WO2010146367A1 - Fluid sensing, sensor apparatus for fluid sensing, fluid sensing systems and fluid sensing methods - Google Patents

Fluid sensing, sensor apparatus for fluid sensing, fluid sensing systems and fluid sensing methods Download PDF

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Publication number
WO2010146367A1
WO2010146367A1 PCT/GB2010/001196 GB2010001196W WO2010146367A1 WO 2010146367 A1 WO2010146367 A1 WO 2010146367A1 GB 2010001196 W GB2010001196 W GB 2010001196W WO 2010146367 A1 WO2010146367 A1 WO 2010146367A1
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Prior art keywords
sensor
apparatus according
phase
sensor device
microcantilever
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PCT/GB2010/001196
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French (fr)
Inventor
Sven Kelling
Stephen Elliott
Victor Ostanin
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Cambridge Enterprise Limited
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    • GPHYSICS
    • G01MEASURING; TESTING
    • G01DMEASURING NOT SPECIALLY ADAPTED FOR A SPECIFIC VARIABLE; ARRANGEMENTS FOR MEASURING TWO OR MORE VARIABLES NOT COVERED IN A SINGLE OTHER SUBCLASS; TARIFF METERING APPARATUS; MEASURING OR TESTING NOT OTHERWISE PROVIDED FOR
    • G01D11/00Component parts of measuring arrangements not specially adapted for a specific variable
    • G01D11/24Housings ; Casings for instruments
    • G01D11/26Windows; Cover glasses; Sealings therefor
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01DMEASURING NOT SPECIALLY ADAPTED FOR A SPECIFIC VARIABLE; ARRANGEMENTS FOR MEASURING TWO OR MORE VARIABLES NOT COVERED IN A SINGLE OTHER SUBCLASS; TARIFF METERING APPARATUS; MEASURING OR TESTING NOT OTHERWISE PROVIDED FOR
    • G01D5/00Mechanical means for transferring the output of a sensing member; Means for converting the output of a sensing member to another variable where the form or nature of the sensing member does not constrain the means for converting; Transducers not specially adapted for a specific variable
    • G01D5/26Mechanical means for transferring the output of a sensing member; Means for converting the output of a sensing member to another variable where the form or nature of the sensing member does not constrain the means for converting; Transducers not specially adapted for a specific variable characterised by optical transfer means, i.e. using infra-red, visible, or ultra-violet light
    • G01D5/264Mechanical constructional elements therefor ; Mechanical adjustment thereof
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01DMEASURING NOT SPECIALLY ADAPTED FOR A SPECIFIC VARIABLE; ARRANGEMENTS FOR MEASURING TWO OR MORE VARIABLES NOT COVERED IN A SINGLE OTHER SUBCLASS; TARIFF METERING APPARATUS; MEASURING OR TESTING NOT OTHERWISE PROVIDED FOR
    • G01D5/00Mechanical means for transferring the output of a sensing member; Means for converting the output of a sensing member to another variable where the form or nature of the sensing member does not constrain the means for converting; Transducers not specially adapted for a specific variable
    • G01D5/26Mechanical means for transferring the output of a sensing member; Means for converting the output of a sensing member to another variable where the form or nature of the sensing member does not constrain the means for converting; Transducers not specially adapted for a specific variable characterised by optical transfer means, i.e. using infra-red, visible, or ultra-violet light
    • G01D5/266Mechanical means for transferring the output of a sensing member; Means for converting the output of a sensing member to another variable where the form or nature of the sensing member does not constrain the means for converting; Transducers not specially adapted for a specific variable characterised by optical transfer means, i.e. using infra-red, visible, or ultra-violet light by interferometric means
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces

Abstract

A measurement apparatus is disclosed, for measuring a response of a sensor device such as a microcantilever which deflects in response to an analyte. The measurement apparatus includes a pixel lated array of detector elements (e.g. digital camera) and a substantially monochromatic light source. The camera is arranged to capture a series of images of the deflectable element, each image including an interference pattern provided by interference between a sample beam and a reference beam, wherein the phase of one of the sample beam and the reference beam is shifted as between one image in the series of images and the next image in the series of images. This allows the deflection profile of the microcantilever to be calculated. Also disclosed is a sensor apparatus for use with the measurement apparatus. The sensor apparatus provides the microcantilever between a support and a cover with a sealing element interposed between and sealing with the support and with the cover.

Description

FLUID SENSING. SENSOR APPARATUS FOR FLUID SENSING. FLUID SENSING SYSTEMS AND FLUID SENSING METHODS

The present invention relates to sensor apparatus for use with fluids, methods for assembling such sensor apparatus, fluid sensing systems and fluid sensing methods. It has particular, but not exclusive, applicability to sensor apparatus including microcantilever sensors. Furthermore, the invention has particular, but not exclusive, applicability to systems and methods for interrogating such sensor apparatus.

Related art

US 2005/0121615 and US 2002/092340 disclose an integrated microcantilever sensing array system for detecting the presence of target substances in various environmental conditions. Such sensors allow the measurement of static and dynamic properties of the microcantilevers, such as deflection, resonant frequency, phase and amplitude as a function of time in response to various target substances. The microcantilever array is located in a flow cell and the properties of the microcantilevers are assessed optically. The microcantilever array is bonded to a mounting stub of inert material. The stub is held in place in the flow cell by one or more magnets to the base of the flow cell. The flow cell has an inlet port and an outlet port to allow the microcantilevers to be exposed to sample fluid. The flow cell is sealed with a transparent window, with an O-ring or gasket interposed between the transparent window and the body of the flow cell.

US-B-6,926,864 discloses a microfluidics device with a plurality of interaction cells, arranged each to receive a different sample fluid. Each interaction cell has an inlet and an outlet to provide sample fluid to each interaction cell, there to interact with a microcantilever sensor. US 2006/0121502 is related to US-B-6,926,864, and similarly discloses a microfluidics device with a plurality of interaction cells, arranged each to receive a different sample fluid. The microfluidics device of US 2006/0121502 further incorporates a cartridge for housing a cantilever chip and the associated interaction cells. The cartridge has a base block and a lid, which are secured to each other via screws. The lid includes a window opening. A window substrate is provided beneath the window opening. The base block has a pocket shape in its upper face for receiving a flat gasket. The microcantilever chip sits on top of the flat gasket. The alignment of the microcantilever chip in the pocket is maintained by alignment means at each end of the pocket. The window substrate has channels formed in its lower face. When the cartridge is assembled, the microcantilever chip is pressed against the gasket so as to form a seal with the gasket, the gasket thereby providing the lower surface of the interaction cell. The channels in the window substrate conduct the sample fluid to the microcantilevers.

US-A-5,443,890 relates to microfluidic systems in which two plate members defining a flow region in the microfluidic system are not permanently bonded together but which may be brought together and taken apart from each other repeatedly. However, in use, there must be a seal formed between the plates. The use of adhesives to form the seal between the plates is not possible if they are to be easily separated. US-A-5,443,890 therefore suggests forming a recessed groove in one plate and flowing a fluid sealing material into the groove to form, when hardened, a resilient seal which projects above the edges of the groove to press against the second plate and thereby form a seal at the side of a microfluidic channel between the plates. The device is intended to be used with an optical biosensor, for example.

US-B-7,207,206 discloses a chemically functionalized cantilever system, in which one side of the cantilever is coated with a reagent or biological species for binding to an analyte of interest. US 2006/0230817 discloses a similar arrangement.

US 2008/0034840 explores the effect of sample flow direction with respect to the orientation of a piezoelectric microcantilever sensor. Helm et al [Reference 15] disclose a method for reading microcantilever sensor arrays by phase shifting interferometry. Wehrmeister et al [Reference 16] disclose the use of Fabry-Perot interferometry for the readout of microcantilever sensor arrays, allowing the simulateous determination of microcantilever bending and changes in the refractive index of media.

Zhang et al [Reference 28] disclose a 4-well microcantilever sensor device with the bending of 16 microcantilevers monitored in parallel. In use, each well contains about 3 μl of sample fluid.

SUMMARY OF THE INVENTION

The present inventors have realised that known sensor systems, such as those set out above, suffer from a disadvantage that it can be difficult reliably to locate the sensor device in the measurement cell. Typically, a clamping arrangement is used, the clamping arrangement itself being located within the measurement cell, the cell being sealed other than for sample fluid inlet and outlet ports. This can make it difficult to design a measurement cell with a small volume, and can also lead to a measurement cell with a significant amount of dead volume. This limits the utility of the sensor systems when only small fluid sample volumes are available. Furthermore, clamping arrangements can cause damage to fragile sensor devices.

The present invention has been devised in order to address at least one of these problems. Preferably, the present invention ameliorates, reduces, avoids or overcomes at least one (and preferably more than one) of these problems.

In a general aspect, the present invention provides a flow channel in a sensor apparatus, the flow channel being provided at least in part by one or more flow channel surfaces of a sealing element, the sealing element also holding a sensor device in position in the apparatus.

In a first preferred aspect, the present invention provides a sensor apparatus having: a support; a sensor device held in the apparatus, the sensor device having an active area and an inactive area; a cover; a sealing element interposed between and sealing with the support and with the cover; a fluid inlet port; and a fluid outlet port, wherein a flow channel provides fluid communication between the fluid inlet port and the fluid outlet port via the active area of the sensor device, the flow channel being provided at least in part by one or more flow channel surfaces of the sealing element, wherein the sensor device is held in position with respect to the flow channel by the sealing element bearing against at least part of the inactive area of the sensor device.

In a second preferred aspect, the present invention provides an apparatus for location of a sensor device, including: a support; a sensor device mounting location, said location having an active location area for location of an active area of the sensor device and an inactive location, for location of an inactive area of the sensor device; a cover; a sealing element to be interposed between and sealing with the support and with the cover; a fluid inlet port; and a fluid outlet port; wherein, when the apparatus is assembled, a flow channel provides fluid communication between the fluid inlet port and the fluid outlet port via the active location area, the flow channel being provided at least in part by one or more flow channel surfaces of the sealing element, wherein the sealing element is adapted to cover at least part of the inactive location area.

In a third preferred aspect, the present invention provides a method of assembling an apparatus according to the first aspect, including the step of locating the sensor device at the support and laying the sealing element over the sensor device and laying the cover over the sealing element.

In a fourth preferred aspect, the present invention provides a method of assembling an apparatus according to the first aspect, including the step of locating the sensor device at the cover and laying the sealing element over the sensor device and laying the support over the sealing element.

In a fifth preferred aspect, there is provided a sensing system having a measurement apparatus adapted for measuring a response of the sensor device in a sensor apparatus according to the first aspect.

In a sixth preferred aspect, there is provides a sensing kit including a sensing system according to the fourth preferred aspect and:

(i) a sensor apparatus according to the first aspect, or

(ii) a plurality of sensor apparatus according to the first aspect.

In a seventh preferred aspect, there is provided a measurement apparatus for measuring a response of a sensor device, the sensor device incorporating a deflectable element, in use the deflectable element deflecting in response to an event to which it is sensitive, wherein the measurement apparatus includes a pixellated array of detector elements, arranged to receive an image of a phase shifting interference pattern provided by the deflectable element with a light source, wherein the light source is a substantially monochromatic light source.

In an eighth preferred aspect of the invention, there is provided a sensing system according to the fifth or sixth aspects, wherein the measurement apparatus is according to the seventh aspect.

In a ninth preferred aspect of the invention, there is provided a sensing method in which the response of a sensor device is measured, the sensor device incorporating a deflectable element, and the method including the step of the deflectable element deflecting in response to an event to which it is sensitive, and the method further including the steps of illuminating the deflectable element using a substantially monochromatic light source and receiving an image of a phase shifting interference pattern provided by the deflectable element at a pixellated array of detector elements.

In a tenth preferred aspect of the invention, there is provided a sensing method according to the ninth aspect, wherein the sensor device is housed in a sensor apparatus according to the first aspect.

Preferred and/or optional features of the present invention will now be set out. These may be applied singly or in any combination to any aspect of the invention, unless the context demands otherwise.

Preferably, the sealing element comprises a resilient material. In use, preferably the sealing element is partially compressed between the support and the cover. The sealing element may be formed of any suitable inert material compatible with the purpose of the sensor apparatus. For example, the sealing element may be formed from a polyurethane or from a silicone polymer such as PDMS. In use, the sealing element may be compressed by up to 5% or, more preferably, by up to 10% or more. In this way, it is preferred that the inactive part of the sensor device is urged against the substrate or cover (depending on the arrangement of the apparatus) by the sealing element.

Suitable compression of the sealing element between the support and cover may be provided by clamping of the support and cover. For example, screws or bolts may be provided to clamp the support and cover. A dead stop may be provided between the support and the cover, in order to limit the pressure applied to the sealing element. This is advantageous since it helps the flow channel to be provided with easily reproducible dimensions.

It is preferred that the sensor device includes at least one cantilever element, such as a microcantilever element. A single device may itself have an array of two or more cantilever elements. The cantilever element typically projects from a supporting base, with the other end being free. The cantilever element may form at least part of the active area of the sensor device. The supporting base may provide the inactive area of the sensor device.

However, it is not essential that the sensor device is a cantilever-based device. Alternative sensor devices may be used, such as a surface plasmon resonance device, a fluorescence substrate or a quartz crystal microbalance (QCM) sensor chip.

As used herein, the term "cantilever" or "microcantilever" is a structural term that refers to a flexible beam that may be bar-shaped, V-shaped, or have other shapes, depending on its application. Microcantilevers are usually of microscopic dimensions, for example, they can be about 50 μm to about 750 μm in length. The microcantilevers suitable for use with the present invention are preferably 200 μm to 700 μm in length, more preferably 250 μm to 600 μm in length, and most preferably 300 μm to 500 μm in length. Further, the width can be, for example, about 50 μm to about 300 μm. Each microcantilever may be from about 0.5 μm to about 4.0 μm thick.

Silicon and silicon nitride are the most typical materials used to fabricate microcantilevers. However, other materials may be used for making microcantilevers, including piezoelectric materials, plastic materials and various metals. The microcantilevers suitable for use with the present invention may be manufactured from ceramics, silicon, silicon nitride, other silicon compounds, metallic elements, alloys or compounds, gallium arsenide, germanium, germanium dioxide, zinc oxide, diamond, quartz, palladium, tantalum pentoxide, and plastic polymers. Suitable plastics can include: polystyrene, polyimide, epoxy, polynorbomene, polycyclobutene, polymethyl methacrylate, polycarbonate, polyvinylidene fluoride, polytetrafluoroethylene, polyphenylene ether, polyethylene terephthalate, polyethylene naphthalate, polypyrrole, and polythiophene.

US-A-6,096,559 and US-A- 6,050,722 describe fabrication of a microcantilever, including use of material such as ceramics, plastic polymers, quartz, silicon nitride, silicon, silicon oxide, aluminum oxide, tantalum pentoxide, germanium, germanium dioxide, gallium arsenide, zinc oxide, and silicon compounds.

Microcantilevers that can be employed in accordance with the invention may have a compound immobilized on the surface of a free end to detect and screen receptor/ligand interactions, antibody/antigen interactions and nucleic acid interactions as is disclosed in US-A-5,992,226. Microcantilevers can be used to detect enzyme activities directed against a substrate located on a surface of the microcantilever. Deflection may be measured using either of optical or piezoelectric methods. Further, the microcantilevers of the embodiments of the invention can measure concentrations using electrical methods to detect phase difference signals that can be matched with natural resonant frequencies as discussed in US-A-6,041 ,642. Determining a concentration of a target species using a change in resonant properties of a microcantilever on which a known molecule is disposed, for example, a biomolecule selected from DNA, RNA, and protein, is described in US-A-5,763,768.

Micromechanical potentiometric sensors as disclosed in US-A-6,016,686 may be used in conjunction with the microcantilevers used in preferred embodiments of the present invention, for measuring physical or chemical properties of the sample fluid. Chemical detection of a chemical analyte in a sample fluid is described in US-A-5,923,421. Further, embodiments of the present invention allow magnetic and electrical monitoring of radioimmune assays, using antibodies specific for target species which cause microcantilever deflection (e.g. magnetic beads binding the target to the microcantilever, as described in US-A-5,807,758).

The term "first surface" as used herein refers to that geometric surface of a microcantilever designed to receive and bind to a ligand and/or to an analyte. One or more coatings can be deposited upon this first surface. The term "second surface" refers to the area of the opposite side of the microcantilever that is designed not to receive the ligand or bind to the analyte. As the second surface is generally not coated, it is generally comprised of the material from which the microcantilever or microcantilever array is fabricated, prior to any coating procedure applied to the first surface. Alternatively, it may be coated with a material different from the coating of the first surface. Coating of micromechanical sensors with various interactive molecules is described in US-A-6,118,124. A coating material may be deposited on a microcantilever by depositing a metal which may be selected from at least one of the group consisting of aluminium, copper, gold, chromium, titanium and silver. Further, a plurality of metals may be deposited on a microcantilever by depositing, for example, a first layer of chromium and a second layer of gold, or a first layer of titanium and a second layer of gold. Coatings may be amalgams or alloys comprising a plurality of metals. A first surface of a microcantilever may be fabricated to have an intermediate layer, for example, sandwiched between the first surface comprising for example, gold, and the second surface, comprising for example silicon nitride. The intermediate layer may be an alloy comprising a plurality of metals. For example, the intermediate layer may be an amalgam comprising mercury with at least one of chromium, silver, and titanium.

A microcantilever may deflect or bend from a first position to at least a second position due to differential stress on a first surface of the microcantilever in comparison to a second surface. That is, a microcantilever may deflect in response to the change in surface stress resulting from exposure of the microcantilever to a component of a particular environment. A microcantilever may also deflect in response to a change in the environment. A change in the environment may occur as the result of adding a sample having or lacking an analyte, having a higher or lower analyte concentration, adding or omitting a specific co-factor of an analyte, having a higher or lower concentration of the co-factor, having or lacking a specific inhibitor of an analyte, or having a higher or lower concentration of an inhibitor. Further, a sample may be diluted or concentrated and a solution may experience a change in temperature, pH, conductivity or viscosity prior to, during or after exposure to a microcantilever.

When one end of a microcantilever is fixed to a supporting base as described above, deflection is measured by measuring a distance the distal end of the microcantilever (i.e., the end distal to the end fixed to the supporting base) has moved. The distal end may move from a first position to a second position. In the first position, the material (e.g. biomaterial) on the first surface of the microcantilever has not yet bound to or reacted with the analyte. In the second position, the material (e.g. biomaterial) on the first surface of the microcantilever has bound to or has reacted with the analyte in the environment. A "deflection characteristic", as used herein, is a pattern of deflection of a microcantilever that is reproducible in extent of distance travelled, for example as measured in nm (typically in terms of the deflection of the microcantilever with distance along the microcantilever, i.e. the deflection profile), and/or frequency per unit time. The deflection characteristic may distinguish specific conditions of ligand and analyte, and further reaction conditions such as temperature, concentration, ionic strength, presence of cation or other co-factors, preservatives, and other conditions understood by the skilled person. The deflection under these conditions thereby may be considered to be a signature for the specific reaction. A deflection characteristic is calculated from a measurement of movement (or profile) of the microcantilever upon addition of a sample, or measurement of movement as a function of concentration of an analyte, a ligand, an inhibitor, or a co-factor. A deflection characteristic may also be calculated as a function of pH, or of temperature, and the like.

Preferably, one of the support, sealing element and the cover (most preferably the support or the sealing element) includes a first pocket shaped to receive the sensor device. This is preferably a recess in the support, sealing element or cover. Preferably, the fluid inlet port and the fluid outlet port open into the first pocket. By careful manufacture of both the sensor device and the support, the first pocket may very precisely locate the sensor device with respect to the support. Preferably, the sensor device makes contact with a sidewall of the first pocket in at least two locations.

Preferably, one of the support and the cover (preferably the support) includes a second pocket shaped to receive the sealing element. Preferably, the area size of the second pocket is greater than that of the first pocket. Furthermore, when the apparatus is assembled, and viewed in plan view, preferably the second pocket envelops the first pocket. Preferably, the sealing element makes contact with a sidewall of the second pocket in at least two locations. Preferably, an upper surface of the sensor device (e.g. an upper surface of the inactive area of the sensor device), when the sensor device is assembled in the apparatus, is substantially level with the top of the first pocket. Where the second pocket is provided in the support, and when the sensor device is assembled in the apparatus, preferably the upper surface of the sensor device is substantially level with the base of the second pocket.

Preferably, the sealing element includes at least one channel or slot. At least one end of said channel or slot may be located to be in registration with the fluid inlet port or the fluid outlet port. In use, the side surfaces of the channel or slot provide the flow channel between the fluid inlet port and the fluid outlet port.

When the sealing element is located in the second pocket, but where the support and cover are not yet clamped together, preferably an upper (or lower) surface of the sealing element projects above (or below) and upper surface of the support (or below a lower surface of the cover). Thus, when the support and cover are clamped together, the sealing element may be compressed.

Preferably, the sealing element and the second pocket are carefully manufactured to provide a precise fit between the sealing element and the second pocket. Thus, provided the channel or slot in the sealing element is also formed carefully, assembly of the sensing device, sealing element, support and cover allows precise location of the fluid flow channel with respect to the active area of the sensing device. This can assist in providing a very low volume for the flow cell and in providing a flow cell with little or no dead volume. Furthermore, sensor device mounting within the apparatus is simple, rapid and reproducible. This is a very significant improvement compared with known apparatus, in which the sensor device must be carefully clamped in position in the sensor cell. There may be provided registration means (e.g. a pin-and-hole arrangement or similar) for ensuring suitable alignment of the cover and the support. Where the second pocket is provided in the cover, this is of particular importance in order to align the sealing element with respect to the sensor device.

Preferably, the sensor device is interrogated optically, in use. In this case, it is preferred that the cover is transparent to the optical wavelength used to interrogate the sensor device, at least in a portion of the cover over the flow channel. Optical interrogation of known apparatus typically requires careful alignment of the sensor device in the measurement cell. However, the preferred embodiments of the present invention greatly simplify this process, since the sensor device can be easily aligned with the remainder of the apparatus. The cover may include a transparent window portion. In this case, the remainder of the cover may be opaque. For example, the remainder of the cover may be formed of PTFE or similar inert material. The window portion may be formed of glass. The window portion is preferably aligned with at least the active area of the sensor device, in order to allow optical interrogation of the sensor device.

Preferably, the volume of the flow channel, from the fluid inlet port to the fluid outlet port, is at least 0.01 μl. More preferably, this volume is at least 0.05 μl, at least 0.1 μl or at least 0.25 μl. The upper limit for the volume of the flow channel, from the fluid inlet port to the fluid outlet port, may be 2 μl, but is preferably lower, e.g. at most 1.5 μl, at most 1 μl, at most 0.8 μl or about 0.5 μl.

Preferably, the sensor device has two or more sensing elements (e.g. 2 or more cantilever arms). Furthermore, preferably the apparatus includes two or more sensing devices. Preferably, the structure of those sensing devices is similar or identical. These may be held in a single support with a single cover. Multiple first pockets may be provided to locate the sensing devices. It is possible to provide corresponding multiple sealing elements and multiple second pockets for the sealing elements. However, preferably there is provided a sealing element (and a corresponding second pocket) that contacts two or more (preferably all) of the sensing devices. There may be provided one or more fluid inlet ports and one or more (preferably one common) fluid outlet ports. Corresponding flow channels may be provided (e.g. in register with the fluid inlet ports and fluid outlet ports) by the sealing element.

Where two or more sensing elements are provided, these may be provided to operate in parallel (e.g. on the same or different sample fluid). Alternatively, these may be provided to operate in series on the same sample fluid in sequence.

The support (and/or the cover) may be provided with fluid conduits in fluid communication with the inlet port(s) and outlet port(s).

The fluid may be gas and/or liquid, and may include entrained solids, provided that the fluid is flowable (e.g. by pumping).

The flow channel may have a length of at least 1 mm. Preferably, the length is at most 10 mm, or at most 5 mm. The flow channel may have a height (thickness) of at least 10 μm, at least 20 μm, at least 30 μm, at least 40 μm or at least 50 μm. Preferably, the height is at most 1 mm, or at 0.5 mm. The flow channel may have a width of at least 10 μm, at least 20 μm, at least 30 μm, at least 40 μm or at least 50 μm. Typically, where the sensor is a microcantilever sensor, the width of the flow channel is slightly greater than the lateral extent of the microcantilever(s) arranged at the sensor. Preferably, the width is at most 1 mm, or at most 0.5 mm.

With respect to the measurement apparatus, it is preferred that the monochromatic light source is a diode light source, for example a light emitting diode, or more preferably a laser diode. The pixellated array of detector elements is preferably an imaging chip, e.g. in a digital camera, such as a CCD chip. Preferably there are provided at least 106 detector elements, more preferably at least 5 x 106, still more preferably at least 10 x 106 detector elements. The advantage of this is that it allows the interference fringes to be imaged more precisely.

Preferably, the image received at the pixellated array of detector elements is magnified compared with the actual area observed. In order to achieve this, it is preferred to incorporate imaging optics between the area observed and the pixellated array of detector elements. For example, a microscope or at least a microscope objective may be used. The advantage here is that it is preferred to use as much of the pixellated array of detector elements as possible, in order to image the interference fringes precisely.

One significant benefit of imaging the whole active area of a sensor device in order to obtain the interference fringes along it is that the overall shape of the active area of the sensor device - whether deflected or undeflected - can be determined. Known measurement systems tend to try to measure very precisely the position of one spot on the sensor device (e.g. a cantilever tip), but this has a drawback in that it requires very careful measurement and errors in the measurement significantly affect the readout of the device. In contrast, measurement of the overall shape of the active area of the sensor device reduces the tendency of errors to significantly affect the readout of the device.

Preferably, the image received is of more than one sensor device (or the active areas of more than one sensor device). For example, the image may capture at least two, four, eight, ten, twenty, fifty, one hundred, one thousand or more sensor devices simultaneously. This allows the readout of a significant number of sensor devices substantially simultaneously, typically allowing real time analysis. Typically, a reference beam is provided from said light source. The reference beam is typically aligned so as to interfere with the sample beam in a recording plane of the pixellated detector. The phase of this beam is preferably shifted during the method, in order to provide a set of interferograms in which the reference beam has a different phase for each interferogram. Preferably, the number of interferograms provided for each measurement is at least 3 or at least 4.

Preferably, the apparatus is arranged to capture a series of images of the deflectable element, each image including an interference pattern provided by interference between the sample beam and the reference beam, wherein the phase of one of the sample beam and the reference beam is shifted as between one image in the series of images and the next image in the series of images.

The apparatus may further include a liquid crystal phase retarder in order to shift the phase of the reference beam or the sample beam. Such a device allows the phase to be shifted in a manner which avoids significant noise, particularly vibration noise.

Preferably, the phase shift as between the one image in the series of images and the next image in the series of images is less than π. More preferably, the phase shift as between adjacent images in the series is between π/3 and π, typically about τr/2. More generally, the phase shift as between the one image in the series of images and the next image in the series of images is less than (aπ + 2bττ), wherein a is any integer or non- integer and is 2 or less and wherein b is 0 or any integer.

Preferably, a deflection profile of the deflectable element is calculated based on a comparison of a reference phase profile of the deflectable element with a phase profile of the deflectable element deflecting in response to an event to which it is sensitive. Preferably, the interference fringes are detected via software analysis (e.g. based only on a consideration of the brightness detected at each pixel), and the corresponding shape of each sensor device's active area computed accordingly.

Further optional features of the invention are set out below, with reference to the preferred embodiments of the invention.

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS

Fig. 1 shows a schematic view of a support for use with an embodiment of the present invention.

Fig. 2 shows a plan view of the support of Fig. 1.

Fig. 3 shows a cross sectional view of the support of Fig. 2.

Fig. 4 shows an arrangement in which a sensor device is mounted in the support of Fig. 1.

Fig. 5 shows a plan view of the arrangement of Fig. 4.

Fig. 6 shows a cross sectional view of the arrangement of Fig. 5.

Fig. 7 shows the arrangement of Fig. 2 further with a sealing element.

Fig. 8 shows a plan view of the arrangement of Fig. 7. Fig. 9 shows a cross sectional view of the arrangement of Fig. 8.

Fig. 10 shows a schematic view of a device according to an embodiment of the invention corresponding to Figs. 1-9.

Fig. 11 shows the device of Fig. 10 clamped together by screws.

Fig. 12 shows a plan view of the device of Fig. 11. Fig. 13 shows a cross sectional view of the device of Fig. 12.

Fig. 14 shows an arrangement for use with an alternative embodiment of the invention.

In Fig. 14a there is shown an arrangement of four sensor devices mounted in a corresponding support, and in Fig. 14b there is shown the arrangement of Fig. 4a further with a sealing element. Fig. 15 shows the arrangement of Fig. 14 with a cover, to form a device according to an alternative embodiment of the invention.

Fig. 16 shows an alternative view of the device of Fig. 15.

Fig. 17 shows a schematic view of a sealing element for use with the device of Fig. 15. Fig. 18 shows a schematic view of an alternative embodiment of the invention.

Figs. 19-21 show a plan view, side view and sectional view, respectively, of a sealing element for use with an embodiment of the invention.

Figs. 22-24 show a plan view, side view and sectional view, respectively, of a sealing element for use with another embodiment of the invention. Fig. 25 shows a schematic view of a phase shifting interferometric microscopy (PSIM) instrument for the simultaneous monitoring of multiple cantilever arrays, based on a modified Twyman-Green interferometer.

Fig. 26 shows the areas selected for analysis of an interferogram superimposed on a two microcantilever array. The chip substrate is shown at the top of the image. Fig. 27 shows representative data of a height-profile map for a 4 x 2 array of microcantilevers.

Fig. 28 shows a photomicrograph of an embodiment of the invention, with a cross- shaped flow channel configuration and with a central sample inlet/outlet port, and with an array of 4 x 2 microcantilevers. Fig. 29 shows a plot of the short term baseline noise for two cantilevers on the same chip measured with the PSIM system according to an embodiment of the invention.

Fig. 30 shows a plot of simultaneously measured displacement of 4 microcantilevers from two separate sensor-chips (MC2-39, MC2-40), each coated on one side with SH-

(CH2)18-COOH, exposed for 100 sec to toluene vapour. Fig. 31 shows a plot of the detection of DMMP by simultaneous monitoring of 4 different microcantilever-array chips with 3 differently functionalized receptor layers. Note that there are two curves for each chip, since each chip has two microcantilevers.

Fig. 32 shows a schematic illustration of a sensor array for use with an embodiment of the invention, each array consisting of 20 commercially available sensor-array chips (NanoWorld, Arrow TL8), holding a total of 160 microcantilevers. The dimensions of the area required for imaging, to allow parallel PSIM readout, is 13.20 x 16.34mm.

Figs. 34-36 illustrate modifications of the embodiment of Figs. 1-13.

Fig. 37 shows a schematic view of a microcantilever imaged only using the sample beam. Fig. 38 corresponds to Fig. 37, except that an interference pattern is provided by the introduction of the reference beam.

Figs. 39-42 show schematic views of interferograms provided by phase shifts of the reference beam.

Fig. 43 illustrates the wrapped phase profile of the microcantilever. Fig. 44 illustrates the unwrapped phase profile of the microcantilever.

Fig. 45 shows a plot of deflection against time for two microcantilevers.

Fig. 46 shows the recorded deflection response of 8 microcantilevers, coated with different polymer films, monitored simultaneously whilst being exposed to ethanol vapour at a concentration of 15,000 ppm.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS. FURTHER

PREFERRED AND/OR OPTIONAL FEATURES

The preferred embodiments of the present invention provide an improvement of gas or fluid sample measurement cells for chemical sensors, biochemical sensors and other sensors, such as MEMS sensors based on microcantilevers.

Known microcantilever sensors are typically held with a clamp inside a sealed measurement cell which has a sample inlet, a sample outlet and a transparent viewport (e.g. glass window) for sensor monitoring. The measurement cell has to be large enough to accommodate the whole sensor chip and the sensor chip clamp inside the measurement cell. However, such large measurement cells require relatively large sample volumes and make it very difficult to design a measurement cell with no or minimal dead volume. Therefore these measurement cell designs limit or prevent the use of microcantilever sensors in areas where only small volumes of samples are available or where sample cross contamination has to be prevented (such as in medical diagnostics or drug development). Furthermore, mounting and aligning fragile sensor chips in a mechanical clamping device is difficult. This makes such a system less suitable for applications requiring frequent sensor chip replacements.

The preferred embodiments of the present invention fix sensors, such as microcantilevers, into a sensor cell and at the same time provide create micro-flow channels via which liquid or gas samples can be delivered to, across and away from the sensor in a well-defined flow pattern. The embodiments presented here allow for typical measurement cell volumes of 0.25 - 0.5 microlitres per cantilever sensor chip, which is one order of magnitude less compared to typically 5 microlitres in current state of the art commercial instruments [see, for example, Reference 27]. Sensor mounting and alignment inside the measurement cell is simple, rapid and reproducible.

The measurement cells described herein can be used with a classical laser-beam reflection readout system, with an interference microscopy readout system or, after inclusion of suitable electrical contacts and sensors (if necessary), with an electrical (e.g. piezoelectric of capacitive) sensor readout system.

Referring now to Figs. 1-13, the sensor mount consists of three main components: a support 100, a sealing element 107 and a cover 200.

The support 100 is made of a material compatible with the sensing application (e.g. bio- compatible, solvent resistant). PEEK can be used, for example. The support has a first pocket 101 into which a sensor chip 106 is to be placed, such that the sensor chip snugly located by the sidewalls of the first pocket 101 and the sensor chip surface is flush with an upper surface of the first pocket 101 (corresponding to a base surface of the second pocket 104 - see below). First pocket 101 is designed so as to allow obstruction-free movement of the mechanical sensing part of the MEMS sensor (e.g. the cantilever arm). The support has a sample inlet hole 102 and a sample outlet hole 103 positioned to allow sample to flow over and along the first pocket. These holes communicate through the support to a bottom surface of the support. Holes 105 in the support are provided alignment of the cover 200. Also provided is a second pocket 104, shallower than and encompassing the first pocket, for location of the seal element 107. The second pocket has a typical depth of 50-200 μm.

Sealing element 107 serves two main functions: it holds the sensor (e.g. a MEMS sensor) in position, located inside the first pocket 101 , and guides the sample over the sensor. The seal is made of a pliable material e.g. the highly elastic polyurethane film Walopur® from Epurex Films GmbH, or Platilon® U (if required to be solvent resistant etc.). When placed in the second pocket 104, with the sensor chip located in the first pocket 101 , the sealing element covers the inactive area of the sensor and the inlet and outlet. A cut-through channel 116 in the sealing element 107 can be formed very precisely by laser cutting, and runs from the sample-inlet hole 102 via the sensor to the sample-outlet hole 103. This channel is designed to have substantially no dead volume and is only wide enough to coincide with and overlie the sensitive part of the sensor chip (i.e. slightly wider than the width of the cantilever(s). The sealing element can be flat on both sides (see Figs. 19-21) or have a lip 110 incorporated on one or both sides for improved sealing (see Figs. 22-24).

The measurement cell is closed with cover 200 which is placed on top of the sealing element. The cover may be aligned with the support using registration features such as dowel pins and corresponding holes. The cover is fixed to the base with a means of clamping, e.g. screws 109 (see Figs. 11-13). Alternative clamping arrangements can be used, as will be understood by the skilled person. A constant 10% compression of the seal (i.e. compressing the seal to 90% of its uncompressed thickness), and thereby a reproducible sample channel width, is achieved by a dead-stop between cover and base. The cover is made from a transparent material to allow monitoring of the MEMS sensor- displacement reaction to a sample, e.g. gas or liquid analyte.

By compressing the sealing element between the support and the cover, the MEMS sensor chip is held in place, and the slot cut from the sealing element provides a vapour- tight or liquid-tight sample-delivery channel.

The sample (gas or liquid) is supplied to connectors (not shown) on the base of the support. The sample flows through the holes in the support into the channel formed by the slot cut in the sealing element. The channel guides the sample flow across the sensor and to the sample outlet hole in the support.

The mounting method described above can be used to mount multiple sensors on one support, as illustrated by Figs. 14-18. The measurement cell illustrated in Figs. 14-17 provides a single support 300 and four sensor elements 302, 304, 306, 308, arranged in a cross shape. A single corresponding sealing element 310 is provided, in which slots are cut in order to form a cross shaped channel 312. This channel guides a flowable sample from inlets to a common outlet. As shown in Fig. 15, a single cover 314 is clamped (via screws in this case) to the support 300 to compress the sealing element 310 and hold the sensor chips in position. At the reverse of the support (see Fig. 16) are provided sample inlet and sample outlet connectors. These may be operated so that there is a common inlet and separate outlets, or so that there are separate inlets and common outlets.

In the arrangement shown in Figs. 14-17, a sample may be caused to flow across each sensor chip simultaneously. In an alternative embodiment, as illustrated in Fig. 18, the measurement cell may be arranged to flow the sample sequentially across the different sensor chips 404-410 from an inlet 400 to an outlet 402, e.g. along a meandering flow channel. Such a flow channel can be formed in a single sealing element. Of course, alternative configurations may be chosen for the flow channel.

Typical dimensions for the sealing element and the flow channel are shown in Figs. 19- 21. The sealing element is typically 25-200 μm thick, with a channel width as narrow as 100 μm and a channel length of a few millimetres. Such a flow channel provides a small sample volume requirement, typically 0.25-0.5 microlitres for the measurement cell volume. There is no or substantially no dead volume in the cell, and there is low or zero risk of sample cross-contamination. The arrangement provides significant design freedom for sequential, simultaneous or independent sample delivery to multiple MEMS sensors. Suitable micro flow channels can be arranged in order to allow individual sensor chip addressing, including in situ sensor-chip coating with receptors. The embodiments provide fast and simple and reproducible sensor-chip mounting. Also, the mounting of the sensor chips here subject the sensor chips to very low stress. Using only a few components makes the assembly process quick. Also, the embodiments described here provide a reversible / non-permanent mount, allowing features of the embodiments to be re-used.

Figs. 34-36 illustrate modifications of the embodiment of Figs. 1-13. These drawings show transverse cross section of the apparatus (as opposed to the longitudinal cross sections shown in Fig. 10, for example. Fig. 34 shows an embodiment very similar to the embodiment of Figs. 1-13. Support 500 has a first pocket 501 in which sensor devices 506 are located. Second pocket 504, of larger areal extent than first pocket 501 , is also located in the support 500. As shown in Fig. 34, the sensor devices 506 are located so that the cantilever arms extend in a direction perpendicular to the intended fluid flow between the inlet and outlet ports (not shown). Fig. 34 further differs from Figs. 1-13 in that screw holes 505 and 605 (in the cover 600) are located on either transverse side of the second pocket. Cover 600 is a transparent cover. Sealing element 507 has a flow channel cut out 516. Seal element fits snugly in the second pocket and is compressed between the second pocket and the cover in use.

Fig. 35 shows a slight modification of the embodiment of Fig. 34. The sealing element, support and sensor devices are the same as in Fig. 34, so are not labelled or described further. However, the cover 650 is different. Cover 650 is formed of a non-transparent material, such as PTFE. Cover 650 includes an aperture 652 having a stepped profile so as to retain a glass window 654 therein. The sealing element is then compressed by the cover 650, window 654 and the second pocket of the support. The window overlies the active areas of the sensor devices, allowing optical interrogation. The advantage of this embodiment is that it is then not necessary to form the whole cover from a transparent material. Particularly where the fluid to be analysed is corrosive or difficult to handle, this allows the cover 650 to be formed an opaque material which is resistant to attack by the fluid, but which allows easy formation of screw holes 655 through the cover.

Fig. 36 shows a modification of the embodiment of Fig. 34. Cover 650a is similar to cover 650 in Fig. 35. Aperture 652a retains glass window 654a, and the cover has screw holes 655 formed in it. Cover 650a also has a pocket, designated the third pocket 660. Support 500a includes screw holes 505a. However, although the support includes second pocket 504a, the support does not have the first pocket. Instead, first pocket 530 is formed in sealing element 507a. Sensor devices 506 are held in first pocket 530. The sealing element 507a also includes the flow channel 516a. Sealing element 507a is located and compressed between second pocket 504a and the third pocket 507a. This construction allows the sensor devices to be held in the sealing element, allowing for more simple manufacture of the support and cover.

In recent years, microcantilevers have been widely used as sensors in research and commercial applications, ranging from quality control [References 1 and 2], environmental monitoring [References 3 and 4], counter-terrorism [References 5-7], proteomics [References 8-10], and medical diagnostics [References 11 and 12] to genomics [References 13 and 14]. While sensitivity levels have been pushed ever lower and cantilever arrays, i.e. substrates with multiple cantilever sensors per chip, can be monitored on a routine basis, existing set-ups suffer from some or all of the following problems: 1) alignment of the sensor chip is very critical, resulting in slow system set-up; 2) multiplexing is achieved by hardware scale up, prohibiting the use of sensor arrays with 100s or 1000s of cantilevers; and 3) if multiple cantilevers are monitored, they are dependent because they are attached to the same substrate chip. This makes it difficult to prepare differently functionalised layers on the surfaces of individual cantilevers, and does not allow for the simultaneous monitoring of cantilevers from completely independent chips made from different materials, or with different chemical or geometrical properties.

One promising approach towards a cost-efficient, scalable, multiplexed readout is based on optical interferometry, because this does not require a special (e.g. piezoresistive) cantilever sensor but works with any mass-produced standard microcantilever. The simultaneous readout of up to 2 micromechanical cantilevers in parallel has recently been demonstrated by different groups using various interferometric techniques [References 15-17].

The present inventors have investigated the idea of using interferometry for microcantilever readout further and have developed a system which in the preferred embodiments addresses all the above mentioned problems. The system is capable of the simultaneous monitoring of multiple independent cantilever sensors from different sensor array chips in a set-up that is not critically dependent on alignment by using

Phase-Shifting Interferometric Microscopy (PSIM). As many cantilever sensors as can be accommodated within the field of view of the instrument's microscope optics can be monitored, which offers the potential for a massively multiplexed readout of microcantilever arrays. To complement the readout system and take full advantage of its capabilities, the present inventors developed the measurement cell described above and further described below. Microcantilever sensors are commonly mounted with a clamping device inside a sealed measurement cell which has a sample inlet and outlet and a transparent viewport (e.g. glass window) for sensor monitoring [References 8, 10, 16]. The measurement cells should be large enough to accommodate the whole sensor chip, and also a sensor chip clamping mechanism. Therefore, such measurement cells have in the past required relatively large sample volumes. This limits, or even prevents, the use of typical microcantilever sensors in applications where only small volumes of samples are available, such as in medical diagnostics or drug development. Furthermore, the mounting and alignment of very small, fragile sensor-chips in a mechanical clamping device is difficult, which makes such a system less suitable for applications requiring frequent sensor-chip replacements. In alternative designs, the sensor chip is mounted permanently inside a flow cell [References 14, 23], which does not allow for simple and fast sensor replacement.

The measurement cell of the preferred embodiments of the present invention overcomes the above-mentioned problems and limitations, including the ability to hold multiple microcantilever array chips, allows for very fast sensor-chip replacement, provides a very small sample volume space, and is capable of supplying the same, or different, vapour- or liquid-phase sample streams to the different sensor chips inside the cell.

The concept of the readout system presented here is to monitor the displacement of multiple, independent cantilever-array sensors by combining a phase-shifting interferometer with a microscope. The microscope optics project an image of the sensor area, containing the cantilever arrays to be monitored, onto a digital recording device. The reference beam can be shifted in phase and is aligned so as to interfere with the image of the sample beam. By recording a set of interferograms in which the reference beam has a different phase in each interferogram, the wavefront phase, including its sign, can be calculated from the irradiance differences between the interferograms for each pixel of the recorded area. Using a phase-unwrapping procedure, the displacement profiles of all cantilevers inside the field of view of the microscope can be calculated with respect to their chip substrates, which serve as reference surfaces.

The present inventors built a proof-of-principle bread-board system, based on a modified Twyman-Green interferometer set-up, shown in Fig. 25. A laser diode module 700 with an adjustable focal lens (CPS198, 670nm, ThorLabs Inc.) illuminates the sample 702 through a cube beam-splitter 704 (CM1-BS1 , 50:50, 400-700nm, ThorLabs Inc.) and the sample image is recorded through a microscope objective 706 (4x/0.10, ThorLabs Inc.) by a digital CMOS camera 708 (SMX-M95C, 2592x1944 pixel, EHD Imaging GmbH) giving a field-of-view of (2.2 x 1.65)mm2. The reference beam 709 is reflected by a mirror 710 mounted on a piezoelectric transducer 712 (P-753 LISA, 0.05nm resolution, Physik lnstrumente GmbH) and aligned to interfere with the sample beam 711 in the recording plane of the camera. By moving the mirror with the piezoelectric transducer along the optical axis A, the optical path length of the reference beam is shifted, and thereby the phase of the reference beam at the camera is changed, and hence different interferograms are generated for each phase step.

Fig. 25 shows the use of a piezoelectric transducer 712 to implement the phase change of the reference beam 709. In an alternative embodiment, a rotating parallel plate can be used. In an alternative, preferred embodiment, it is possible to use instead an adjustable phase shifter (such as an adjustable phase retarder) that does not require mechanical movement of a mirror, prism or other optical element. For example, a liquid crystal phase retarder (not shown) may be used to implement the phase change of the reference beam. Suitable measurement techniques employing liquid crystal phase retarders are set out in Reference 29, the content of which is hereby incorporated by reference in its entirety. To recover the phase map from a set of interferogram images, use a universal mathematical method is used that allows the analysis of datasets with any number of phase steps, N.

This is first discussed in simple terms, with reference to Figs. 37-45.

In Fig. 37, a schematic plan view of a microcantilever 802 is shown, attached to a base 804. This is a schematic view of the image seen at the camera of a single microcantilever, before the reference beam is included.

Next, as shown in Fig. 38, a reference beam is added. The result of this is the creation of an interference pattern in the image of the microcantilever. The interference pattern is a series of bright (806) and dark (808) fringes.

The interference pattern shown in Fig. 38 is recorded by the camera. Next, the phase of the reference beam is changed, for example to differ from the initial phase of the reference beam by a phase angle Φ of π/2. The effect of this is shown by a comparison between Fig. 39 (Φ = 0, i.e. the initial reference beam) and Fig. 40 (Φ = π/2, i.e. the phase shifted reference beam). Fig. 40 shows a corresponding view to Fig. 39. As can be seen, the location of the interference fringes changes depending on the phase angle Φ. Fig. 41 shows the interference pattern when Φ = π and Fig. 42 shows the interference pattern when Φ = 3τr/2. Note that in Figs. 39-41 , only the microcantilever is shown - the base part 804 is not shown (although this is shown in Figs. 37 and 38). Also note that in the progression of Fig. 39-42, the actual shape (i.e. the deflection profile of the microcantilever_ is not changing - the difference in the interference pattern recorded at the camera is only due to the difference in phase of the reference beam. In this preferred embodiment, the phase of the reference beam is altered sequentially between four values (here 0, ττ/2, π and 3τr/2). It is possible to vary the phase of the reference beam between fewer values - the minimum being three values in order to obtain a useful result. Five values is preferred in some embodiments.

For each pixel of the image (corresponding to a point on the surface of the microcantilever), the phase of the wavefront can be calculated based on the intensities of light at that pixel for each recorded phase shift image. The result of this analysis is a wrapped phase profile of the microcantilever surface, as shown in Fig. 43. In effect, this shows a "wrapped" plot of a measurement of the location of various points on the microcantilever surface with distance from the base of the microcantilever. This plot can be "unwrapped" to produce a measurement of the location of various points on the microcantilever surface with distance from the base of the microcantilever, as shown in Fig. 44. This is referred to as a phase profile of the microcantilever, at time t=0.

The t=0 phase profile of the microcantilever can then be stored as a reference. Next, a sample is introduced into the apparatus, for interaction with the microcantilever. The steps in the paragraph above can then be repeated at a time t later. The new phase profile is recorded. This is then subtracted from the t=0 phase profile in order to obtain a plot of the microcantilever displacement profile relative to t=0. It is important at this stage to note that it is assumed that the microcantilever base is fixed, so that its position is the same in the t=0 profile and in the later profile.

The steps in the paragraph above can then be repeated in order to measure the displacement of the microcantilever (e.g. the tip of the microcantilever) with time. Fig. 45 shows exemplary plots for the deflection of two microcantilevers with time. Fig. 46 shows the recorded deflection response of 8 microcantilevers, coated with different polymer films, monitored simultaneously whilst being exposed to ethanol vapour at a concentration of 15,000 ppm.

The following section explains the analysis in more detail.

For each cantilever to be monitored, an image area is selected which contains both the tip of the cantilever and the substrate chip reference base, as shown for a 2-cantilever set-up in Fig. 26. For each pixel (i,j) in all of these areas, the irradiance /y is recorded for N different phases of the reference beam. Due to the number of unknown parameters, the number N of phase steps has to be at least three. For example, there may be four. These N-dimensional vectors of irradiance IiJn) can be expressed as a linear combination of a constant offset, a slope, a cosine and a sine component,

I T; , ( //?) N = a + b IL - + c • cos ( — ^ ά CLi λ + a J • si n ( —4π

Figure imgf000031_0001

7I = LJV (1)

/V > 4 with δ being the phase step width and λ being the wavelength of the laser diode. For each pixel, the coefficients a, b, c and d of equation (1) are calculated using a general least-squares fitting algorithm. The phase of the wave field at the detector is calculated for each pixel (i,j) in the selected areas from the coefficients of the sine and cosine components, c and d, using the arctangent function:

Figure imgf000031_0002
= arctanl — (2)

This works in quadrants I and IV where the arctangent function returns a value between

- ττ/2 and ττ/2. But care must be take if both c and d are negative as (c/d) will be the same as if they were both positive. Also, provisions have to be taken for d=0, to prevent division by zero. So the rules for converting to polar coordinates have to be more complex:

arctan(x, y) - if v < X then : π/2 sign(y)(l - sign(x)) + arctan(x / y) else : π/2 sign(y) - arctan(x / >J)

(3) where : sign(q) = 1 if a > 0

- l z/ σ < 0 0 if a = 0

A phase shift of π/2 (90°) between images allows calculating the phase for each pixel with simple, common algorithms. Depending on how many phase steps are recorded the phase can be calculated as follows:

Three step: φ(iJ)

Figure imgf000032_0001

Four step:

Figure imgf000032_0002

Five step: φ(i, j) = arctan (72 (*> •/) " *(*>/)) (Schwider-Hariharan algorithm)

[21,(Uj) - I5(Uj)- I1 (Uj) J with:

I1(IJ) measured irradiance at φi = 0° I2(i,j) measured irradiance at φ2 = 90° I3(i,j) measured irradiance at φ3 = 180° I4(i,j) measured irradiance at φ4 = 270°

Is(U) measured irradiance at φ5 = 360°

Having calculated the phase for each pixel in the observed areas, the 2π phase ambiguity has to be removed before the topography for each cantilever can be reconstructed. As the surface of the cantilever sensors in the selected areas is continuous, i.e. without steps greater than λ/2 between adjacent pixels, the unwrapped phase profile for a line of pixels is obtained by following the calculated phase values for this line from the cantilever base to the tip and adding or subtracting 2π whenever a phase jump occurs.

For the present calculations, the functions offered by the National Instruments LabWindows/CVI programming language are used. The function called atan2(x,y) calculates the correct phase angle automatically, and the function UnWrapi D unwraps the phase, so it exhibits a linear and continuous curve when plotted.

The obtained phase map represents the relative phase difference between sample beam and reference beam for each recorded pixel and is proportional to a height profile of the cantilever sensors. To create a surface topography map, the height h(i,j) for each pixel (i,j) is calculated as:

Figure imgf000033_0001

The height map h(i,j) offers not only information about the cantilever-tip displacement, i.e. the height difference between substrate-chip reference base and cantilever tip, as in classical optical-lever cantilever-sensor readout systems, but also reveals the complete cantilever-displacement profile from base to tip, as illustrated for an array of 4 x 2 cantilevers in Fig. 27.

The readout method presented here is very robust and reliable because, rather than imaging the deflections of just one spot as in optical-lever readout, the displacement of each cantilever is calculated from a multitude of pixels. Furthermore, pixel-to-pixel intensity variations due to non-uniformities in the light source or detector are uncritical because the phase is calculated for each pixel independently. The above-described analysis method was implemented using the National Instruments LabWindows/CVI programming platform to create a user-friendly control interface for the simultaneous monitoring of currently up to 8 microcantilever sensors from 4 different sensor chips. On a video image of the measurement cell, the user selects the number, position and orientation of the cantilever sensors to be monitored. A number of variables, including the number of phase steps, the width of the area to monitor on each cantilever and the number of video frames over which to average, can be set by the user. After starting the monitoring process, cantilever displacement profiles from base to tip are calculated and displayed for each cantilever and the displacement histories are plotted and recorded.

The PSIM system was tested with microcantilever-arrays holding 2 cantilevers per chip. The sensor chips, with single-sided gold coatings, were purchased from Windsor Scientific (Arrow TL2Au, NanoWorld) and coated with self-assembled monolayers (SAMs) of thiols with different head groups, acting as functionalised sensor-receptor layers. An illustration of the measurement cell, showing parts of the flow channels and the microcantilevers, is shown in Fig. 28.

To prove the functionality of the readout concept and determine the short-term noise of the system, a 2-cantilever sensor chip, coated with an alkane SAM on the gold-covered side, was monitored without sample flow. These alkane SAM microcantilevers were obtained by immersion of the cleaned chips in a 1 mM ethanol solution of octadecanethiol for 18 hours. An example of a 10-minute baseline is shown in Fig. 29. The typical baseline noise level of the PSIM system according to this embodiment of the invention was found to be 0.5nm. These experiments were performed on a gas- cushioned optical table to decouple the system from external vibrations.

The system has been demonstrated simultaneously to monitor cantilever sensors from different chips by using two microcantilever-array chips, each holding 2 cantilevers and each coated with an alkane SAM. For these experiments, a constant flow of nitrogen carrier gas was run through the measurement cell. To introduce a gas sample, the carrier gas flow can be switched to bubble through a number of different liquid samples before being admitted to the measurement cell. Fig. 30 shows the result of an experiment in which the flow of nitrogen gas was replaced for 1 min by a mixture of nitrogen and toluene vapour while the cantilever displacement was monitored with the PSIM system. All 4 cantilevers show the same response characteristics to the exposure with toluene vapour, comparable to the results of experiments performed by Lim et al. [Reference 22].

The system may also be used as a tool for the rapid screening and analysis of functionalized receptor layers developed for microcantilever-sensing applications in liquid and gas phases. This capability is demonstrated by measuring the response of 4 different microcantilever-array chips, holding 2 microcantilever sensors each, to an exposure to dimethyl methylphosphonate (DMMP) vapour, shown in Fig. 31. Of the 8 cantilevers monitored in this experiment, 2 were functionalized with an alkane thiol, 2 were coated with a phenolic thiol, and 4 were coated with a thiol presenting a dichlorobenzene head-group. The phenol and dichlorobenzene head-groups were prepared by copper-catalysed Huisgen 'click' reaction [Reference 24]. Firstly, an azide monolayer was formed on the chips by immersion in an ethanol solution of bis(11-azido undecanyl)disulfide. Then, microcantilevers with a phenol functional group were prepared by click reaction of the azide-coated chips with 4-propargyloxyphenol under the conditions described by Chidsey and co-workers [References 25, 26]. Similarly, dichlorobenzene-thiol coated chips were obtained by click reaction with 3,4- dichloropropargyloxybenzene. This method represents a convenient route to produce functionalized microcantilevers presenting a wide variety of head-groups.

All 8 microcantilever-sensors, shown in Fig. 28, respond to the DMMP exposure. It can be noticed that the dichlorobenzene-thiol-coated sensors have a slower on-rate compared to the alkane-thiol coated cantilever-sensors. However, much more significant is the fact that, by responding with tensile stress, the phenolic-thiol-coated microcantilevers display a qualitatively different response to the same exposure and thus can be used selectively to detect DMMP.

The data-acquisition rate of the prototype system (June 2009) was 1 data point per second. The camera of that system was able to take 96 frames per second, the rate- limiting steps are the movement of the piezo-stage and the data processing, which both have room for improvement.

The PSIM system, together with the measurement-cell concept, presented here offers the prospect of a very powerful tool for research and commercial applications, and which has several advantages over existing microcantilever-sensor devices.

The PSIM sensor-readout system allows for the monitoring of multiple microcantilever chips in parallel for liquid- and gas-phase samples. The setup is extremely adaptable and suitable for true multiplexing, not requiring a scale-up in hardware. The number of microcantilever sensors to be monitored can be increased with only minor modifications of the geometry, to ensure that all sensors are within the field of view of the camera, and without requiring any additional components. As each pixel is analysed independently, and with the availability of cheap multi-megapixel CMOS cameras, this readout method offers for the first time the potential to develop low-cost devices capable of monitoring, say, more than 150 microcantilevers in parallel.

To illustrate this fact, it is possible to create an array of 5 x 4 commercially available microcantilever arrays, each holding 8 microcantilevers (e.g. Arrow TL8, NanoWorld). When designing a measurement cell in which the sensors are arranged as shown in Fig. 32 and Fig. 33, the size of the area to image is 13.2 x 16.3 mm. Using a 10.3 mega pixel (MP) camera with 3916 x 2638 pixels, each pixel images a square of 5x5 μm, i.e. 100 pixels would image the length of the freestanding part of a 500 μm long cantilever. This is sufficient to ensure that no phase jumps are missed and the displacement of all 160 cantilever sensors is read out correctly. Using custom designed microcantilever arrays, the number of cantilever sensors to be monitored with one 10.3 MP camera can be increased even further.

Being able simultaneously to monitor cantilevers from different sensor-array chips also offers a number of advantages. Firstly, rather than having to prepare sensor chips with multiple functionalized surfaces on the different cantilevers of one sensor-array chip, multiple chips with different surface chemistries can be used. This simplifies the sensor- preparation process, as most sensor chemistries are developed using an immersion- coating process which results in uniform, reliable and stable sensor surfaces. Transferring the coating process to microcapillary or inkjet-printing systems requires an extra development effort, additional instrumentation and potentially compromises the sensor surface quality. Secondly, the sensor chips to be monitored can be mixed and matched at will and, if required, the very same reference chip can be used in different measurements. Thirdly, an ensemble of different types, makes and geometries of microcantilever sensors can be monitored simultaneously with the setup presented here.

In contrast to other microcantilever-readout methods, PSIM as used in the preferred embodiments of the invention measures the whole cantilever profile, rather than just the displacement of one point, e.g. at the tip. This offers the significant advantage that changes in the refractive index of the sample will not affect the sensor readout, as for each data point, the absolute height difference between cantilever base and tip is calculated. Furthermore, having information on the complete cantilever profile, it is possible to use a microcantilever sensor with sections of differently functionalized surface coatings along its length. Two methods of using interferometry for the readout of microcantilever sensors have previously been reported by Berger, Helm and co-workers [References 15, 16]. However, the proposed readout by use of optical fibres and Fabry-Perot interferometry [Reference 16] still requires very accurate alignment for each individual microcantilever to be monitored and only tracks the deformation of the microcantilever on a single spot. By using a commercial white light phase shifting microscope the same group reported the readout of a full bending profile for a single microcantilever [Reference 15]. In contrast to the low cost approach of using a laser LED, as presented here, the short coherence length of white light puts very high requirement on the experimental set-up in order to match the path lengths of reference-beam and sample-beam to obtain interference fringes.

Furthermore, by combining multiple cantilever-sensor readout with small sample volumes, fast sensor replacement and individual sensor addressing, the system presented here addresses key requirements for sensor devices in compound screening and research applications.

In summary, a system for the simultaneous monitoring of multiple cantilever sensors from different sensor arrays has been developed and tested for gas- and liquid-phase applications. The cantilever sensors are operated in static-deflection mode and the readout is achieved with Phase-Shifting lnterferometric Microscopy (PSIM). In contrast to existing cantilever-sensor readout methods, PSIM is not dependent on alignment and allows the monitoring of the displacements of all cantilevers within the field of view, using just one light source. To complement the PSIM readout, a sample cell has been developed which can hold multiple cantilever-array chips, allows for very fast sensor-chip replacement, has very low sample-volume requirements and allows for individual or common addressing of all chips in the sample cell. This work has been reported in Reference 30, the content of which is incorporated by reference in its entirety. The embodiments of the present invention have been described by way of example. Modifications of these embodiments, further embodiments and modifications thereof will be apparent to the skilled person on reading this disclosure and as such are within the scope of the present invention.

REFERENCES

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19 Cantilever transducers as a platform for chemical and biological sensors, N.V. Lavrik, M.J. Sepaniak, P.G. Datskos, Rev. Sci. Instrum., Vol. 75, 2229-2253, 2004 20 Monitoring haemodialysis using electronic nose and chemometrics, R Fend, C Bessant, AJ Williams, et at., Biosensors & Bioelectronics, Vol. 19, 1581-1590, 2004

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Claims

1. A measurement apparatus for measuring a response of a sensor device, the sensor device incorporating a deflectable element, in use the deflectable element deflecting in response to an event to which it is sensitive, wherein the measurement apparatus includes a pixellated array of detector elements, arranged to receive an image of a phase shifting interference pattern provided by the deflectable element with a light source, wherein the light source is a substantially monochromatic light source.
2. A measurement apparatus according to claim 1 , operable to provide a reference beam from said light source, aligned so as to interfere with a sample beam in a recording plane of the pixellated array of detector elements, wherein the apparatus is arranged to capture a series of images of the deflectable element, each image including an interference pattern provided by interference between the sample beam and the reference beam, wherein the phase of one of the sample beam and the reference beam is shifted as between one image in the series of images and the next image in the series of images.
3. A measurement apparatus according to claim 2 further including a liquid crystal phase retarder in order to shift the phase of the reference beam or the sample beam.
4. A measurement apparatus according to claim 2 or claim 3 wherein the phase shift as between the one image in the series of images and the next image in the series of images is less than (aπ + 2bπ), wherein a is any integer or non-integer and is 2 or less and wherein b is 0 or any integer.
5. A measurement apparatus according to any one of claims 2 to 4 wherein at least three images are taken in the series, the phase shift as between adjacent images in the series being between ττ/3 and π, typically about π/2.
6. A measurement apparatus according to any one of claims 2 to 5 wherein a deflection profile of the deflectable element is calculated based on a comparison of a reference phase profile of the deflectable element with a phase profile of the deflectable element deflecting in response to an event to which it is sensitive.
7. A measurement apparatus according to any one of claims 1 to 6 wherein the image received at the pixellated array of detector elements is magnified compared with the actual area observed.
8. A measurement apparatus according to any one of claims 1 to 7, operable to receive an image of more than one sensor device simultaneously.
9. A measurement apparatus according to any one of claims 1 to 8, wherein the sensor device is located in a sensor apparatus according to any one of claims 15 to 29.
10. A sensing method in which the response of a sensor device is measured, the sensor device incorporating a deflectable element, and the method including the step of the deflectable element deflecting in response to an event to which it is sensitive, and the method further including the steps of illuminating the deflectable element using a substantially monochromatic light source and receiving an image of a phase shifting interference pattern provided by the deflectable element at a pixellated array of detector elements.
11. A sensing method according to claim 8 further including the steps of providing a reference beam from said light source, aligned so as to interfere with a sample beam in a recording plane of the pixellated array of detector elements, and capturing a series of images of the deflectable element, each image including an interference pattern provided by interference between the sample beam and the reference beam, wherein the phase of one of the sample beam and the reference beam is shifted as between one image in the series of images and the next image in the series of images.
12. A sensing method according to claim 11 wherein the phase of the reference beam or sample beam is shifted in order to provide a set of at least 3 interferograms in which the reference beam has a different phase for each interferogram.
13. A sensing method according to any one of claims 10 to 12 wherein a deflection profile of the deflectable element is calculated based on a comparison of a reference phase profile of the deflectable element with a phase profile of the deflectable element deflecting in response to an event to which it is sensitive.
14. A sensing method according to any one of claims 10 to 13, wherein the sensor device is located in a sensor apparatus according to any one of claims 15 to 29.
15. A sensor apparatus having: a support; a sensor device held in the apparatus, the sensor device having an active area and an inactive area; a cover; a sealing element interposed between and sealing with the support and with the cover; a fluid inlet port; and a fluid outlet port, wherein a flow channel provides fluid communication between the fluid inlet port and the fluid outlet port via the active area of the sensor device, the flow channel being provided at least in part by one or more flow channel surfaces of the sealing element, wherein the sensor device is held in position with respect to the flow channel by the sealing element bearing against at least part of the inactive area of the sensor device.
16. A sensor apparatus according to claim 15 wherein the sealing element comprises a resilient material and, in use, is partially compressed between the support and the cover.
17. A sensor apparatus according to claim 15 or claim 16 wherein a dead stop is provided between the support and the cover, in order to limit the pressure applied to the sealing element.
18. A sensor apparatus according to any one of claims 15 to 17 wherein the sensor device includes at least one cantilever element, such as a microcantilever element.
19. A sensor apparatus according to any one of claims 15 to 18 wherein the sensor device is capable of sensing chemical, magnetic, electrostatic, biochemical and/or biological species.
20. A sensor apparatus according to any one of claims 15 to 19 wherein one of the support, the sealing element and the cover includes a first pocket shaped to receive the sensor device.
21. A sensor apparatus according to claim 20 wherein the fluid inlet port and the fluid outlet port open into the first pocket.
22. A sensor apparatus according to claim 20 or claim 21 wherein, in use, the sensor device makes contact with a sidewall of the first pocket in at least two locations.
23. A sensor apparatus according to any one of claims 20 to 22 wherein one or both of the support and the cover includes a second pocket shaped to receive the sealing element.
24. A sensor apparatus according to claim 23 wherein the area size of the second pocket is greater than that of the first pocket and wherein, when viewed in plan view, the second pocket envelops the first pocket.
25. A sensor apparatus according to claim 23 or claim 24 wherein the sealing element makes contact with a sidewall of the second pocket in at least two locations.
26. A sensor apparatus according to any one of claims 15 to 25 wherein the sealing element includes at least one channel or slot, wherein at least one end of said channel or slot is located to be in registration with the fluid inlet port or the fluid outlet port, so that in use the side surfaces of the channel or slot provide the flow channel between the fluid inlet port and the fluid outlet port.
27. A sensor apparatus according to any one of claims 15 to 26 wherein registration means are provided for ensuring suitable alignment of the cover and the support.
28. A sensor apparatus according to any one of claims 15 to 27 wherein the volume of the flow channel, from the fluid inlet port to the fluid outlet port, is in the range 0.01 μl to 2 μl.
29. A sensor apparatus according to any one of claims 15 to 28 wherein the apparatus includes two or more sensing devices, held in a single support with a single cover and a single sealing element for contacting said sensing devices.
30. A sensing system having a measurement apparatus adapted for measuring a response of the sensor device in a sensor apparatus according to any one of claims 15 to 29.
1. A sensing kit including a sensing system according to claim 30 and: (i) a sensor apparatus according to any one of claims 15 to 29, or (ii) a plurality of sensor apparatus according to any one of claims 15 to 29.
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