Classifications

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

Definitions

• the invention regards a new sensor assembly and method of fluid delivery to the sensor, and more specifically pertains to a sensor assembly for fluid sample testing that includes a rigid attachment of the core sensing device to a mounting substrate to minimize and control all direct physical contact to the core sensing device of the assembly in conjunction with a unique method of test fluid delivery to control pressure fluctuations upon the core sensing device during operation.
• Oscillating crystal resonators can be used as very sensitive mass sensors in gas and liquid phase. It was shown by Sauerbrey (Sauerbrey, G., Z. Phys. 155 (1959), p.206-222) that material deposited onto a resonator surface will change the resonators fundamental oscillation frequency proportional to the mass of the deposited material. Due to the extreme sensitivity of these resonators to changes in mass on their surfaces, oscillating crystal resonators can be employed to determine mass changes on a molecular level, and are often referred to as Quartz Crystal Microbalances or QCM.
• An oscillating crystal resonator generally consists of a thin plate of piezoelectric material, such as a quartz crystal wafer, with metal electrodes deposited on each face of the plate. Applying an electric field between the electrodes, or across the piezoelectric plate, causes a physical displacement in the piezoelectric material. Due to this "piezoelectric phenomenon" caused the by the electric current, steady oscillations of piezoelectric plates can be achieved through the application of a stable electric field in this manner. Once stable, changes in oscillation of the piezoelectric plates due to the addition or subtraction of mass from their surface can be quantified with great accuracy.
• a form of quartz sensor called a biosensor has been used to measure the presence and interactions of proteins, such as antibodies and hormones, nucleic acids, as well as pharmaceutical drugs, in liquid samples ranging from bodily fluids to organic solvents.
• proteins such as antibodies and hormones, nucleic acids, as well as pharmaceutical drugs
• liquid samples ranging from bodily fluids to organic solvents.
• oscillating crystal resonators as a liquid phase sensor it is a requirement that the liquid sample interact with only one of the electrode coated surfaces on the resonator. The reasons for this are two-fold: 1) to eliminate electrical short-circuits between the electrodes of the resonator, and 2) to minimize loss of the resonator Q-factor (ratio of stored energy to dissipated energy in the piezoelectric plate) due to the liquids viscosity.
• the resonator mount design must isolate the back (driving / non-sensing) electrode from the front (sensing) electrode such that only the sensing electrode is exposed to the liquid under test.
• the viscosity of liquids can significantly dampen or even completely stop the oscillation of a crystal resonator.
• the oscillating crystal resonator needs to be physically interfaced with liquid delivery unit so that only the sensing surface comes in contact with the liquid sample.
• the mounting structure e.g., the O-rings, etc.
• the vast majority of resonator mounting designs to date have employed the use of elastic mounting seals or elastic adhesives to hold the resonator in place and create the liquid tight seal for the test sample chamber.
• a primary requirement for the use of mounted oscillating crystal resonators in liquid based applications is the ability to expose sample-containing liquids to the sensing surface of the resonator as discrete volumes or plugs within a continuously flowing stream of a sample-less liquid.
• the mounting design would affix the oscillating crystal resonator to the mounting substrate in a highly stable, highly reproducible manner, fully isolating the liquid sample exposure to only the sensing surface of the resonator, while requiring only a minimal amount of physical contact between the mounting and sample delivery assembly and the oscillating resonator surfaces.
• a sensor is provided with a crystal resonator that is affixed to a substrate for the sensor with an adhesive that forms a rigid bond between the resonator and the substrate when cured.
• the rigid bond between the resonator and the substrate effectively causes the resonator to vibrate in a manner that is not affected by the connection of the resonator to the substrate.
• This rigid connection greatly enhances the reproducibility of the vibration that can be generated within the resonator by effectively isolating the resonator from the substrate.
• the rigid connection between the resonator and the substrate prevents any dampening of the vibrations within the resonator as a result of this connection, as opposed to prior art flexible connections between the substrate and resonator.
• the resonator is rigidly affixed to the substrate, during operation the resonator will not "creep" or shift position with regard to the substrate. As such, the resonator will remain in the same position throughout multiple uses of the sensor, such that the vibration characteristics of the resonator will not change, further adding to the reproducibility of the vibrations in the resonator.
• the adhesive forming the rigid bond between the resonator and the substrate is present around the entire periphery of the resonator.
• the resonator is mounted to a substrate of a sensor that enables the sample fluid to be injected into a stream of a control fluid already passing over the resonator.
• the streams of the control fluid can be reduced in volume. This maintains the overall pressure of the fluid streams passing over the resonator at a constant level, such that the only effects on the vibration of the resonator are produced by the sample fluid.
• Figure 1 is a cross-sectional view of a sensor mounting assembly constructed according to the present invention
• Figure 2 is a top plan view of the assembly of Fig. 1;
• Figure 3 is a cross-sectional view of a second embodiment of the sensor mounting assembly of the present invention.
• Figure 4 is a top plan view of a number of laminar fluid streams flowing over a sensor mounting assembly constructed according to the present invention.
• the assembly 100 is a dry side sensor mounting assembly for a single sensing spot crystal resonator 30 assembled into a sample delivery flow cell 1000.
• the assembly 100 is formed with a substrate 10 of a fluid-impervious and non-conductive material that includes a central bore 20 and a pair of electrode contact bores 22, 24 disposed on opposite sides of the central bore 20, though the bores 22, 24 can be located in any suitable location around the bore 20. Additionally, the central bore 20 and the bores 22, 24 are shaped as desired to accommodate the particular structure of the assembly 100, and therefore can have any desired shape.
• An oscillating crystal resonator 30 formed of a conventional quartz crystal material is positioned on the upper surface 62 of the substrate 10, and includes a driving electrode 32 and a sensing electrode 34 disposed on opposite sides of the resonator 30.
• the driving electrode 32 is positioned adjacent the upper surface 62 of the substrate 10, while the sensing electrode 34 is primarily positioned on the surface of the resonator 30 opposite the driving electrode 32.
• the sensing electrode 34 does include a wrap-around portion 36 that extends from the sensing electrode 34 around the resonator 30 onto the surface of the resonator 30 against which the driving electrode 32 is positioned.
• the wrap-around portion 36 of the sensing electrode 34 terminates at a point spaced from the driving electrode 32, and does not contact the driving electrode 32 to prevent a short circuit across the electrodes 32 and 34 on the resonator 30.
• the bores 22, 24 are each filled with a conductive adhesive plug 50 that extend a short distance above the upper surface 62 of the substrate 10.
• the portion of these plugs 50 that extends above the upper surface 62 of the substrate 10 contacts the driving electrode 32 and the wrap-around portion 36 of the sensing electrode 34, respectively.
• the plugs 50 are each operably connected with one of a pair of conductive tracks 60 formed on the lower surface 64 of the substrate 10.
• the conductive tracks 60 formed on the lower surface 64 of the substrate 10 can be formed in any conventional manner, such as by being printed on the substrate 10 with a conductive ink, and terminate at electrical contacting pads 68 at the edges of the lower surface 64 of the substrate 10, enabling the mounted resonator 30 and the electrodes 32, 34 thereon to be easily interfaced with corresponding detection electronics systems, as are known in the art.
• the driving or non-sensing electrode 32 of the resonator 30 faces the mounting substrate 10, and is positioned directly over the bore 20 such that the majority of the driving electrode 32 is not physically contacting the mounting substrate 10.
• the resonator 30 is also positioned onto the mounting substrate 10 such that only the terminal end of the end wrap-around portion 36 of the electrode 34 is in contact with the substrate 10.
• the only actual part of the electrodes 32 and 34 that is in direct contact with the substrate 10 are those portions in contact with the conductive adhesive plugs 50 and a rigid adhesive 40, to be described.
• the mounting substrate 10 can include multiple bores 20 for the driving electrodes 32, and multiple bores 22 and 24 for accommodating a number of conductive adhesive plugs 50, with one bore 22, 24 and corresponding plug 50 for each driving electrode 32 and sensing electrode 34.
• the bores 20-24 will be of a size such that the majority of each of the driving electrodes 32 and sensing electrodes 34 do not physically contact the substrate 10 when the resonator 30 is mounted thereto.
• the resonator 30 with electrodes 32 and 34 is mounted, or affixed, onto the substrate 10 such that the electrodes 32 and 34 are disposed in contact with the plugs 50 using a very low viscosity, non-conductive, rigid bond-forming, and solvent resistant adhesive 40.
• a very low viscosity, non-conductive, rigid bond-forming, and solvent resistant adhesive 40 is the adhesive sold under the trade name Loctite 3491, by Henkel of D ⁇ sseldorf, Germany.
• a small amount of adhesive 40 is deposited onto the upper surface 62 immediately around the driving electrode bores 20, 22, and 24 in the substrate 10.
• the resonator 30 is placed onto the substrate 10 with the driving electrode 32 facing the substrate 10 and in such a manner that the adhesive 40 remains only in the areas between the resonator 30 and the upper surface 62 of the substrate 10.
• the low viscosity of the adhesive 40 facilitates capillary distribution of the adhesive 40 to form a uniform thin film over the entire area of the upper surface 62 of the substrate 10 between the substrate 10 and resonator 30.
• the very small volume of adhesive 40 in part due to the particular properties of the adhesive 40, will not spread across the resonator 30 in areas where the substrate 10 has bores 20, 22, and 24, due to lack of capillary action.
• the adhesive 40 does not cover any of the adjacent surface area of the driving electrode 32 or the wrap-around portion 36 of the sensing electrode 34 of the resonator 30 disposed across the central bore 20, or the electrode bores 22, 24 in the substrate 10.
• This distribution of the adhesive 40 between the resonator 30 and the mounting substrate 10 forms a rigid and liquid-tight seal around the central bore 20 in the substrate 10, and around all of the electrode bores 22, 24 also formed in the substrate 10, which are disposed preferably immediately adjacent the central bore 20.
• the adhesive 40 When cured in a suitable manner, such as by heat, UV light or over time, the adhesive 40 creates a rigid permanent seal mounting the resonator 30 to the substrate 10 while minimizing any physical contact of the adhesive 40 or the substrate 10 with the driving electrode 32 and sensing electrode 34 on the resonator 30.
• the resonator 30 is rigidly secured to the substrate 10 in a manner that prevents the fluid being sensed by the sensing electrode 34 from also coming into contact with the driving electrode 32 and creating a short between the electrodes 32 and 34.
• the assembly 100 simultaneously isolates, to the extent possible, the electrodes 32 and 34 from the substrate 10, and provides a stable attachment of the resonator 30 to the substrate 10 to maintain the vibration properties of the resonator 30 constant.
• the electrodes 32 and 34 of the resonator 30 are also connected to the conductive tracks 60 on the lower surface 64 of the substrate 10 by the plugs of conductive adhesive 50 subsequently formed in the electrode bores 22, 24 present in the substrate 10.
• the conductive adhesive such as the adhesive sold under the trade name Silver Conductive Paint by RS Components Ltd of Auckland, NZ, is applied into the bores 22 and 24 after attachment of the resonator 30m to the substrate 10 to form the plugs 50 in a manner such that that, when fully formed, each plug 50 contacts one of the resonator electrodes 32 and 34 at one end through the open areas in the mounting adhesive 40 remaining above the bores 22, 24 in the substrate 10, and the conductive tracks 60 on the formed on the lower surface 64 of the substrate 10 opposite the electrodes 32, 34 at the opposite end.
• the conductive adhesive such as the adhesive sold under the trade name Silver Conductive Paint by RS Components Ltd of Auckland, NZ
• the assembly 100 In order to form the assembly 100 into a flow cell 1000 for delivery of sample fluids to the resonator 30 for analysis, the assembly 100 has a liquid sealing gasket 70 of a known height positioned on the substrate 10 around the resonator 30.
• the gasket 70 can be formed of any desired material, with a fluid-impervious solvent resistant rubber or silicone being especially preferred.
• a fluid delivery block 80 formed of a material similar to that used for the substrate 10 is secured to the gasket 70 opposite the substrate 10.
• the fluid delivery block 80 is affixed to the gasket 70 in any suitable fluid-tight manner to enclose and define the interior 85 of the flow cell 1000, and is shaped to have a number of fluid delivery ports 90 formed therein.
• the shape and height of the sealing gasket 70 determines the shape and total volume of the flow cell 1000, and is selected such that neither the sealing gasket 70 nor the fluid delivery block 80 will make physical contact with the mounted resonator 30 when the gasket 70 and fluid delivery block 80 are engaged with the substrate 10, such as by clamping the gasket 70 and block 80 to the substrate 10.
• the positions of the fluid delivery ports 90 on the fluid delivery block 80 are disposed relative to the shape of the sealing gasket 70 such that fluid samples entering the cell must pass over the sensing electrode 34 on the mounted resonator 30 prior to exiting the cell 1000.
• the number of ports 90 formed in the block 80 can be selected as desired based on the number of fluid sources that are to be introduced into the flow cell 1000.
• the positions of the ports 90 can be located such that the fluid streams introduced into the flow cell can be removed from the cell 1000 after passing over the resonator 30.
• the driving electrode 32 is designed so that only the 'neck' of the driving electrode 32 on the resonator 30 physically contacts the mounting substrate 10. In this configuration, the amount of the surface of the driving electrode 32 that contacts the substrate 10 via the adhesive 40 and the plug 50 is further minimized
• FIG. 3 another alternative construction for the assembly 100' is illustrated that utilizes an adhesive channel 140.
• This assembly 100 is very similar to the assembly 100' illustrated in Fig. 1 , with the key difference being the fact that the mounting adhesive 40 that bonds the resonator 30 to the mounting substrate 10 is contained within an etched channel 140 cut into the upper surface 62 of the of the substrate 10. By confining the mounting adhesive 40 to the etched channel 140 when the resonator 30 is mounted, the portion of the driving electrode 32 on the resonator 30 that is to be connected to the plug 50 partially rests flush against the upper surface 62 of the mounting substrate 10.
• the use of the adhesive channel 140 ensures that this portion of the driving electrode 32 contacts the upper surface 62 of the mounting substrate 10 in a uniform and rigid manner, which results in more uniform and reproducible pressure on the driving electrode 32.
• the channel 140 also helps to ensure the entire surface area of sensing electrode surface 34 is an equidistant height from the upper surface 62 of the mounting substrate 10.
• an amount of the adhesive 40 sufficient to contact those parts of the resonator 30 that are to be located directly over the channel 140 is deposited into the channel 140.
• the resonator 30, with driving electrode 32 facing the mounting substrate 10 is placed onto the substrate 10 so that the majority of the driving electrode 32 lies within or over the central bore 20 which is circumscribed by the channel 140, and the driving and sensing electrodes 32 and 34 are located in alignment with the conductive adhesive bores 22 and 24 and also circumscribed by the channel 140. Any excess adhesive 40 present in the channel 140 during the mounting process will escape through a number of adhesive exhaust holes 150 formed in the substrate 10 below the channel 140.
• the resonator 30 can first be properly positioned onto the mounting substrate 10 over and/or partially within the channel 140, and then mounting adhesive 40 can be injected into the adhesive channel 140 through one or more of the adhesive exhaust holes 150 with any excess adhesive 40 escaping through the other exhaust holes 150.
• the adhesive 40 cures, it contracts, slightly pulling the resonator 30 into tight engagement against the mounting substrate 10 and forms a rigid, liquid tight bond between the resonator 30 and substrate 10.
• the width of the adhesive channel 140 in relation to the size of the resonator 30 is in a ratio that is small enough not to cause the resonator 30 to bend as the curing adhesive 40 contracts.
• the conductive adhesive plugs 50 can then be formed within the bores 22 and 24 to connect the electrodes 32 and 34 on the resonator 30 to the conductive tracks 60 on the lower surface 64 of the substrate 10.
• a close up section of the previous describe flow cell embodiments where only a flow cell area 1000 is illustrated that includes the sensing electrode 34 of a substrate mounted resonator 30 in any one of the above-described manners, and a fluid delivery block 80 disposed above the resonator 30 and engaged with the substrate by a gasket 70.
• the fluid delivery block 80 is not shown as in the previous embodiments, but it is implied that the various fluid streams 300, 400 and 500 are introduced into the flow cell 1000 through the respective fluid delivery ports 90 located in the delivery block 80.
• Fig. 4 the various fluid streams 300, 400 and 500 are introduced into the flow cell 1000 through the respective fluid delivery ports 90 located in the delivery block 80.
• the substrate onto which the resonator 30 is mounted is not shown in detail as in previous embodiment, but is implied to constitute the entire surface area beneath the resonator 30 and within the gasket 70 boundaries.
• the two guide fluid streams 300 and 400 are continuously directed into the flow cell 1000 prior to the introduction of any sample fluid stream 500. These guide fluid streams 300 and 400 also provide a baseline hydrostatic pressure exerted onto the sensing electrode 34 of the resonator 10.
• the guide fluid streams 300 and 400 are able to control the position and width of the sample or reagent fluid stream 500 through the flow cell 1000 via the process of hydrodynamic focusing described previously.
• the flow rate of the guide fluid streams 300 and 400 By controlling the flow rate of the guide fluid streams 300 and 400 relative to that of the sample or reagent fluid stream 500, it is possible to direct or position the sample or reagent fluid stream 500 over the portion of the sensing electrode 3 of the resonator 30 that is positioned directly over the driving electrode 32, located on the back side of the resonator 30) or the 'sweet spot' of detection defined by the relative positions of the electrodes 32 and 34 located on either face of the resonator 30. In addition, as with any enclosed chamber, the addition or removal of fluid from that chamber will change the hydrostatic pressure on all walls of the chamber.
• the guide fluid streams 300 and 400 are introduced through one or more of the fluid delivery ports 90 to continuously flow through the flow cell 1000 defined by the mounting substrate, the fluid delivery block 80 and the liquid sealing gasket 70.
• These guide fluid streams 300 and 400 create a specific and constant pressure upon the sensing electrode 34 of the mounted resonator 30 within the flow cell 1000 based on their rate of flow.
• the flow rate of the guide fluid streams 300 and 400 already flowing in the cell 1000 are lowered by a rate corresponding or equivalent to the rate of flow of the newly introduced fluid stream 500.
• This adjustment is in addition to the adjustment of the flow rates of the guide fluid streams 300 and 400 relative to the flow of the sample fluid stream 500 to direct the sample fluid stream 500 over the sensing electrode 34 in such a manor that it is focused on a path equivalent to the width of the driving electrode 32 on the backside of the resonator 10.
• the flow rates of the guide fluid streams 300 and 400 are increased to compensate for the loss of fluid entering the cell 1000, and maintain the constant pressure level on the sensing electrode 3 of the resonator 30.

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• Physics & Mathematics (AREA)
• Acoustics & Sound (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Analytical Chemistry (AREA)
• Biochemistry (AREA)
• General Health & Medical Sciences (AREA)
• General Physics & Mathematics (AREA)
• Immunology (AREA)
• Pathology (AREA)
• Piezo-Electric Or Mechanical Vibrators, Or Delay Or Filter Circuits (AREA)
• Measuring Fluid Pressure (AREA)

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  • 2007-11-28 EP EP07871611A patent/EP2215466A2/de not_active Withdrawn
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