified to facilitate detection.

The device and method can be used with several biochemical assay types, e.g. binding/unbinding assay, sandwich assay, competition assay, displacement assay, enzymatic assay, etc. It is especially suitable for DNA detection because large scale multiplexing is easily possible and different oligos can be spotted via ink-jet printing on the optical substrate. - The device and method are suited for sensor multiplexing (i.e. the parallel use of different sensors and sensor surfaces), label multiplexing (i.e. the parallel use of different types of labels) and chamber multiplexing (i.e. the parallel use of different reaction chambers).

The device and method can be used as rapid, robust, and easy to use point-of-care biosensors for small sample volumes. The reaction chamber can be a disposable item to be used with a compact reader, containing the one or more field generating means and one or more detection means. Also, the device, methods and systems of the present invention can be used in automated high- throughput testing. In this case, the reaction chamber is e.g. a well-plate or cuvette, fitting into an automated instrument.

Finally it is pointed out that in the present application the term

"comprising" does not exclude other elements or steps, that "a" or "an" does not exclude a plurality, and that a single processor or other unit may fulfill the functions of several means. The invention resides in each and every novel characteristic feature and each and every combination of characteristic features. Moreover, reference signs in the claims shall not be construed as limiting their scope.

Claims

CLAIMS:

1. A wetting detector (100) for detecting which one of a first and a second medium is present at a contact surface (212) of a carrier (200), comprising a) a light source (110) for emitting a primary light beam (LO) onto a test region (213, 213a, 213b) of the contact surface (212) at an angle (θ) of incidence between the critical angles (θ_c,_a, θ_{c f}) of total internal reflection with respect to the first and the second medium, respectively, b) a light detector (120) for detecting a secondary light beam (LR, LT) that originates from a reflection or a refraction of the primary light beam (LO) at the contact surface (212).

2. A microelectronic sensor device for the examination of a sample, comprising a) a carrier (200) with a sample chamber (202) and with a transparent light channel comprising the light path of a light beam (LO, LR) that propagates from an entrance window (215) to a test region (213, 213a, 213b) at a contact surface (212) of the sample chamber and that is reflected from there; b) a wetting detector (100) according to claim 1 for emitting a primary light beam (LO) through the entrance window onto the test region (213, 213a, 213b).

3. The microelectronic sensor device according to claim 2, characterized in that it comprises an optical, magnetic, mechanical, acoustic, thermal or electrical sensor element, particularly a coil, a Hall sensor, a planar Hall sensor, a flux gate sensor, a SQUID, a magnetic resonance sensor, a magneto- restrictive sensor, or magneto -resistive sensor like a GMR (220), a TMR, or an AMR element.

4. The microelectronic sensor device according to claim 2, characterized in that it comprises a fluid-movement-device for inducing a flow of a sample in the sample chamber (202).

5. A wetting detector (100) according to claim 1 or a microelectronic sensor device according to claim 2, characterized in that one of the first and the second medium is a liquid and the other is a gas.

6. A wetting detector (100) according to claim 1 or a microelectronic sensor device according to claim 2, characterized in that it comprises an evaluation unit (130) for evaluating the detection signal provided by the light detector (120) with respect to the presence of the first or the second medium at the contact surface (212).

7. A wetting detector (100) according to claim 1 or a microelectronic sensor device according to claim 2, characterized in that at least two different test regions (213, 213a, 213b) at the contact surface (212) are or can be examined.

8. A wetting detector (100) or a microelectronic sensor device according to claim 6 and 7, characterized in that the evaluation unit (130) is adapted to infer which one of the first and the second medium is present in a zone (213) of the contact surface (212) between the two different test regions (213a, 213b).

9. A wetting detector (100) or a microelectronic sensor device according to claim 6, characterized in that the evaluation unit (130) is adapted to detect a misalignment of the carrier (200) with respect to the wetting detector (100).

10. A method for detecting which one of a first and a second medium is present at a contact surface (212) of a carrier (200), comprising a) emitting a primary light beam (LO) onto a test region (213, 213a, 213b) of the contact surface (212) at an angle (θ) of incidence between the critical angles (θ_c,_a, θ_c,f) of total internal reflection with respect to the first and the second medium, respectively, b) detecting a secondary light beam (LR) that originates from a reflection or a refraction of the primary light beam (LO) at the contact surface (212).

11. Use of the microelectronic sensor device according to any of the claims 2 to 9 for molecular diagnostics, biological sample analysis, or chemical sample analysis.