Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N1/00—Sampling; Preparing specimens for investigation
  • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
  • G01N1/30—Staining; Impregnating ; Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis
  • G01N1/31—Apparatus therefor
  • G01N1/312—Apparatus therefor for samples mounted on planar substrates
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
  • G01N27/02—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
  • G01N35/1002—Reagent dispensers
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
  • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
  • G01N35/1016—Control of the volume dispensed or introduced
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01V—GEOPHYSICS; GRAVITATIONAL MEASUREMENTS; DETECTING MASSES OR OBJECTS; TAGS
  • G01V3/00—Electric or magnetic prospecting or detecting; Measuring magnetic field characteristics of the earth, e.g. declination, deviation
  • G01V3/02—Electric or magnetic prospecting or detecting; Measuring magnetic field characteristics of the earth, e.g. declination, deviation operating with propagation of electric current
  • G01V3/06—Electric or magnetic prospecting or detecting; Measuring magnetic field characteristics of the earth, e.g. declination, deviation operating with propagation of electric current using AC
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
  • G01N35/10—Devices for transferring samples or any liquids to, in, or from, the analysis apparatus, e.g. suction devices, injection devices
  • G01N35/1009—Characterised by arrangements for controlling the aspiration or dispense of liquids
  • G01N2035/1025—Fluid level sensing

Definitions

• a system for detecting fluid coverage of a substrate, that includes a substrate holder for holding the substrate, an array of capacitive plates in proximity to the substrate holder, a fiuid supply configured to deliver a fluid to the substrate held on the substrate holder, and sensing electronics in electrical connection to the array of capacitive plates, wherein the sensing electronics periodically connect two poles of a current to at least one pair of plates and detects an output signal indicative of an electric property between the at least one pair of plates.
• the disclosed system automatically detects and confirms sufficient coverage of a sample or the substrate in an analysis or treatment with the fluid.
• the substrate is a microscope slide and the array of capacitive plates is contained in a structure supporting the slide, is contained in the slide itself, or is supported above the slide so as to directly sense the fluid on the slide, such as a puddle of fluid on the slide.
• Detecting the impedance may be done by applying an electrical current to one of the plates of the capacitor formed by the plates of a sensor element and receiving a signal at the other of the plates, which may be in the form of an output current from the other plate and from which impedance may be determined by the drop in voltage or the drop in amperage. Also a degree of coverage may be determined from the sensing.
• the step of applying the reagent can then be performed using a fluid supply mechanism operated by electrical circuitry, and the method can further include controlling the fluid supply mechanism (or other means of affecting coverage) using data derived from the detecting of the impedance of the sensor elements so as to cover a predetermined coverage area of the slide with the reagent fluid.
• the method further includes detecting bubble formation in the reagent fluid by detecting the impedances.
• sensor array plate 17 has a matrix of generally planar capacitance pads or platesl9 with upwardly facing surfaces.
• the plates 19 are each approximately 3 mm x 3mm square, but differently sized plates may be used, for example, that are from about 2 mm to about 4 mm square, and in different shapes, such as rectangular shapes.
• a protective layer or thin plate of material may be used overlying the plates 19, provided that the protective layer does not prevent the sensing of fluid on the slide. Sensor operation
• the sensor plate 17 operates similarly to a capacitive touch screen on a cell phone, as is illustrated in the detail diagram of FIG. 5.
• Sensing electronics 21 are connected with the sensor plate 17, and selectively supplies electrical power to the plates 19 to scan the capacitive properties of each plate 19.
• the sensing electronics 21 periodically connect two poles of a current, preferably an AC current at a voltage of from 1 to 10 volts, to plate 19a and one or more adjacent plates 19b.
• plate 19a and the adjacent plates 19b act as a capacitor, forming an electrical field 23 between the plates 19a and 19b.
• the puddle 11 eventually extends into the effective area of the electrical field of capacitor plate 19a in the sensor plate 17.
• the puddle fluid may be aqueous, although for some tissue analysis it may be organic or other types of fluid, and the material of the sample 3, while very thin, may be any sort of organic tissue or material.
• the presence of the puddle 11, and to some lesser degree the sample 3 alters the impedance between the plates 19a and 19b, and alters properties of the output signal produced responsive to the electric field established through the puddle by application of the input current or signal.
• the sensing electronics 21 detect electrical properties of the electric field established across the capacitor 19a/19b and transmit data indicative of those properties or some comparative data derived from those detected values to the other circuitry of the apparatus, as will be described below.
• a comparison of the properties of the output signal when the plates 19a and 19b are connected to the current source as compared to a baseline impedance of the slide 1 alone with only air over it, and no sample or fluid present allows a determination of the impedance created by the puddle and/or the sample, from which a number of conclusions may be drawn, as will be described below.
• the apparatus is a computerized system that includes one or more microprocessors and electronic data storage connected with the microprocessors.
• the electronic data storage stores data that constitutes software instructions executed by the microprocessor or microprocessors so as to control operation of the apparatus, as is well known and common in the art.
• the excitation circuit 33 supplies the current to signal multiplexing component 35, which is essentially a switching component controlled by a control and synchronization component 37.
• the control component 37 is controlled by the computerized apparatus, preferably by a microprocessor in the apparatus operating according to stored control software data stored in computer accessible memory.
• Signal multiplexing component 35 controls switches so that it communicates the current from the excitation circuit 33 in series to each of the various sensors 27 of the sensor array 17, which are all polled each polling cycle. The polling takes place periodically and continually, with a duty cycle appropriate to the operation of the apparatus, e.g., every 1 to 20 seconds.
• the sensor detect circuit 39 receives the output current from signal multiplexing component 35 and also a reference input signal from excitation circuit 33 so as to compare these two and make determinations of the relative electrical properties, which may include, for example, amplitude or amperage, voltage, and phase shift of the A/C signal that are imparted by the given capacitor.
• the sensor plate is polled to derive a current sensor value for each plate 19 derived from one or more detected electrical properties of the input and output signals across each sensor plate 19, such as, e.g., the output voltage or the ratio of output to input voltage.
• This current sensor data for each plate is compared at decision 53 with the baseline threshold level of the given plate as determined in step 51. If the current sensor data indicates that the level of impedance for the plate 17 has remained constant, i.e., there has been not enough fluid added to the slide to cause a change in impedance, then decision 53 loops to the next duty cycle, and it keeps on looping and polling the sensor array until the currently polled sensor array data indicates that the fluid is present on some of the plates 18. This indicates that the puddle 11 is beginning to be formed on the slide 1.
• the system scans the sensor or array 17 and identifies those plates 19 of the sensor array 17 that, based on a comparison of their current sensor data to the baseline data, have fluid partly or completely overlying them.
• the specific differences between the output and input signals applied to the individual capacitors 19 of the sensor array 17 are usually a constant value until the fluid is applied to the slide.
• the fluid is initially applied to the slide, if there is only partial coverage of a given area of a plate, there is only a slight increase in the output signal compared to the input signal due to a fractional change of the effective dielectric strength of the medium between the plates.
• this output signal value should exceed some pre-determined threshold level to ensure that the area of the plate 19 is entirely covered by the fluid, and also to ensure that there are no bubbles or other interruptions in the full application of the puddle 11 to the slide and sample, such as where an oil drop is trapped below an aqueous puddle, which would result in an unusually low output signal due to the non-polar nature of the oil in the drop.
• the results of the coverage map scanning 55 may be also used in a software- implemented control loop to automatically control the fluid supply mechanism that supplies the fluid forming the puddle 11 on the slide, so that fluid continues to be supplied until the predetermined desired coverage area or the entire slide is completely covered. This allows efficient application of the fluid to the entire slide by a completely automatic process.
• the effect of different fluid compositions on the input to output voltage ratio is a variable and to a degree distinctive for each of the exemplary fluids, i.e., bluing solution, hematoxylin solution, eosin, a differentiating solution, a wash solution and air.
• the ratio of voltage in to voltage out starts at approximately .5 and increases up until approximately 10 kHz, whereupon a plateau is reached at different levels for the different compositions of fluid, and then, subsequently, the impedance of the given fluids results in the differing levels of output voltage over a range of frequencies.

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• Life Sciences & Earth Sciences (AREA)
• Health & Medical Sciences (AREA)
• General Physics & Mathematics (AREA)
• Physics & Mathematics (AREA)
• Chemical & Material Sciences (AREA)
• Immunology (AREA)
• Biochemistry (AREA)
• General Health & Medical Sciences (AREA)
• Analytical Chemistry (AREA)
• Pathology (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• Molecular Biology (AREA)
• General Life Sciences & Earth Sciences (AREA)
• Environmental & Geological Engineering (AREA)
• Geology (AREA)
• Remote Sensing (AREA)
• Geophysics (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Electrochemistry (AREA)
• Sampling And Sample Adjustment (AREA)
• Investigating Or Analyzing Materials By The Use Of Electric Means (AREA)

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• 2016
  • 2016-12-02 AU AU2016361911A patent/AU2016361911B2/en active Active
  • 2016-12-02 EP EP16816218.8A patent/EP3384271B1/en active Active
  • 2016-12-02 JP JP2018528688A patent/JP6799597B2/ja active Active
  • 2016-12-02 CA CA3003636A patent/CA3003636C/en active Active
  • 2016-12-02 WO PCT/EP2016/079547 patent/WO2017093462A1/en not_active Ceased
• 2018
  • 2018-05-23 US US15/987,799 patent/US11181450B2/en active Active
• 2021
  • 2021-10-16 US US17/503,294 patent/US11592370B2/en active Active

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