Classifications

• • 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
  • G01N27/72—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables
  • G01N27/74—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids
  • G01N27/745—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating magnetic variables of fluids for detecting magnetic beads used in biochemical assays
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
  • G01R33/00—Arrangements or instruments for measuring magnetic variables
  • G01R33/12—Measuring magnetic properties of articles or specimens of solids or fluids
  • G01R33/1215—Measuring magnetisation; Particular magnetometers therefor

Definitions

• This invention relates generally to sensing the presence of magnetic particles
• the ligand is accomplished through the use of a second molecular species
• the antiligand or the receptor which specifically binds to the ligand of interest.
• the presence of the ligand of interest is detected by measuring, or inferring, either directly
• antiligand which are typically an antigen and an antibody.
• the teaching of Elings is to
• the scanner may be based on fluorescence, optical density, light scattering, color and reflectance, among others.
• Elings further teaches that the magnetic
• particles of interest proteins, viruses, cells, DNA fragments, for example.
• earth magnets and iron pole pieces are commercially available for this purpose.
• Radioactive methods present health and disposal problems of the resulting low-level radioactive waste, and they are also relatively slow. Fluorescent or phosphorescent techniques are limited in their quantitative accuracy and dynamic range because emitted
• photons may be absorbed by other materials in the sample (see Japanese patent publication 63-90765, published 21 Apr. 1988, Fujiwara et al.). Furthermore, the signal from the sample
• fluorescent or phosphorescent molecules normally decays over a period of hours or perhaps
• the force is measured as an apparent change in the
• the pair of coils (such as magnetic particles which are part of magnetic bound complexes) the pair of coils
• the oscillating drive field produces a corresponding oscillating magnetization in the magnetic particles, which can then be detected by the
• the high frequency oscillating field (typically
• sensors such as fluxgate, giant magneto-resistance (GMR), colossal magneto-resistance (CMR), and Hall effect sensors, all still employing an AC drive field.
• GMR giant magneto-resistance
• CMR colossal magneto-resistance
• Hall effect sensors all still employing an AC drive field.
• the detection system described by Simmonds exploits the fundamental magnetic behavior of the material comprising the magnetic particles to detect and measure their magnetization.
• the beads used in these applications are typically described as
• the beads are magnetic only when placed in an applied magnetic field. More specifically, they are not magnetic in the absence of an externally
• the tape or disc is specifically designed to have a high remanent magnetization and a large
• the magnetic particles typically used in biotechnology applications are comprised
• iron oxide which is typically a mixture of Fe 3 O 4 and Fe 2 O 3 , and measurements on
• the sensors must be of the type which
• the present invention provides a greatly simplified and
• a central feature of this invention is the use of a DC magnetic field (which replaces
• the requisite DC magnetic field can be generated without power consumption
• DC magnetic field cost less than about 25 cents.
• the components used to generate the high frequency AC field used in previous devices cost in excess of twenty dollars and require significant power.
• Hall sensors is not substantially degraded in high fields.
• Hall sensors can be designed
• the sensor area should also be matched
• a typical Hall sensor that might be used in this type of implementation is biased
• the dielectric properties in the sample substrate can cause significant impairment
• one sensor is subtracted from the other to form a resultant signal indicative of the difference
• the measurement is performed by moving a well-defined pattern of magnetically susceptible particles past the two Hall sensors and in close proximity to them,
• the pattern of magnetic particles is detected by the first Hall sensor as it moves past, and then after
• the difference signal between the two sensors is a function of the position of the two sensors
• Fig. 1 is a perspective representation of a preferred embodiment of the apparatus of
• Fig. 2 shows a Hall sensor as employed in the Fig. 1 embodiment
• Fig. 3 is a perspective view of an alternative embodiment of the invention.
• Fig. 4 is a block diagram of exemplary circuitry which would be employed with the
• Fig. 5 is a block diagram of exemplary circuitry which could be employed with the
• Fig. 6 is a block diagram incorporating an alternative manner of biasing the Hall
• Fig. 7 is a schematic cross section showing the motion of the sample relative to the sensors of Fig. 1;
• Fig. 8 is a plot of sensor outputs pursuant to the motion illustrated in Fig. 7.
• structure 11 is shown as having an E configuration, with gap 12 formed between middle leg
• the magnet is comprised of magnet elements 11 A and 1 IB and iron pole pieces 11C and 11D.
• Hall sensors 15 and 16 are mounted on surface 17, which is
• J: ⁇ 1730 ⁇ 043wo ⁇ Application.doc contemplated to be a flexible printed circuit board providing all the external connections
• Sample 21 is placed in a defined pattern (generally 1mm x 2mm) on substrate 22
• Fig. 4 circuitry, for example, as discussed in detail below. Further details of this motion
• substrate 22 may be formed with extension 20 on
• bar code 19 which is printed bar code 19.
• the bar code is read by optical detector or bar code reader 28, shown with appropriate electrical leads 29.
• the bar code is spaced from sample pattern 21 by a predetermined distance and reader 28 has a fixed position with respect to the Hall
• the signals from the reader can then provide information about the position of the sample pattern with respect to the Hall sensors.
• the optical detector is a fairly sophisticated commercial device
• the first pulse corresponds to the leading edge of the bar coded line
• the second pulse in quadrature
• these pulses are used to trigger the data collection electronics which
• the pulses from the optical detector can be used to initiate and terminate the data collection process.
• code information can tell the electronic control system when to start and stop the data
• the applied magnetic field from magnet 11 is
• the circuit of Fig. 4 relates to the Fig. 1 embodiment. This preferred embodiment
• This circuitry then produces signals indicative of the sum and difference of the sensor signals in the pair. Further signal processing by balancing stage 27 is accomplished by adjusting the balance gain by means of element 30 to minimize the output signal of this stage in the absence of a magnetic sample in the proximity of the sensors. The resultant
• the output of the lock-in stage represents the amount of
• the lock-in stage is employed for signal processing by the lock-in technique.
• alternating excitation means 24 is the current
• This difference signal may be
• the output signal of the lock-in stage will be indicative of the amount of particle material 21 present. It is desirable to select the excitation frequency such that signal detection occurs in a region of frequency space where sensor noise and
• the implementation may also include analog-to-digital or digital-to-analog conversion, or both.
• the requisite DC magnetic field may
• single sided magnet design does allow the use of larger and bulk substrates, it has
• Fig. 1 embodiment cannot be used and a • good estimate of the particle count is needed.
• This measurement in the Fig. 3 apparatus is made by moving a well-defined pattern of magnetically susceptible particles 36 on substrate 37 into proximity of sensor 41 in the
• Magnet structure 43 is comprised of permanent
• the mounting device may be any non-conductive material such as plastic.
• plastic 40 A may be filed with plastic 40 A. That may be a separate plastic
• Mounting device 40 is configured
• Signal balancing occurs by adjusting the balancing gain in balancing
• stage 47 with balancing device 48 to minimize the output signal of this stage in the absence
• the output of the lock-in stage represents the amount of particle material 36 present.
• Hall sensors 15, 16 are connected in series, so exactly the same bias current flows in both sensors. Since any variations in the bias current
• Hall sensors 15, 16 is connected in parallel. This design is more susceptible to erroneous
• the voltage taps of the two Hall sensors are connected together and a single differential amplifier 56 is used to detect the difference of the Hall voltages across the two sensors.
• Reference input through amplifier 57 and balancing stage 58 and lock-in stage 59 function in the same manner as previously described.
• Fig. 8 illustrates an ensemble of measurements plotted versus sample position.
• the solid curve represents a curve fit of an ideal response function using the method of least squares. It is clear that using both the position and signal voltage information, an absolute
• magnet pole pieces are preferably made of iron, the requirement is to
• the pole pieces could be curved so that the gap
• Substrate 22 could be a lateral flow membrane having region of interest 21.
• the substrate is preferably non-conductive and made of non-magnetic material, and could be made of plastic, wood, or other material satisfying these requirements.
• Substrate 22 can be made of plastic, wood, or other material satisfying these requirements.
• J: ⁇ 1730 ⁇ 043wo ⁇ Application.doc be moved by hand past the sensors, or the motion may be mechanized by using a stepper
• the system of the invention has excellent sensitivity, in the range of 1 nanovolt to
• the invention is for a very sensitive magnetic sensor in the
• N is the voltage change detected
• I is the bias current
• n is the carrier density
• B is the applied field
• d is the thickness of the sensing surface
• e is the carrier charge.

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• Physics & Mathematics (AREA)
• Chemical & Material Sciences (AREA)
• General Physics & Mathematics (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Electrochemistry (AREA)
• Condensed Matter Physics & Semiconductors (AREA)
• Life Sciences & Earth Sciences (AREA)
• Analytical Chemistry (AREA)
• Biochemistry (AREA)
• General Health & Medical Sciences (AREA)
• Immunology (AREA)
• Pathology (AREA)
• Investigating Or Analyzing Materials By The Use Of Magnetic Means (AREA)
• Measuring Magnetic Variables (AREA)

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• 2001
  • 2001-02-16 US US09/785,403 patent/US6518747B2/en not_active Expired - Lifetime
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