EP2077750A2 - Method and apparatus for noninvasive probe/skin tissue contact sensing - Google Patents

Method and apparatus for noninvasive probe/skin tissue contact sensing

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Publication number
EP2077750A2
EP2077750A2 EP07863843A EP07863843A EP2077750A2 EP 2077750 A2 EP2077750 A2 EP 2077750A2 EP 07863843 A EP07863843 A EP 07863843A EP 07863843 A EP07863843 A EP 07863843A EP 2077750 A2 EP2077750 A2 EP 2077750A2
Authority
EP
European Patent Office
Prior art keywords
sample
signal
sample probe
optical
contact
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07863843A
Other languages
German (de)
French (fr)
Other versions
EP2077750A4 (en
Inventor
Timothy L. Ruchti
James M. Welch
Christopher Slawinski
Thomas B. Blank
Stephen L. Monfre
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sensys Medical Inc
Original Assignee
Sensys Medical Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sensys Medical Inc filed Critical Sensys Medical Inc
Publication of EP2077750A2 publication Critical patent/EP2077750A2/en
Publication of EP2077750A4 publication Critical patent/EP2077750A4/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059—Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A61B5/1459—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters invasive, e.g. introduced into the body by a catheter
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
    • A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
    • A61B5/6843—Monitoring or controlling sensor contact pressure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/14—Coupling media or elements to improve sensor contact with skin or tissue
    • A61B2562/146—Coupling media or elements to improve sensor contact with skin or tissue for optical coupling
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/053—Measuring electrical impedance or conductance of a portion of the body
    • A61B5/0531—Measuring skin impedance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0205—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows
    • G01J3/0218—Optical elements not provided otherwise, e.g. optical manifolds, diffusers, windows using optical fibers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/027—Control of working procedures of a spectrometer; Failure detection; Bandwidth calculation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
    • G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
    • G01J3/02—Details
    • G01J3/0278—Control or determination of height or angle information for sensors or receivers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
    • G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light

Definitions

  • the invention relates to a method and apparatus for performing noninvasive analyte property determination. More particularly, the invention relates to determining proximity and/or contact of an optical sample probe with skin tissue.
  • Spectroscopy based noninvasive analyzers deliver external energy in the form of light to a sample site, region, or volume of a human body where the photons interact with a tissue sample, thus probing chemical and physical features. Some of the incident photons are specularly reflected, diffusely reflected, scattered, and/or transmitted out of the body where they are detected. An algorithm is used to determine a property of the body using knowledge of the detected photons.
  • noninvasive analyzers are analyzer based upon: magnetic resonance imaging (MRI's); X- rays; and those based upon visible, near-infrared, and/or infrared light.
  • Noninvasive ⁇ sampling a deformable object is complicated by optical and mechanical mechanisms occurring before and/or during sampling.
  • the analytical signal is strong, where strong refers to a signal that is visibly observed in a spectrum after signal processing.
  • a pulse oximeter uses the relatively large oxy- and deoxyhemoglobin signals in a matrix having relatively few interferences. In this case, the applied pressure at the sample site is tolerated by the measurement due to the relatively large analytical signal of hemoglobin and deoxyhemoglobin used in determination of the oxygen concentration.
  • the analytical signal measured by a noninvasive analyzer is relatively weak, where a weak signal is not visibly observed in a spectrum after signal processing and requires multivariate analysis in order to resolve a spectral response to the analyte due to the presence of multiple interferences where at least one interference is spectrally more intense than the analytical signal of interest.
  • a noninvasive glucose concentration analyzer using mid- or near-infrared glucose absorbance bands from 1100 to 2500 nm, relies on relatively small analytical signals that are often present amongst a multitude of interfering signals and uses a plurality of wavelengths, such as three, four, or more wavelengths. In this later case, perturbation of the sample by the noninvasive analyzer degrades analytical performance of the analyzer.
  • the second class of noninvasive analyzers optionally sample without contacting the sample.
  • specular reflectance and/or stray light often substantially degrades the analytical signal.
  • Optomechanical approaches designed to minimize reduction of detected specularly reflected light are hindered by that fact that skin diffusely scatters light.
  • algorithms used to reduce the effects of specular reflectance are complicated by specularly reflected light contributing in an additive manner to the resultant spectrum. The additive contribution results in a nonlinear interference, which results in a distortion of the spectrum that is difficult to remove.
  • the problem of the relatively large specularly reflected light is greatly enhanced as the magnitude of the analyte signal decreases.
  • specularly reflected light is preferably avoided.
  • an analyte property such as glucose or urea concentration
  • the second class of noninvasive analyzers contact the sample before and/or during sampling.
  • an optical probe of the analyzer deforms the sample upon contact with the sample.
  • the optical properties of the sample are changed due to contact, such as contact with an optical sample probe.
  • Changed optical properties due to movement of a sample before or during sampling include:
  • the deformation of the sample with the resulting change in optical properties of the sample is often detrimental.
  • the changes in the sample resulting from sampling degrade resulting analyte property determination.
  • the relative changes in the sample due to sampling result in increasing difficulty in extraction of analyte signal.
  • the sampling induced changes preclude precise and/or accurate analyte property determination from a sample spectrum.
  • a sample probe contacting skin of a human alters the sample. Changes to the skin sample upon contact, during sampling, and/or before sampling include: • stretching of skin;
  • the changes are often time dependent and methodology of sampling dependent.
  • the degree of contact to the sample by the spectrometer results in nonlinear changes to a resulting collected spectrum.
  • manually manipulating a spectrometer during optical sampling relies upon human dexterity, attentiveness, and training. Humans are limited in terms of dexterity, precision, reproducibility of movement, and sight. For example, placing a spectrometer in contact with an object during sampling is complicated by a number of parameters including any of:
  • NONINVASIVE TECHNOLOGIES There are a number of reports on noninvasive glucose technologies. Some of these relate to general instrumentation configurations, such as those required for noninvasive glucose concentration estimation, while others refer to sampling technologies. Those related to the present invention are briefly reviewed here:
  • 6,040,578 (March 21 , 2000) describe a method and apparatus for determination of an organic blood analyte using multi-spectral analysis in the near-infrared.
  • a plurality of distinct nonoverlapping regions of wavelengths are incident upon a sample surface, diffusely reflected radiation is collected, and the analyte concentration is determined via chemometric techniques.
  • Specular reflectance R. Messerschmidt, D. Sting Blocker device for eliminating specular reflectance from a diffuse reflectance spectrum
  • U.S. patent no. 4,661 ,706 (April 28, 1987) describe a reduction of specular reflectance by a mechanical device.
  • a blade-like device "skims" the specular light before it impinges on the detector.
  • a disadvantage of this system is that it does not efficiently collect diffusely reflected light and the alignment is problematic.
  • R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. patent no. 5,935,062 (August 10, 1999) and R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. patent no. 6,230,034 (May 8, 2001) describe a diffuse reflectance control device that discriminates between diffusely reflected light that is reflected from selected depths. This control device additionally acts as a blocker to prevent specularly reflected light from reaching the detector. Malin, supra, describes the use of specularly reflected light in regions of high water absorbance, such as 1450 and 1900 nm, to mark the presence of outlier spectra wherein the specularly reflected light is not sufficiently reduced.
  • the arm sample site platform is moved along the z-axis that is perpendicular to the plane defined by the sample surface by raising or lowering the sample holder platform relative to the analyzer probe tip.
  • the '012 patent further teaches proper contact to be the moment specularly reflected light is about zero at the water bands about 1950 and 2500 nm.
  • Glycerol is a common index matching fluid for optics to skin.
  • the index-matching medium is a composition containing both perfluorocarbons and chlorofluorocarbons.
  • index-matching medium to improve the interface between the sensor probe and skin surface during spectroscopic analysis.
  • the index-matching medium is preferably a composition containing chlorofluorocarbons with optional added perfluorocarbons.
  • U.S. patent no. 6,381 ,489, April 30, 2002 describes a measurement condition setting fixture secured to a measurement site, such as a living body, prior to measurement. At time of measurement, a light irradiating section and light receiving section of a measuring optical system are attached to the setting fixture to attach the measurement site to the optical system.
  • J. Roper, D. Bocker, System and method for the determination of tissue properties U.S. patent no. 5,879,373 (March 9, 1999) describe a device for reproducibly attaching a measuring device to a tissue surface.
  • Optical sampling interface system for in-vivo measurement of tissue world patent publication no. WO 2003/105664 (filed June 11 , 2003) describe an optical sampling interface system that includes an optical probe placement guide, a means for stabilizing the sampled tissue, and an optical coupler for repeatably sampling a tissue measurement site in-vivo.
  • Rensen Catheter head WIPO publication no. WO 2004/093669 (filed April 23, 2004); and M. Van Beek, J. Horsten, M. Van Der Voort, G. Lucassen, P. Caspers, Method and apparatus for determining a property of a fluid which flows through a biological tubular structure with variable numerical aperture, WIPO publication no. WO 2005/009236 (filed July 26, 2004) describe a monitoring (targeting) system used to direct a Raman excitation system to a blood vessel.
  • Noninvasive A wide range of technologies serve to analyze the chemical make-up of the body. These techniques are broadly categorized into two groups, invasive and noninvasive. Herein, a technology is referred to as invasive if the measurement process acquires any biosample from the body for analysis or if any part of the measuring apparatus penetrates through the outer layers of skin into the body. Noninvasive procedures do not penetrate into the body or acquire a biosample outside of their calibration and calibration maintenance steps.
  • Coordinate system Herein, positioning and attitude are defined. Positioning is defined using a x-, y-, and z-axes coordinate system relative to a given body part. For example, an x,y,z-coordinate system is used to define the sample site, movement of objects about the sample site, changes in the sample site, and physical interactions with the sample site. A relative x-, y-, z- axes coordinate system is used to define a sample probe position relative to a sample site. The x-axis is defined along the length of a body part and the y- axis is defined across the body part.
  • the x-axis runs between the elbow and the wrist and the y-axis runs across the axis of the forearm.
  • the x-axis runs between the base and tip of the digit and the y-axis runs across the digit.
  • the z-axis is aligned with gravity and is perpendicular to the plane defined by the x- and y-axis.
  • the orientation of the sample probe relative to the sample site is defined in terms of attitude.
  • Attitude is the state of roll, yaw, and pitch.
  • Roll is rotation of a plane about the x-axis
  • pitch rotation of a plane about the y-axis
  • yaw is the rotation of a plane about the z-axis. Tilt is used to describe both roll and pitch.
  • the invention relates to a method and apparatus for performing noninvasive analyte property determination. More particularly, the invention relates to determining proximity and/or contact of an optical sample probe with skin tissue.
  • Figure 1 is a block diagram of a control system
  • Figure 2 is a block diagram of a qualification system
  • Figure 3 is a block diagram of a conductive contact system
  • Figure 4 provides an electrical schematic of a conductive contact system
  • Figure 5 is a flow diagram of a qualification / monitoring system
  • Figure 6 provides exemplary contact response data as a function of time/position
  • Figure 7 provides exemplary contact response data as a function of time/position
  • Figure 8 provides exemplary contact response data as a function of time/position
  • Figure 9 illustrates a sample probe configured with capacitive sensors
  • Figure 10 illustrates a first capacitive sensor probe circuit
  • Figure 11 illustrates a second capacitive sensor probe circuit
  • Figure 12 illustrates a sample probe tip configured with capacitive sensors.
  • the invention comprises a method and apparatus for directing proximate contact of a sample probe of a noninvasive analyzer or noninvasive spectrometer with a skin tissue sample.
  • a deformable matrix has fluid like properties that conforms to the shape of a contacting surface.
  • skin tissue conforms to the shape of a sample probe tip during a timescale of collecting a noninvasive scan, such as about one to sixty seconds with an applied pressure of less than 0.02 pounds per square inch.
  • TISSUE DISPLACEMENT CONTROL Displacement of the tissue sample by the sample probe results in changes in noninvasive spectra. Displacement of the sample tissue is related to pressure applied to the sample tissue. However, as the tissue is deformed the return force applied by the tissue sample to the sample probe varies. Therefore, it is preferable to discuss that sample / tissue interaction in terms of displacement instead of pressure.
  • Displacement of the tissue sample by the sample probe is preferably controlled between an insufficient and excessive displacement or pressure.
  • Insufficient contact of the sample probe with the tissue sample is detrimental.
  • the surface of the skin tends to be rough and irregular. Insufficient contact results in a surface reflection.
  • Contact between the sample probe and the tissue sample minimizes air pockets and reduces optical interface reflections that contain no useful information.
  • Contact or close proximity of the sample probe tip to the sample site preferably provides good optical transmission of source illumination into the capillary layer where the analytical signal exists while minimizing reflections from the surface of the skin that manifest as noise. Excessive displacement of the tissue sample by the sample probe is detrimental.
  • the primary region of interest for measurement of blood borne analytes is the capillary bed of the dermis region, which is approximately 0.1 to 0.4 mm beneath the surface.
  • the capillary bed is a compressible region and is sensitive to pressure, torque, and deformation effects.
  • the accurate representation of blood borne analytes that are used by the body through time, such as glucose, relies on the transport of blood to and from the capillary bed, so it is not preferable to restrict this fluid movement. Therefore, contact pressure/displacement is preferably minimal so as not to excessively restrict or to partially restrict for an extended period of time flow of blood and interstitial fluids to the sampled tissue region.
  • a tip of a sample probe is displaced less than about 0.1 millimeters into the deformable skin/tissue sample matrix.
  • two or more signals or signal types are used in the process of positioning a sample probe tip relative to a sample site.
  • a first signal is used to position the sample probe coarsely relative to the sample site and a second sensor is used to control sample probe positioning at a closer distance to the sample site.
  • a third sensor is used to still more finely position the sample probe tip relative to the sample site.
  • positioning is performed using one or more sensors.
  • Each of the sensors provides a distinct signal.
  • one sensor is based upon a vision system
  • a second uses a capacitance reading while a third is generated from a conductance and/or optical signal.
  • Different sensors are used for different levels of positioning. Generally as positioning goes from gross alignment to fine alignment:
  • This system allows for various sensors that are best used to estimate position of the sample probe at different distances from the sample site to be used serially or in a parallel fashion.
  • a first sensor is used for coarse alignment. Examples include:
  • the first sensor is used to bring the tip of the sample probe into a coarse position relative to the sample site.
  • the first sensor is for example used to move the sample probe in the range of about 0.2 to 10+ mm from the sample site. Examples of a targeting / vision system are provided, infra.
  • a second sensor such as a capacitance sensor, is optionally used with or without a first sensor.
  • the second sensor provides a signal distinct from the signal from the first sensor.
  • the second sensor is used to estimate distances of the sample probe tip to the sample site that are generally smaller than the first sensor, described supra.
  • the second sensor is used in positioning the sample probe in a range of about 0 to 1 mm from the sample site or ranges therein.
  • Examples of a capacitance sensor are described, infra.
  • An example of a third sensor is a conductance sensor.
  • a conductive sensor is used in positioning a sample probe tip at distances less than one-tenth of a millimeter from a sample tissue site.
  • Each of the sensor types are used individually or in combination.
  • a sample probe is placed near a sample site.
  • a capacitive sensor provides a time constant to the controller.
  • the controller uses the time constant to determine distance between the tip of the sample probe and the sample site.
  • the controller then sends a signal to one or more actuators that reposition the sample probe.
  • the capacitive sensor signaling process is iterated and the sample probe tip is moved toward the sample site.
  • two or more capacitive sensors yield corresponding time constants that are used by the controller to determine the tilt of the sample probe relative to the surface of the sample site.
  • the controller sends directions to one or more actuators to adjust the sample probe.
  • this second iterative process is repeated until the surface of the sample probe tip is about parallel to the sample site surface.
  • One or both of the first and second iterative processes are repeated either sequentially or in parallel.
  • a third sensor such as an optical sensor or a conductive sensor, yields a signal interpreted by the controller to yield a decision about fine movement of the sample probe relative to the sample site, typically in terms of z-axis position as tilt was previously adjusted.
  • This process iteratively uses optical signal to finely position the sample probe tip in contact with or in proximate contact with the sample site surface.
  • the first process uses sensor 1 to control z-axis position; the second process uses sensor(s) 2 to control the tilt of the sample probe relative to the tissue sample site; and the third process uses sensor 3 to finely position the sample probe tip into proximate contact or contact with the sample site.
  • a targeting / vision system is used to initially position a sensor relative to the sample site, such as in the x- and y- axes.
  • a second sensor is then used to adjust the probe, such as in tilt of the sample probe relative to a sample site and/or distance between the sample probe tip and the sample site.
  • a third sensor is used to finely control the sample probe tip, such as to proximate contact with, initial contact to, and/or displacement into a sample site.
  • a targeting system is used to position a measuring system, such as an optical probe of a noninvasive glucose concentration analyzer.
  • a targeting system targets a tissue area or volume of a sample.
  • a targeting system targets a surface feature, one or more volumes or layers, and/or an underlying feature, such as a capillary or blood vessel.
  • the measuring system preferably contains a sample probe, which is optionally separate from or integrated into the targeting system.
  • the sample probe of the measuring system is preferably directed to the targeted region or to a location relative to the targeted region either while the targeting system is active or subsequent to targeting.
  • a controller is used to direct the movement of the sample probe in at least one of the x-, y-, and z-axes via one or more actuators.
  • the controller directs a part of the analyzer that changes the observed tissue sample in terms of surface area or volume.
  • the controller communicates with the targeting system, measuring system, and/or controller.
  • a targeting system is further described, infra.
  • Controlled positioning of a tip of an optical probe with a skin tissue sample site is required for precise and accurate noninvasive analyte property determination, such as determination of glucose or urea concentration in blood and/or tissue.
  • analyte property determination such as determination of glucose or urea concentration in blood and/or tissue.
  • the tip of the optical probe is positioned in a manner allowing both the amount of collected specularly reflected light and the degree of sample probe movement induced change in the optically sampled tissue volume to not degrade analytical performance of the analyzer beyond acceptable error limits.
  • Control of a portion of an analyzer preferably uses a signal indicative of the relative distance between the optical probe tip and the skin tissue sample site.
  • signals are optionally used separately or in combination in positioning the optical probe relative to the sample site, including use of any of:
  • An example of an electrical signal is conductance and/or resistance between a voltage source and the skin tissue site, typically measured with a current flow.
  • Examples of optical signals include use of the optical signal used by the analyzer in determination of the analyte property and/or use of a visualization system, such as a camera. Further descriptions of electrical, optical, and capacitive sensors are provided, infra.
  • An algorithm controls the sample probe placement and/or orientation relative to a sample site in a dynamic and/or static fashion.
  • the sample probe tip relative to a sample site is controlled with respect to one or more of: • x-axis position; • y-axis position;
  • x- and y- axis positioning is used to sample the same location on a sample.
  • z-axis positioning is used to position the probes to ensure minimal collection of spectrally reflected light and/or to provide any of:
  • Tilt control is used to prevent excessive skin stretch when a flat surface, such as a sample probe tip or a guide, is brought into contact with a deformable sample site, such as tissue where tissue is often irregular and has generally non-flat measurement topology.
  • Tilt control allows the sensing portion of an sample probe, such as a center of an optical probe tip, to be brought into contact with a sample site without displacement and hence stretching of nearby skin by the edges of the optical probe as the sample probe tip is brought into contact at an angle normal to the irregular sample surface.
  • a contact, positioning, and/or contact sensor is used in control or positioning of analyzer relative to a tissue sample site.
  • a sample probe tip of the analyzer is positioned into proximate contact with the tissue sample site.
  • FIG 1 an example of a control loop 10 for an analyzer 11 is presented.
  • the analyzer has at least one part, such as a sample probe, that is moved into proximate contact or contact with a skin tissue sample 12.
  • One or more inputs 13 for controlling the position of the sample control include any of:
  • a vision sensor system 14 sensing a sample feature or sample topology
  • a transducer such as a mechanical to electrical transducer
  • a second optical system such as a laser distancing and/or ranging system
  • At least one of the sensor systems provides input to an algorithm 19 that directs an actuator 19 that moves the relative position of the skin tissue sample and the analyzer.
  • Each of contact or positioning sensors are optionally integrated into the analyzer or are external to the analyzer. Each of the contact or positioning sensors are further described, infra. QUALIFICATION
  • sample probe also referred to as a sample sensor probe
  • optical contact is not guaranteed but must be qualified. Acceptable optical contact is ascertained on the basis of one or more contact sensors, which surround or are in close proximity to the detection optic.
  • a signal is generated by the contact sensor which indicates a contact event. For example, a conductive contact is detected when the signal changes from its mean level by an amount greater than two times the standard deviation of the noise.
  • the contact event leads the controller into a new mode of operation involving collection of the spectroscopic information that is used to make the noninvasive measurement, which is used for analyte property determination.
  • the determination of the point at which the change in modes occurs is an important aspect of the invention and leads to superior quality of measurement.
  • two or more of the above named sensor types are used cooperatively in positioning the sample probe of the analyzer relative to the sample.
  • the various sensor systems are used in control of the motion of the sample probe at different distances between a tip of the sample probe and the tissue sample.
  • a target/vision system is used to find a tissue sample site to move the analyzer probe head toward, a capacitive sensor system is used to orient the tilt of the probe head to nominally match that of the skin surface at the sample site, the capacitive sensor is further used in positioning the sample probe head close to the sample site, and a conductive sensor system is used in fine positioning of the tip of the sample probe headed to distances of less than a tenth of a millimeter and preferably about a hundredth of a millimeter from the tissue sample site.
  • a conductive sensor system is used in fine positioning of the tip of the sample probe headed to distances of less than a tenth of a millimeter and preferably about a hundredth of a millimeter from the tissue sample site.
  • a sensor probe of an analyzer 31 is positioned manually or through use of an actuator 10.
  • a sensor position reading 22 and/or a noninvasive optical reading 23 are collected.
  • the sensor position reading is optionally collected before, concurrently with, and/or after the noninvasive optical reading.
  • one or both of the sensor position reading and the noninvasive optical reading 24 are used to reposition the sensor probe using the actuator 19.
  • the noninvasive reading is qualified for use in any of: a calibration model 25 and used for predicting 25 and analyte property.
  • a vision system 14 provides gross alignment
  • a capacitive sensor system 16 provides fine alignment
  • a conductive sensor system 17 output is used to control very fine positioning of the sample probe, such as at distances of less than about 0.1 millimeter.
  • a conductive contact sensing system 30 is used that includes at least a power supply 31 , such as a voltage source, replaceably interfaced to a skin tissue sample 12.
  • the voltage source is preferably a low voltage source, such as a source providing about 1 , 3, 6, or 12 volts.
  • the voltage is converted to a current carried over one or more electrical conduits 33, 34 through an power meter
  • the circuit is initially open and is closed when the electrical conduits 33, 34 are brought into contact with the skin tissue 12, such as through one or more connections 36, 37.
  • current flows from the power source 31 to the skin through a first electrical conduit 33 and through a contacting element 36, such as a tip of a sample probe of an analyzer.
  • a contacting element 36 such as a tip of a sample probe of an analyzer.
  • current returns to the voltage source via a separate electrical conduit 34, such as a conducting line.
  • the first and second contacting elements 36, 37 are optionally contained in one housing or in two housings.
  • the current entering the skin tissue sample 32 completes an electrical circuit by passing to ground from the skin, the power supply also being grounded.
  • a change in current is observed when the circuit is completed.
  • the circuit is completed when the relative distance between the contacting element 36 and skin tissue 12 is reduced to a contacting distance of less than about 0.1 millimeter and typically to a distance of less than about 0.01 millimeters.
  • the power supply 31 such as a bias voltage of about six volts
  • the power supply 31 is an input to an operational amplifier 41.
  • the voltage is converted to current across a resistor 42, such as resistor of about 100 MOhm resistance.
  • a resistor 42 such as resistor of about 100 MOhm resistance.
  • the observed current is compared with the bias current using a differential amplifier 44 and the resulting signal is converted to a voltage at an analog to digital converter 45.
  • the bias current is filtered using a low pass filter 43, such as a 2.5 Hertz low pass filter.
  • a flowchart of an example of use of a sample probe 40 is provided.
  • tissue movement 51 of the sample relative to the sample probe is performed.
  • the sample probe is moved 41 and contact between the sample probe and tissue sample is sought 42 using a contact sensor, such as any described herein.
  • This process is iterative or the sensing signal is sought while the sample probe is moved.
  • acquisition of data commences.
  • data is additionally acquired as contact between the sample probe and tissue sample is sought.
  • a contact qualification monitoring system 50 is used to determine contact or proximate contact of the sensor system with a tissue sample.
  • the conductive sensor provides a feedback signal to a controlling algorithm or actuator telling the analyzer when to stop moving the sample probe.
  • Spectral data is acquired is acquired during the contact sensing process and/or after contact is established.
  • the contact sensing process is also referred to herein as a hunt process.
  • the conductive sensor system acts as a system for monitoring continued contact. If contact is lost, the analyzer is preferably directed to reestablish contact between the optical probe and the tissue sample.
  • the spectral data acquisition system, conductive contact determination/monitoring system, and actuator movement system are optionally used serially, iteratively, and/or in parallel with each other.
  • a current monitored contact event between an analyzer and a skin tissue sample is demonstrated.
  • a sample probe of an analyzer is moved toward a skin tissue sample as a function of time.
  • a response of a conductive contact sensor is provided as the sample probe moves.
  • a bias voltage from an analog to digital converter is obtained, which is nominally flat as a function of time.
  • the observed voltage rises rapidly to a new level.
  • the returned voltage stabilizes at a new level. Both the slope of the rising response curve and the difference between the initial and final observed voltages are indicative of the contacting event.
  • the high slope between the bias and stabilized voltage is indicative of the contact event occurring over a short time period.
  • the difference is indicative of the quality of the contact and also of the state of the skin tissue. For example, a fully hydrated skin sample will yield a larger difference than a poorly hydrated skin sample.
  • the current magnitude also provides information about the contact event, such as a coupling fluid thickness between the skin and the probe. For instance, since FC-40 has a high resistance, the observed contact current increases as the thickness of the FC40 layer on the skin decreases.
  • Figure 7 illustrates the conductive contact event as a tip of the sample probe is moved into contact with skin tissue.
  • the slope of the rising response curve is illustrative of conductive contact being made over a longer time period, such as occurs when the skin sample stretches as the tip of the sample probe hits the skin surface.
  • the sample probe further displaces the tissue before a stabilized contact is obtained.
  • Selection of later optical samples collected when the electrical contact is stabilizing with acceptable contact allows calibration and/or prediction using the optical samples where good contact between the sample probe and skin tissue sample is present. This process yields samples with smaller changes in optically sampled tissue volume as a function of time.
  • the selection of samples based upon the electrical contact sensor response thus leads to selection of prediction samples bounded by calibration data, thereby leading to more robust, accurate, and precise analyte property estimations.
  • the use of one or more contact responses in selection of corresponding optical samples for use in calibration and/or prediction is further described, infra.
  • the use of the conductive contact response in selection of corresponding optical samples for use in calibration and/or prediction is beneficial. For instance, only optical samples having full contact are selected for calibration and/or prediction. Alternatively, samples are selected having any contact, such as samples having a conductive contact response greater than the initial bias voltage plus two times the noise of the initial non- contacting samples.
  • the use of conductive contact is also useful data in determining validity of an optical contact metric, as described infra.
  • FIG 8 yet another example of a conductive contact sensor response is provided.
  • the tip of an optical sample probe configured with a conductive contact sensor, is moved toward a skin tissue sample. Initially, no contact is made. At sample number eighteen initial contact is made; full contact is made within a few additional samples. The observed voltage response of the conductive contact sensor subsequently fell due to loss of contact. Falling contact voltages result from a number of scenarios, such as skin movement, skin slipping or sagging relative, or perturbation of the sample by the probe.
  • the sample probe tip was repositioned and the conductive contact sensor indicates when contact is reestablished after moving the probe, such as by monitoring the response voltage until movement of the sample probe brings the response back up to a contact level meeting specification or to a full contact level. In this case, the sample probe was moved toward the skin to regain full contact.
  • a current-measurement contact sensor is placed adjacent to or surrounding an optical detection fiber.
  • a metal tube can surround the optical fiber and the contact sensor uses the tube for its measurement interface.
  • the tip of optical collection means such as the end of a fiber optic, is also making contact and the measurement may be made.
  • the tip of the sample probe is preferably driven into the tissue sample along the z-axis a small amount, such as about 25 to 200 ⁇ m, in order to ensure the probe is in contact with the skin throughout the duration of the measurement.
  • sensors are placed at away from the center of the tip of the sample probe.
  • the circumferentially distributed contact sensors are used to indicate when the probe comes down at an angle and a corner of the tip of the sample probe contacts the skin tissue before the center of the sample probe.
  • These contact sensors are optionally in a ring that indicates contact at any point around the probe or are sensors that indicate contact at specific locations, such as at corners or edges of the tip sample probe.
  • sensors are placed along each of the axial, y-axis, and longitudinal axis, x-axis of a body part so that the phasing of the sensors contacting in time may be analyzed to help interpret the geometry changes occurring during the contact event.
  • a single circuit is preferably multiplexed with multiple sensors to minimize the amount of additional cabling required with additional sensors.
  • a current reading from a given sensor is be taken before contact to establish a baseline.
  • the current is periodically monitored during a measurement sweep and more frequently as the probe approaches the arm in order to prevent a crash into skin due the probe stopping too late.
  • the contact-current is compared to the intensity at about 1290 or about 1450 nm returning from the arm or to capacitance measurements to assess the approach of the probe to the arm and slow its descent as necessary.
  • a conductive sensor around the perimeter of the optical detection fiber is used to identify measurements and scans within a dynamic measurement that have intimate contact between the skin and the optical detection fiber. Such a sensor is used to control the dynamics of probe contact and/or to select the scans with the most intimate contact for use in calibration and for qualifying prediction spectra.
  • CAPACITIVE SENSOR / CAPACITANCE PROBE CONTROL In yet another embodiment of the invention, capacitance sensors or touch sensors are used for determining any of:
  • a capacitive sensor is used to adjust tilt of the sample probe relative to the sample site tissue morphology and/or in positioning of the tip of the sample probe in close proximity to the tissue sample.
  • a conductive sensor as described supra, is used for determining contact and/or for positioning of the tip of the sample probe from distances of -0.05 to 0.1 mm from the nominal position of the skin tissue surface.
  • Figure 9A is a side view of a sample module having a sample probe 902 having a sample probe tip 903 illustrated relative to a tissue sample or sample site.
  • the sample probe 902 is illustrated with an optional collection optic 904, and two halves of two separate capacitance conductors 905, 906.
  • An end view of the sample probe 902 is illustrated in Figure 9B.
  • the circuit 1001 used to determine proximity of a subject's sample site to the sample probe includes a capacitor 1002 and a first resistor 1003.
  • the capacitance, C is calculated according to equation 1 , a
  • capacitance, C is proportional to the area, A, of the capacitor divided by the distance, d, between the capacitor plates.
  • the capacitor has two plates.
  • the first capacitor plate 1004 is integrated or connected to the sample module, preferably the sample module sample probe tip.
  • the second capacitor 1005 is the deformable material, such as a skin sample, body part, or a the tissue sample site. The assumption is that the person is a capacitor.
  • a typical adult has a capacitance of about 120 pF. Capacitance of different people or kids will vary.
  • the time constant, T is equal to the resistance, R, times the capacitance.
  • the distance between the capacitor plates is calculated through the combination of equations 1 and 2 through the measurement of the circuit time constant.
  • the time constant is the time required to trip a set voltage level, such as about 2.2 volts, given a power supply of known power, such as about 3.3 volts.
  • the time constant is used to calculate the capacitance using equation 2.
  • the capacitance is then used to calculate the distance or relative distance through equation 1. For example, as a distance between a sample site, such as a forearm or digit of a hand, and the capacitor plate decreases, the time constant increases and the capacitance increases.
  • the measure of distance is used in positioning the probe at or in proximate contact with the sample site without disturbing the sample site as described, infra.
  • a second circuit 1101 using the capacitance 1002 / resistor 1003 combination of the first circuit is enhanced to amplify the signal to noise using an operational amplifier 1102 and a second resistor 1103.
  • the gain of the circuit is the ratio of the first resistor 1103 and the second resistor 1103.
  • the voltage between the wire leading to the operation amplifier and a surrounding tube/shell is held at or about zero to minimize parasitic capacitance of the long wire and/or to minimize changes in capacitance caused by changes in the environment.
  • a microprocessor used to measure the time constant is attached to any of the circuits herein described.
  • the distance or relative distance between the sample probe tip and the sample site is determined, preferably before the tip of the sample probe displaces localized sample site skin/tissue which, as described supra, can lead to degradation of the sample integrity in terms of collected signal-to-noise ratios and /or sampling precision. Examples are used to illustrate the use of the capacitance sensor in the context of a noninvasive analyte property determination.
  • the distance or relative distance between the sample probe tip and the sample site is determined using a single capacitor.
  • the sample probe is brought into close proximity with the sample site using the time constant/distance measurement as a metric. In this manner, the sample probe is brought into close proximity to the sample site without displacing the sample site. Due to the inverse relationship between capacitance and distance, the sensitivity to distance between the sample site and the sample probe increases as the distance between decreases.
  • the distance between the sample site and the tip of the sample probe is readily brought to a distance of less than about one millimeter. Capacitance sensors as used herein can also readily be used to place the sample probe tip with a distance of less than about 0.1 millimeter to the sample site.
  • a conductance sensor is subsequently used in positioning the sample probe tip at distances less than one-tenth of a millimeter from the undisturbed tissue sample site surface.
  • multiple capacitors are optionally used to yield more than one distance reading between the sample probe tip and the sample site.
  • Multiple capacitive sensors are optionally used to control tilt along x- and/or y- axes.
  • Two or more capacitance sensors are optionally used for leveling the tip of the sample probe relative to the morphology of the sample site.
  • the distance between the sample site and the probe tip is measured using two or more capacitor pairs.
  • Figure 11 shows a first and second capacitor plate in the sample probe tip. If one capacitor reads a larger distance to the sample site than the second capacitor, then the probe tip is moved to level the probe by moving the larger distance side toward the sample, the smaller distance side away from the sample, or both.
  • the sample probe tip tilt or angle is either moved manually or by mechanical means, described infra.
  • exemplary capacitance layouts on the tip of a sample probe are provided.
  • four capacitance sensors 1201-1204 are used allowing for detection of tilt along the x-, y-, or x and y-axis by comparison of signal strength between two or more of the four sensors 1201-1204.
  • signals from two or more capacitors are combined, such as via a summation or an addition.
  • signals from sensors 1201 and 1202 are combined and compared against the combined signals of sensors 1203 and 1204.
  • the combined signals are used as a feedback to a controller controlling tilt, such as along the y-axis.
  • four capacitance based sensors are placed at or near the surface of a probe tip.
  • the sensors are placed along the x- and y-axis for ease in determining x- and y-axis level of the sensor probe.
  • two capacitance sensors 1201 , 1203 are shown off axis on a round sample probe tip.
  • five capacitance sensors 1201-1205 are shown that vary in position along a single direction, the x-axis as shown. As orientated, the five sensors are used to detect tilt of the sample probe relative to the sample site and/or proximity of the sample probe tip to the sample site.
  • any number of capacitance sensors are used in any geometric configuration on, near, or within a sample probe tip of any geometry.
  • Capacitive sensors have multiple advantages including: cost, response time, weight, size, and sensitivity.
  • the capacitance sensors are optionally embedded into the sample probe tip providing a dielectric barrier between the sensor and the subject, which is beneficial in terms of safety requirements, such as government regulatory requirements.
  • an optical sensor such as an infrared sensor, is used to detect distance between a sample probe tip and a sample, tilt of a sample probe relative to a sample, and/or contact or proximate contact of a sample probe tip with a sample site.
  • the optical sensors are optionally configured in the orientation of any of the above described orientations of the capacitance proximity sensors, such as at or near the edges of the sample probe tip.
  • Each of the optical sensors includes an illumination source and a detector.
  • the source is optionally independent for each sensors, such as through one or more light emitting diodes. Alternatively, two of more of the sensors share a common source, such as a single light emitting diode or an incandescent source, such as a tungsten halogen lamp.
  • the detectors are optionally placed within the sample probe tip, near the sample probe tip, or at a distance from the sample probe tip. In the later case, light is coupled to the detector via optics, such as fiber optics.
  • the optical sensors are preferably used to detect contact or near contact of the sample probe tip with the sample through the use of over absorbed wavelengths in human tissue, such as about 1450 nm where the surface reflection intensity dominates over signal returning via scattering from within the tissue sample.
  • the sample probe is moved down the z-axis until the specular light approaches zero. Movement of the sample probe is as described using the capacitance sensor and includes movement under manual control or automated control with or without the use of one or more actuators and with or without a feedback sensor and controller.
  • a second mode as surface reflection intensity is known to be a function of distance, the surface intensities from two or more optical sensors are compared in order to determine relative tilt of the sample probe relative to the tissue sample and the information used to adjust tilt until near tangential contact is achieved.
  • the optical signal from the source of the analyzer that is detected by the detector used to generate a signal for subsequent an analyte property determination, is used to determine proximity to or contact of the sample probe tip with the sample site. For instance, the spectrum determined using photons gathered by the collection fiber is used to determine proximity of or contact of the sample probe with the tissue sample site.
  • An illustrative example of an optical probe is provided. Photons from a source are reflected off of a backreflector through a first optic and through a second optic to a sample, such as skin.
  • the first optic is optionally used to remove unwanted emanating photons from the source that would otherwise optically heat the sample.
  • the second optic passes light and is optionally used to stabilize any of: sample site topology, sample site hydration, and to mechanically stabilize or locate a collection optic, such as a fiber optic.
  • detectors are used to detect light from the sensor source in order to control tilt of the sample probe relative to the sample and/or distance between the tip of the fiber optic and the sample.
  • a machine vision system 14 is used in determining a sample site and/or in reproducibly targeting a sample site, such as a determined sample site.
  • the targeting system and measuring system optionally use a single source that is shared or have separate sources.
  • the targeting is optionally used to first target a region and the measuring system subsequently samples at or near the targeted region.
  • the targeting and measuring system are used over the same period of time so that targeting is active during sampling by the measuring system.
  • the targeting system and measuring system optionally share optics and/or probe the same tissue area and/or volume.
  • the targeting and measuring system use separate optics and/or probe different or overlapping tissue volumes.
  • neither, one, or both of the targeting system and measuring system are brought into contact with the skin tissue at or about the sample site.
  • Targets include any of:
  • tissue morphology • tissue morphology; • a target below the skin surface;
  • marking features added to the skin include a tattoo, one or more dyes, one or more reflectors, a crosshair marking, and positional markers, such as one or more dots or lines.
  • a skin surface feature include a wart, hair follicle, hair, freckle, wrinkle, and gland.
  • Tissue morphology includes surface shape of the skin, such as curvature and flatness.
  • specifications for a dermis thickness include a minimal thickness and a maximum depth.
  • the target is a volume of skin wherein the analyte, such as glucose, concentration is higher.
  • the measuring system is directed to image photons at a depth of the enhanced analyte concentration.
  • a targeting system targets a target.
  • a targeting system typically includes a controller, an actuator, and a sample probe.
  • Examples of targeting systems include a planarity detection system, optical coherence topography (OCT), a proximity detector and/or targeting system, an imaging system, a two-detector system, and a single detector system.
  • Examples of targeting system technology include impedence, acoustic signature, ultrasound, use of a pulsed laser to detect and determine distance, and the use of an electromagnetic field, such as radar and high frequency radio-frequency waves.
  • Sources of the targeting system include a laser scanner, ultrasound, and light, such as ultraviolet, visible, near-infrared, mid-infrared, and far- infrared light.
  • Detectors of the targeting system are optionally a single element, a two detector system, an imaging system, or a detector array, such as a charge coupled detector (CCD) or charge injection device or detector (CID).
  • CCD charge coupled detector
  • CID charge injection device or detector
  • One use of a targeting system is to control movement of a sample probe to a sampling location.
  • a x second example of use of a targeting system is to make its own measurement.
  • a third use is as a primary or secondary outlier detection determination. In its broadest sense, one or more targeting systems are used in conjunction with or independently from a measurement system.
  • mid- infrared light samples surface features to the exclusion of features at a depth due to the large absorbance of water in the mid-infrared.
  • a second example uses the therapeutic window in the near-infrared to image a feature at a depth within tissue due to the light penetration ability from 700 to 1100 nm. Additional examples are targeting with light from about 1100 to 1450, about 1450 to 1900, and/or about 1900 to 2500 nm, which have progressively shallower penetration depths of about 10, 5, and 2 mm in tissue, respectively.
  • a further example is use of visible light for targeting or imaging greater depths, such as tens of millimeters.
  • Raman targeting system such as in WIPO international publication number WO 2005/009236 (February 3, 2005), which is incorporated herein in its entirety by this reference thereto.
  • a Raman system is capable of targeting capillaries. Multiple permutations and combinations of optical system components are available for use in a targeting system.
  • a controller controls the movement of one or more sample probes via one or more actuators.
  • the controller optionally uses an intelligent system for locating the sample site and/or for determining surface morphology. For example, the controller hunts in the x- and y-axes for a spectral signature.
  • the controller moves a sample probe via the actuator toward or away from the sample along the z-axis.
  • the controller optionally uses feedback from the targeting system, from the measurement system, or from an outside sensor in a closed-loop mechanism for deciding on targeting probe movement and for sample probe movement.
  • the controller optimizes a multivariate response, such as response due to chemical features or physical features.
  • Examples of chemical features include blood/tissue constituents, such as water, protein, collagen, elastin, and fat.
  • physical features include temperature, pressure, and tissue strain. Combinations of features are used to determine features, such as specular reflectance.
  • specular reflectance is a physical feature optionally measured with a chemical signature, such as water absorbance bands centered at about 1450, 1900, or 2600 nm.
  • Controlled elements include any of the x-, y-, and z-axis position of sampling along with rotation or tilt of the sample probe. Also optionally controlled are periods of light launch, intensity of light launch, depth of focus, and surface temperature.
  • the controller controls elements resulting in pathlength and/or depth of penetration variation.
  • the controller controls an iris, rotating wheel, backreflector, or incident optic, which are each described infra.
  • the controller moves the targeting probe and/or sample probe so as to make minimal and/or controlled contact with the sample to control stress and/or strain on the tissue, which is often detrimental to a noninvasive analyte property estimation.
  • Strain is the elongation of material under load. Stress is a force that produces strain on a physical body. Strain is the deformation of a physical body under the action of applied force. In order for an elongated material to have strain there must be resistance to stretching. For example, an elongated spring has strain characterized by percent elongation, such as percent increase in length.
  • Skin contains constituents, such as collagen, that have spring-like properties. That is, elongation causes an increase in potential energy of the skin. Strain induced stress changes optical properties of skin, such as absorbance and scattering. Therefore, it is not desirable to make optical spectroscopy measurements on skin with varying stress states. Stressed skin also causes fluid movements that are not reversible on a short timescale. The most precise optical measurements are therefore conducted on skin in the natural strain state, such as minimally or non-stretched stretched skin. Skin is stretched or elongated by applying loads to skin along any of the x-, y-, and z- axes, described infra. Controlled contact reduces stress and strain on the sample. Reducing stress and strain on the sample results in more precise sampling and more accurate and precise glucose concentration estimations.
  • the displacement of the tissue sample by the sample probe results in compression of the sample site.
  • the displacement results in a number of changes including at least one of:
  • An example of using light to measure a physical property, such as contact, stress, and/or strain, in tissue is provided.
  • Incident photons are directed at a sample and a portion of the photons returning from the sample are collected and detected.
  • the detected photons are detected at various times, such as when no stress is applied to the tissue and when stress is applied to the tissue. For example, measurements are made when a sample probe is not yet in contact with the tissue and at various times when the sample probe is in contact with the tissue, such as immediately upon contact and with varying displacement of the sample probe into the tissue.
  • the displacement into the tissue is optionally at a controlled or variable rate.
  • the collected light is used to determine properties.
  • One exemplary property is establishing contact of the sample probe with the tissue.
  • a second exemplary property is strain.
  • Changes in the ratio are indicative of hydration.
  • data collection routines are varied depending upon the determined state of the tissue.
  • the probing tissue displacement is varied with change in hydration.
  • the strain measurement is optionally made with either the targeting system or measurement system.
  • the tissue state probe describe herein is optionally used in conjunction with a dynamic probe, described infra.
  • a coupling fluid is applied between the tip of the sample probe and the tissue sample site. It is determined that highly viscous coupling fluid degrade the noninvasive analyte determination system.
  • a highly viscous coupling fluid requires increased pressure to be applied between the tip of a sample probe and a tissue sample site in order to displace the viscous coupling fluid.
  • Fluorolube is a viscous paste that is not readily displaced. The pressure required for the tip of the sample probe to displace the Fluorolube results in tissue stress and strain that degrades the analytical quality of the noninvasive signal. Therefore, less viscous coupling fluids are required, such as FC-70 or FC-40.
  • the viscosity of the coupling fluid should not exceed that of FC-70 and preferably the viscosity of the coupling fluid should not exceed that of FC-40.
  • an analyzer comprises at least a source coupled via optics to a detector.
  • the analyzer is handheld.
  • the analyzer sits upon a supporting surface during use.
  • the analyzer is split having a base module physically separated from the sample module, where the sample module interfaces with the sample site during operational use.
  • the base module is connected to the sample module via wireless communication, is connected via a communication bundle, or is connected through a semi-rigid weight support system, where the weight support system serves to support at least a portion of the weight of the sample module during use.
  • the weight support system preferably operates as an automated positioning system or an actuation system.
  • the communication bundle preferably carries any of: optical signal, data signal, power, electrical control signal, and a fluid between the base module and the sample module.
  • the weight support system carries any of:
  • the analyzer is preferably a split analyzer where the weight support system additionally operates as a communication bundle.
  • optical components such as a source; backreflector; guiding optics; lenses; filters; mirrors; a wavelength separation device; and at least one detector, are optionally positioned in the base module and/or sample module.
  • the noninvasive analyzer contains a base module interfaced to a sample module.
  • the base module is any of:
  • the sample module interfaces with a sample.
  • Means for analyzing collected data, such as spectra and subject data are preferably contained within or coupled to the base module.
  • any of the embodiments described herein are operable in a home environment, public facility, or in a medical environment, such as an emergency room, critical care facility, intensive care unit, hospital room, or medical professional patient treatment area.
  • the split analyzer is operable in a critical care facility where the sample module is positioned in proximate contact with a subject or patient during use and where the base module is positioned on a support surface, such as a rack, medical instrumentation rack, table, or wall mount.
  • At least a portion of the sample module is movable with respect to a subject or patient sample site along any of the x-, y- , and z-axes, and/or in terms of rotation or tilt.
  • the sample site such as a forearm remains stationary while at least a portion of the analyzer, such as the sample probe head, moves to interface with the sample in terms of an X-, y-, and/or z-axis and/or with respect to rotation or tilt.
  • the components defining the optical train of an analyzer are moved as a unit to reposition the sample probe tip relative to a sample site.
  • Moving the optical units of an analyzer together allows for fixed optics or optics with tighter constraints in terms of movement than a fiber optic. For instance moving the sample probe head to the sample does not change the collection optic pathway so that collection optics can spatially fixed or controlled in terms of optically coupling the tip of the fiber bundle to the detection element.
  • optics in the optical train from the sample to the detector are moved together in a controlled fashion.
  • the analyzer is held in a fixed position while the tissue sample site is moved relative to the analyzer by moving a body part, such as with an adjustable platform, along any of the x-, y-, and z-axes, and/or in terms of rotation or tilt.
  • the movable portion of the sample module moves in an active or passive manner.
  • a controller is preferably used to position the tip of the sample probe relative to a tissue sample site.
  • a command input is sent to an actuator system within the analyzer, where the actuator system is preferably in the sample module.
  • the actuator system controls the position of a probe system having a sensor. The position is relative to a sample site.
  • the signal from the sensor is either used in the measurement of an analyte property value of the sample or is used as input for a controller that sends additional input to the actuator system to further control position or movement of the probe system via the actuator system.
  • the actuator system preferably contains electronics used in conjunction with electro-mechanical conversion of the movable aspect of the analyzer, such as the tip of the probe system within the sample module in terms of one or more of: x-position, y-position, z-position, tilt, and rotation of the sample probe tip relative to the sample site.
  • Movement of the sample probe is preferably performed using an electro- mechanical converter.
  • an actuator system is preferably controlled using a controller provided with signal from the probe system sensor. For example, if a capacitance sensor indicates that the probe tip is too far from the sample, an electro-mechanical converter is used to translate the sample probe along the z-axis toward the sample site. Similarly, if two capacitance signals from opposite sides of the sample probe tip indicate that the sample probe tip is not normal to the sample site, then one or more actuators are used to adjust the tilt of the sample probe or the level of the sample probe tip relative to the sample site surface. In one case, one or more sensors are used in combination with one or more actuators to control sample probe position in terms of any of:
  • a partial vacuum is optionally applied at or near the sample site.
  • the partial vacuum pulls the skin into full contact with the sample probe tip.
  • a benefit of this system is ease of use.
  • a second benefit is that it allows the skin to have twitching movement without altering the optical sample site.
  • the probe contact event is complicated by fluid drag properties that include contact inconsistencies in the contact at the measurement interface.
  • One potential is for the development of liquid lensing of the optical fluid in the low pressure area near the optical detection fiber.
  • Feature extraction is used to qualify optical contact between a tip of a sample probe of an analyzer and a tissue sample.
  • the contact event of the measurement process is difficult to determine using optical methods as an optical signal used is a mixture of light that has been diffusely reflected from the arm and light that has been reflected from the arm as a first-surface reflector. This, along with dynamic nature of the skin makes it difficult to assign an absolute threshold that designates when contact has occurred.
  • noninvasive spectra of human tissue contain features related to chemical and physical structures of the sampled tissue.
  • the response signal in a region that is scattering dominated increases in magnitude while the response signal in a region that is absorbance dominated decreases in value, such as at about 1450 nm.
  • the ratio of two features or the change in direction of a magnitude of a feature as a function of distance between the sample probe and the tissue sample is an indicator of sample contact and is used to qualify the invention.
  • the interface to the skin tissue and related deformation is dependent upon the orientation of the contact surface to the skin tissue and the approach angle of the device probe as it contacts and deforms the skin.
  • the problem is related to the necessity for optical contact between the probe optics and the skin surface. This contact is achieved by moving the optical interface into contact with skin surface and optionally displacing skin tissue as the point of optical contact recedes in response to the presence of the probe.
  • a portion of the probe is likely to displace a greater portion of the skin tissue than desired, leading to a change in the scattering and absorption properties of the targeted measurement site.
  • the displacement and/or stretch of the tissue caused by a mismatch of the tissue surface and optical interface may lead to a push of interstitial fluid away from the point of measurement and/or a plastic deformation of the skin tissue. Both effects increase the level of spectral interference and reduce the signal to noise ratio of the measurement system.
  • the problem is especially severe in the case of a probe system which controls the z-axis (movement to and from the skin) on the basis of optical contact.
  • the actuator system may displace a significant volume of tissue in an effort to achieve the desired optical contact.
  • the problem is exacerbated with the angle between the probe surface and skin varies from sample to sample. In this case both the scattering properties of the skin are varied in addition to effects related to tissue displacement.
  • Adjustment of the angle between the probe surface and the skin tissue measurement site is accomplished either through a change in the orientation of the subject's body position, an in particular, the orientation of their forearm to the probe surface, the adjustment of the probe itself relative to the surface of the targeted point of measurement, the determination of a point of contact possessing a parallel point relative to the optical interface of the probe surface, or the tissue measurement site.
  • the probe is relatively stationary and the subject's forearm is adjusted to achieve a measurement angle that is within the desired limits (plus or minus one degree). This is accomplished by a rotation of the arm and height adjustments of the subject's hand/wrist and elbow support systems.
  • a hand/wrist and elbow support system is set up for a subject in a manner that achieves a near tangent point of measurement.
  • adjustments to the measurement angle are made by changing the angle of the subject's hand/wrist support system.
  • the adjustments are made either manually by the patient on the basis of a display providing directions or through an automated feedback control system which detects the measurement angle through proximity sensors and directs an actuator to modify the angle of the wrist/hand support system.
  • the probe itself is adjusted to achieve a small measurement angle.
  • the desired point of measurement has been located using criteria other than the measurement angle and therefore necessitate an adjustment of the probe to .
  • the measurement angle is reduced by changing the orientation of the measurement probe itself.
  • a targeting system is employed to achieve a reproducible measurement site using either an adjustable forearm support system or an adjustable probe positioning system.
  • actuators are used, on the basis of the estimated measurement angle, to change the orientation of the probe itself such that a tangent point of contact occurs and optionally a z-axis displacement that is perpendicular to the probe surface.
  • a point of tangency (measurement angle close to zero) is used to set the point of measurement by using a search algorithm on the basis of forearm topology.
  • the topology of the forearm is determined using an imaging system and a point of tangency determined by locating the measurement point extremum.
  • the topology of the forearm is mapped in the vicinity of the desired measurement site using proximity sensors. The measurement site is again determined as that point in which the slope relative to the probe surface is zero. In particular, on the bottom of the forearm the lowest point is determined as the point of measurement.
  • the forearm can be mapped by moving proximity sensors across the surface or hunted for by repeatedly mapping a small region.
  • the point of measurement is hunted for using a feedback control system which adjusts the x-y position of the probe on the basis of the measurement angle.
  • the error in the measurement angle is used to direct movement of the probe in either x and/or y directions until either a suitable measurement angle is achieved or a failure occurs (actuator moves beyond x-y bounds).
  • a proximity sensor can be moved closed to the skin surface in the vicinity of the desired measurement site.
  • the measurement angle in both the x and y axis is determined.
  • the probe is then repeatedly moved in the direction that is likely to reduce the measurement angle. Specifically, the probe is moved in the direction opposite of the measurement angle.
  • the magnitude of movement may be fixed, it has been determined to be more efficient to adjust the movement step size on the basis of both the measurement angle and prior adjustments and/or measurement angles in a manner similar to a gradient descent or conjugate gradient descent optimizer or alternately, a proportional- integral-derivative (PID) controller.
  • PID proportional- integral-derivative
  • the tissue volume itself is mechanically controlled or constrained in a manner that achieves a low measurement angle.
  • Optical spectroscopic measurements of living human skin are used to calibrate an instrument to measure blood glucose concentration noninvasively.
  • n surface roughness of skin and the optical index of refraction
  • surface reflections lead to the rise of nonlinear stray light type effects. That is nonlinear effects result from incident light that is reflected off the sample and measured instead of being transmitted into the sample and diffusely reflected and measured.
  • calibration models are built using data of a specified sample probe / tissue contact level. For example, highly contacting samples are used in a first calibration, mid-level contacting samples are used in a second calibration, and low-level contacting samples are used in a third calibration. Prediction spectra are subsequently classified into a contacting specification and applied to the corresponding calibration model.

Abstract

The invention relates to a method and apparatus for performing noninvasive analyte property determination. More particularly, the invention relates to determining proximity and/or contact of an optical sample probe with skin tissue.

Description

METHOD AND APPARATUS FOR NONINVASIVE PROBE / SKIN TISSUE CONTACT SENSING
CROSS-REFERENCE TO RELATED APPLICATION This application claims benefit of U.S. provisional patent application no. 60/864,375 filed November 3, 2006, which is incorporated herein in its entirety by this reference thereto.
BACKGROUND OF THE INVENTION FIELD OF THE INVENTION
The invention relates to a method and apparatus for performing noninvasive analyte property determination. More particularly, the invention relates to determining proximity and/or contact of an optical sample probe with skin tissue.
DESCRIPTION OF RELATED ART
Spectroscopy based noninvasive analyzers deliver external energy in the form of light to a sample site, region, or volume of a human body where the photons interact with a tissue sample, thus probing chemical and physical features. Some of the incident photons are specularly reflected, diffusely reflected, scattered, and/or transmitted out of the body where they are detected. An algorithm is used to determine a property of the body using knowledge of the detected photons. Common examples of noninvasive analyzers are analyzer based upon: magnetic resonance imaging (MRI's); X- rays; and those based upon visible, near-infrared, and/or infrared light.
Noninvasive^ sampling a deformable object is complicated by optical and mechanical mechanisms occurring before and/or during sampling. In a first class of noninvasive analyzers the analytical signal is strong, where strong refers to a signal that is visibly observed in a spectrum after signal processing. For example, a pulse oximeter uses the relatively large oxy- and deoxyhemoglobin signals in a matrix having relatively few interferences. In this case, the applied pressure at the sample site is tolerated by the measurement due to the relatively large analytical signal of hemoglobin and deoxyhemoglobin used in determination of the oxygen concentration. In a second class of noninvasive analyzers, the analytical signal measured by a noninvasive analyzer is relatively weak, where a weak signal is not visibly observed in a spectrum after signal processing and requires multivariate analysis in order to resolve a spectral response to the analyte due to the presence of multiple interferences where at least one interference is spectrally more intense than the analytical signal of interest. For example, a noninvasive glucose concentration analyzer, using mid- or near-infrared glucose absorbance bands from 1100 to 2500 nm, relies on relatively small analytical signals that are often present amongst a multitude of interfering signals and uses a plurality of wavelengths, such as three, four, or more wavelengths. In this later case, perturbation of the sample by the noninvasive analyzer degrades analytical performance of the analyzer.
In order to avoid sampling errors, the second class of noninvasive analyzers optionally sample without contacting the sample. When the analyzer does not contact the sample, specular reflectance and/or stray light often substantially degrades the analytical signal. Optomechanical approaches designed to minimize reduction of detected specularly reflected light are hindered by that fact that skin diffusely scatters light. Further, algorithms used to reduce the effects of specular reflectance are complicated by specularly reflected light contributing in an additive manner to the resultant spectrum. The additive contribution results in a nonlinear interference, which results in a distortion of the spectrum that is difficult to remove. The problem of the relatively large specularly reflected light is greatly enhanced as the magnitude of the analyte signal decreases. Thus, for the second class of noninvasive analyzers or for low signal-to-noise ratio measurements, specularly reflected light is preferably avoided. For example, noninvasively determining an analyte property, such as glucose or urea concentration, from a spectrum of the body is complicated by additive specularly reflected light in the collected spectrum.
Alternatively, the second class of noninvasive analyzers contact the sample before and/or during sampling. For objects or samples that are deformable, an optical probe of the analyzer deforms the sample upon contact with the sample. As a result of the deformation, the optical properties of the sample are changed due to contact, such as contact with an optical sample probe.
Changed optical properties due to movement of a sample before or during sampling include:
• scattering;
• anisotropy; and
• absorbance.
For analyzers relying upon small optical signals and/or optical signals in the presence of high noise or interference, the deformation of the sample with the resulting change in optical properties of the sample is often detrimental. The changes in the sample resulting from sampling degrade resulting analyte property determination. As the signal level of the analyte decreases, the relative changes in the sample due to sampling result in increasing difficulty in extraction of analyte signal. In some instances, the sampling induced changes preclude precise and/or accurate analyte property determination from a sample spectrum. For example, a sample probe contacting skin of a human alters the sample. Changes to the skin sample upon contact, during sampling, and/or before sampling include: • stretching of skin;
• compression of skin; and
• altered spatial distribution of sample constituents.
Further, the changes are often time dependent and methodology of sampling dependent. Typically, the degree of contact to the sample by the spectrometer results in nonlinear changes to a resulting collected spectrum. Further, manually manipulating a spectrometer during optical sampling relies upon human dexterity, attentiveness, and training. Humans are limited in terms of dexterity, precision, reproducibility of movement, and sight. For example, placing a spectrometer in contact with an object during sampling is complicated by a number of parameters including any of:
• not being able to reach and see the sample at the same time;
• the actual sampling area being visually obscured by part of the spectrometer or sample;
• placing the analyzer relative to the sample within precision and/or accuracy specifications at, near, or beyond human control limits; and
• repeatably making a measurement due to human fatigue and frailty.
What is needed is a method of sampling where the tissue is not deformed or is minimally deformed during optical sampling.
NONINVASIVE TECHNOLOGIES There are a number of reports on noninvasive glucose technologies. Some of these relate to general instrumentation configurations, such as those required for noninvasive glucose concentration estimation, while others refer to sampling technologies. Those related to the present invention are briefly reviewed here:
P. Rolfe, Investigating substances in a patient's bloodstream, U.K. patent application ser. no. 2,033,575 (August 24, 1979) describes an apparatus for directing light into the body, detecting attenuated backscattered light, and using the collected signal to determine glucose concentrations in or near the bloodstream. C. Dahne, D. Gross, Spectrophotometric method and apparatus for the noninvasive, U.S. patent no. 4,655,225 (April 7, 1987) describe a method and apparatus for directing light into a patient's body, collecting transmitted or backscattered light, and determining glucose concentrations from selected near-infrared wavelength bands. Wavelengths include 1560 to 1590, 1750 to 1780, 2085 to 2115, and 2255 to 2285 nm with at least one additional reference signal from 1000 to 2700 nm.
R. Barnes, J. Brasch, D. Purdy, W. Lougheed, Non-invasive determination of analyte concentration in body of mammals, U.S. patent no. 5,379,764 (January 10, 1995) describe a noninvasive glucose concentration estimation analyzer that uses data pretreatment in conjunction with a multivariate analysis to estimate blood glucose concentrations.
M. Robinson, K. Ward, R. Eaton, D. Haaland, Method and apparatus for determining the similarity of a biological analyte from a model constructed from known biological fluids, U.S. patent no. 4,975,581 (December 4, 1990) describe a method and apparatus for measuring a concentration of a biological analyte, such as glucose concentration, using infrared spectroscopy in conjunction with a multivariate model. The multivariate model is constructed from a plurality of known biological fluid samples.
J. Hall, T. Cadell, Method and device for measuring concentration levels of blood constituents non-invasively, U.S. patent no. 5,361 ,758 (November 8, 1994) describe a noninvasive device and method for determining analyte concentrations within a living subject using polychromatic light, a wavelength separation device, and an array detector. The apparatus uses a receptor shaped to accept a fingertip with means for blocking extraneous light. S. Malin, G Khalil, Method and apparatus for multi-spectral analysis of organic blood analytes in noninvasive infrared spectroscopy, U.S. patent no. 6,040,578 (March 21 , 2000) describe a method and apparatus for determination of an organic blood analyte using multi-spectral analysis in the near-infrared. A plurality of distinct nonoverlapping regions of wavelengths are incident upon a sample surface, diffusely reflected radiation is collected, and the analyte concentration is determined via chemometric techniques.
Specular reflectance R. Messerschmidt, D. Sting Blocker device for eliminating specular reflectance from a diffuse reflectance spectrum, U.S. patent no. 4,661 ,706 (April 28, 1987) describe a reduction of specular reflectance by a mechanical device. A blade-like device "skims" the specular light before it impinges on the detector. A disadvantage of this system is that it does not efficiently collect diffusely reflected light and the alignment is problematic.
R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. patent no. 5,636,633 (June 10, 1997) describe a specular control device for diffuse reflectance spectroscopy using a group of reflecting and open sections.
R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. patent no. 5,935,062 (August 10, 1999) and R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. patent no. 6,230,034 (May 8, 2001) describe a diffuse reflectance control device that discriminates between diffusely reflected light that is reflected from selected depths. This control device additionally acts as a blocker to prevent specularly reflected light from reaching the detector. Malin, supra, describes the use of specularly reflected light in regions of high water absorbance, such as 1450 and 1900 nm, to mark the presence of outlier spectra wherein the specularly reflected light is not sufficiently reduced.
K. Hazen, G. Acosta, A. Abul-Haj, R. Abul-Haj, Apparatus and method for reproducibly modifying localized absorption and scattering coefficients at a tissue measurement site during optical sampling, U.S. patent no. 6,534,012 (March 18, 2003) describe a mechanical device for applying sufficient and reproducible contact of the apparatus to the sampling medium to minimize specular reflectance. Further, the apparatus allows for reproducible applied pressure to the sample site and reproducible temperature at the sample site.
Temperature
K. Hazen, Glucose Determination in Biological Matrices Using Near-Infrared Spectroscopy, doctoral dissertation, University of Iowa (1995) describes the adverse effect of temperature on near-infrared based glucose concentration estimations. Physiological constituents have near-infrared absorbance spectra that are sensitive, in terms of magnitude and location, to localized temperature and the sensitivity impacts noninvasive glucose concentration estimation.
Pressure
E. Chan, B. Sorg, D. Protsenko, M. O'Neil, M. Motamedi, A. Welch, Effects of compression on soft tissue optical properties, IEEE Journal of Selected Topics in Quantum Electronics, Vol. 2, no. 4, pp.943-950 (1996) describe the effect of pressure on absorption and reduced scattering coefficients from 400 to 1800 nm. Most specimens show an increase in the scattering coefficient with compression.
K. Hazen, G. Acosta, A. Abul-Haj, R. Abul-Haj, Apparatus and method for reproducibly modifying localized absorption and scattering coefficients at a tissue measurement site during optical sampling, U.S. patent no. 6,534,012 (March 18, 2003) describe in a first embodiment a noninvasive glucose concentration estimation apparatus for either varying the pressure applied to a sample site or maintaining a constant pressure on a sample site in a controlled and reproducible manner by moving a sample probe along the z- axis perpendicular to the sample site surface. In an additional described embodiment, the arm sample site platform is moved along the z-axis that is perpendicular to the plane defined by the sample surface by raising or lowering the sample holder platform relative to the analyzer probe tip. The '012 patent further teaches proper contact to be the moment specularly reflected light is about zero at the water bands about 1950 and 2500 nm.
Coupling Fluid
A number of sources describe coupling fluids with important sampling parameters.
Index of refraction matching between the sampling apparatus and sampled medium to enhance optical throughput is known. Glycerol is a common index matching fluid for optics to skin.
R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. patent no. 5,655,530 (August 12, 1997), and R. Messerschmidt Method for non-invasive blood analyte measurement with improved optical interface, U.S. patent no. 5,823,951 (October 20, 1998) describe an index-matching medium for use between a sensor probe and the skin surface. The index-matching medium is a composition containing both perfluorocarbons and chlorofluorocarbons.
M. Robinson, R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. patent no. 6,152,876
(November 28, 2000) and M. Rohrscheib, C. Gardner, M. Robinson, Method and apparatus for non-invasive blood analyte measurement with fluid compartment equilibration, U.S. patent no. 6,240,306 (May 29, 2001) describe an index-matching medium to improve the interface between the sensor probe and skin surface during spectroscopic analysis. The index-matching medium is preferably a composition containing chlorofluorocarbons with optional added perfluorocarbons.
T. Blank, G. Acosta, M. Mattu, S. Monfre, Fiber optic probe guide placement guide, U.S. patent no. 6,415,167 (July 2, 2002) describe a coupling fluid of one or more perfluoro compounds where a quantity of the coupling fluid is placed at an interface of the optical probe and measurement site. Perfluoro compounds do not have the toxicity associated with chlorofluorocarbons.
M. Makarewicz, M. Mattu, T. Blank, G. Acosta, E. Handy, W. Hay, T. Stippick, B. Richie, Method and apparatus for minimizing spectral interference due to within and between sample variations during in-situ spectral sampling of tissue, U.S. patent application ser. no. 09/954,856 (filed September 17, 2001) describe a temperature and pressure controlled sample interface. The means of pressure control are a set of supports for the sample that control the natural position of the sample probe relative to the sample.
Positioning
E. Ashibe, Measuring condition setting jig, measuring condition setting method and biological measuring system, U.S. patent no. 6,381 ,489, April 30, 2002 describes a measurement condition setting fixture secured to a measurement site, such as a living body, prior to measurement. At time of measurement, a light irradiating section and light receiving section of a measuring optical system are attached to the setting fixture to attach the measurement site to the optical system. J. Roper, D. Bocker, System and method for the determination of tissue properties, U.S. patent no. 5,879,373 (March 9, 1999) describe a device for reproducibly attaching a measuring device to a tissue surface.
J. Griffith, P. Cooper, T. Barker, Method and apparatus for non-invasive blood glucose sensing, U.S. patent no. 6,088,605 (July 11 , 2000) describe an analyzer with a patient forearm interface in which the forearm of the patient is moved in an incremental manner along the longitudinal axis of the patient's forearm. Spectra collected at incremental distances are averaged to take into account variations in the biological components of the skin. Between measurements rollers are used to raise the arm, move the arm relative to the apparatus and lower the arm by disengaging a solenoid causing the skin lifting mechanism to lower the arm into a new contact with the sensor head.
T. Blank, G. Acosta, M. Mattu, S. Monfre, Fiber optic probe placement guide, U.S. patent no. 6,415,167 (July 2, 2002) describe a coupling fluid and the use of a guide in conjunction with a noninvasive glucose concentration analyzer in order to increase precision of the location of the sampled tissue site resulting in increased accuracy and precision in noninvasive glucose concentration estimations.
T. Blank, G. Acosta, M. Mattu, M. Makarewicz, S. Monfre, A. Lorenz, T. Ruchti, Optical sampling interface system for in-vivo measurement of tissue, world patent publication no. WO 2003/105664 (filed June 11 , 2003) describe an optical sampling interface system that includes an optical probe placement guide, a means for stabilizing the sampled tissue, and an optical coupler for repeatably sampling a tissue measurement site in-vivo.
Targeting G. Lucassen, G. Puppels, P. Caspers, M. Van Der Voort, E. Lenderink, M. Van Der Mark, R. Hendricks, J. Cohen, Analysis of a composition, U.S. patent no. 6,609,015 (August 19, 2003); G. Lucassen, R. Hendricks, M. Van Der Voort, G. Puppels, Analysis of a composition, U.S. patent no. 6,687,520 (February 3, 2004); G. Lucassen, G. Puppels, M. Van Der Voort, Analysis Apparatus and Method, WIPO publication no. WO 2004/058058 (filed December 4, 2003); F. Schuurmans, M. Van Beek, L. Bakker, W. Rensen, B. Hendricks, R. Hendricks, T. Steffen, Optical analysis system, WIPO publication no. WO 2004/057285 (filed December 19, 2003); G. Lucassen, G. Puppels, M. Van Der Voort, R. Wolthuis, Apparatus and method for blood analysis, WIPO publication no. WO 2004/070368 (filed January 19, 2004); R. Hendricks, G. Lucassen, M. Van Der Voort, G. Puppels, M. Van Beek, Analysis of a composition with monitoring, WIPO publication no. WO 2004/082474 (filed March 15, 2004); M. Van Beek, C. Liedenbaum, G. Lucassen, W. Rensen Catheter head, WIPO publication no. WO 2004/093669 (filed April 23, 2004); and M. Van Beek, J. Horsten, M. Van Der Voort, G. Lucassen, P. Caspers, Method and apparatus for determining a property of a fluid which flows through a biological tubular structure with variable numerical aperture, WIPO publication no. WO 2005/009236 (filed July 26, 2004) describe a monitoring (targeting) system used to direct a Raman excitation system to a blood vessel.
DEFINITIONS
Noninvasive: A wide range of technologies serve to analyze the chemical make-up of the body. These techniques are broadly categorized into two groups, invasive and noninvasive. Herein, a technology is referred to as invasive if the measurement process acquires any biosample from the body for analysis or if any part of the measuring apparatus penetrates through the outer layers of skin into the body. Noninvasive procedures do not penetrate into the body or acquire a biosample outside of their calibration and calibration maintenance steps.
Coordinate system: Herein, positioning and attitude are defined. Positioning is defined using a x-, y-, and z-axes coordinate system relative to a given body part. For example, an x,y,z-coordinate system is used to define the sample site, movement of objects about the sample site, changes in the sample site, and physical interactions with the sample site. A relative x-, y-, z- axes coordinate system is used to define a sample probe position relative to a sample site. The x-axis is defined along the length of a body part and the y- axis is defined across the body part. As an illustrative example using a sample site on the forearm, the x-axis runs between the elbow and the wrist and the y-axis runs across the axis of the forearm. Similarly, for a sample site on a digit of the hand, the x-axis runs between the base and tip of the digit and the y-axis runs across the digit. The z-axis is aligned with gravity and is perpendicular to the plane defined by the x- and y-axis. Further, the orientation of the sample probe relative to the sample site is defined in terms of attitude. Attitude is the state of roll, yaw, and pitch. Roll is rotation of a plane about the x-axis, pitch is rotation of a plane about the y-axis, and yaw is the rotation of a plane about the z-axis. Tilt is used to describe both roll and pitch.
There exists a need in noninvasive technologies for controlling optical based sampling methods to minimize collection of specularly reflected light, for minimizing collection of stray light, and for minimizing sampling related changes resulting from sample site deformation. For optical sampling of a deformable object, it would be desirable to provide a method and apparatus that automatically reduces the effects of non-contact and excessive contact of the sample during sampling.
SUMMARY OF THE INVENTION
The invention relates to a method and apparatus for performing noninvasive analyte property determination. More particularly, the invention relates to determining proximity and/or contact of an optical sample probe with skin tissue. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a block diagram of a control system;
Figure 2 is a block diagram of a qualification system;
Figure 3 is a block diagram of a conductive contact system;
Figure 4 provides an electrical schematic of a conductive contact system;
Figure 5 is a flow diagram of a qualification / monitoring system;
Figure 6 provides exemplary contact response data as a function of time/position;
Figure 7 provides exemplary contact response data as a function of time/position;
Figure 8 provides exemplary contact response data as a function of time/position;
Figure 9 illustrates a sample probe configured with capacitive sensors;
Figure 10 illustrates a first capacitive sensor probe circuit;
Figure 11 illustrates a second capacitive sensor probe circuit; and Figure 12 illustrates a sample probe tip configured with capacitive sensors.
DETAILED DESCRIPTION OF THE INVENTION The invention comprises a method and apparatus for directing proximate contact of a sample probe of a noninvasive analyzer or noninvasive spectrometer with a skin tissue sample.
Herein, methods and apparatus for estimating glucose concentration from noninvasive spectra are used as a specific example of the invention.
However, the invention generally applies to sampling any deformable matrix and/or to sampling any sample having a diffusely reflecting sample site surface. A deformable matrix has fluid like properties that conforms to the shape of a contacting surface. For example, skin tissue conforms to the shape of a sample probe tip during a timescale of collecting a noninvasive scan, such as about one to sixty seconds with an applied pressure of less than 0.02 pounds per square inch.
TISSUE DISPLACEMENT CONTROL Displacement of the tissue sample by the sample probe results in changes in noninvasive spectra. Displacement of the sample tissue is related to pressure applied to the sample tissue. However, as the tissue is deformed the return force applied by the tissue sample to the sample probe varies. Therefore, it is preferable to discuss that sample / tissue interaction in terms of displacement instead of pressure.
Displacement of the tissue sample by the sample probe is preferably controlled between an insufficient and excessive displacement or pressure.
Insufficient contact of the sample probe with the tissue sample is detrimental. The surface of the skin tends to be rough and irregular. Insufficient contact results in a surface reflection. Contact between the sample probe and the tissue sample minimizes air pockets and reduces optical interface reflections that contain no useful information. Contact or close proximity of the sample probe tip to the sample site preferably provides good optical transmission of source illumination into the capillary layer where the analytical signal exists while minimizing reflections from the surface of the skin that manifest as noise. Excessive displacement of the tissue sample by the sample probe is detrimental. For noninvasive glucose concentration determination using near- infrared spectroscopy, the primary region of interest for measurement of blood borne analytes is the capillary bed of the dermis region, which is approximately 0.1 to 0.4 mm beneath the surface. The capillary bed is a compressible region and is sensitive to pressure, torque, and deformation effects. The accurate representation of blood borne analytes that are used by the body through time, such as glucose, relies on the transport of blood to and from the capillary bed, so it is not preferable to restrict this fluid movement. Therefore, contact pressure/displacement is preferably minimal so as not to excessively restrict or to partially restrict for an extended period of time flow of blood and interstitial fluids to the sampled tissue region. Preferably, a tip of a sample probe is displaced less than about 0.1 millimeters into the deformable skin/tissue sample matrix.
MULTIPLE SENSORS
In one embodiment of the invention, two or more signals or signal types are used in the process of positioning a sample probe tip relative to a sample site. For example a first signal is used to position the sample probe coarsely relative to the sample site and a second sensor is used to control sample probe positioning at a closer distance to the sample site. Optionally, a third sensor is used to still more finely position the sample probe tip relative to the sample site.
For example, after manual positioning the sample probe, even at instrument setup, positioning is performed using one or more sensors. Each of the sensors provides a distinct signal. For instance, one sensor is based upon a vision system, a second uses a capacitance reading while a third is generated from a conductance and/or optical signal. Different sensors are used for different levels of positioning. Generally as positioning goes from gross alignment to fine alignment:
• distance between a sample probe tip and a sample site decreases;
• different sensors are used as input at different distances between the sample probe tip and the sample site;
• precision of positioning increases; and
• different sensors or associated positioning algorithms are used at various levels.
This system allows for various sensors that are best used to estimate position of the sample probe at different distances from the sample site to be used serially or in a parallel fashion. For example, a first sensor is used for coarse alignment. Examples include:
• machine vision;
• a targeting / vision system; and
• use of a fluorescence tag.
Generally, the first sensor is used to bring the tip of the sample probe into a coarse position relative to the sample site. The first sensor is for example used to move the sample probe in the range of about 0.2 to 10+ mm from the sample site. Examples of a targeting / vision system are provided, infra. A second sensor, such as a capacitance sensor, is optionally used with or without a first sensor. The second sensor provides a signal distinct from the signal from the first sensor. The second sensor is used to estimate distances of the sample probe tip to the sample site that are generally smaller than the first sensor, described supra. For example, the second sensor is used in positioning the sample probe in a range of about 0 to 1 mm from the sample site or ranges therein. Examples of a capacitance sensor are described, infra. An example of a third sensor is a conductance sensor. Preferably a conductive sensor is used in positioning a sample probe tip at distances less than one-tenth of a millimeter from a sample tissue site. Each of the sensor types are used individually or in combination.
For example, a sample probe is placed near a sample site. Initially, a capacitive sensor provides a time constant to the controller. The controller uses the time constant to determine distance between the tip of the sample probe and the sample site. The controller then sends a signal to one or more actuators that reposition the sample probe. Typically, the capacitive sensor signaling process is iterated and the sample probe tip is moved toward the sample site. As the tip of the sample probe approaches the sample site, two or more capacitive sensors yield corresponding time constants that are used by the controller to determine the tilt of the sample probe relative to the surface of the sample site. The controller sends directions to one or more actuators to adjust the sample probe. Typically, this second iterative process is repeated until the surface of the sample probe tip is about parallel to the sample site surface. One or both of the first and second iterative processes are repeated either sequentially or in parallel. A third sensor, such as an optical sensor or a conductive sensor, yields a signal interpreted by the controller to yield a decision about fine movement of the sample probe relative to the sample site, typically in terms of z-axis position as tilt was previously adjusted. This process iteratively uses optical signal to finely position the sample probe tip in contact with or in proximate contact with the sample site surface.
Herein, the first process uses sensor 1 to control z-axis position; the second process uses sensor(s) 2 to control the tilt of the sample probe relative to the tissue sample site; and the third process uses sensor 3 to finely position the sample probe tip into proximate contact or contact with the sample site. In another example, a targeting / vision system is used to initially position a sensor relative to the sample site, such as in the x- and y- axes. A second sensor is then used to adjust the probe, such as in tilt of the sample probe relative to a sample site and/or distance between the sample probe tip and the sample site. Optionally, a third sensor is used to finely control the sample probe tip, such as to proximate contact with, initial contact to, and/or displacement into a sample site.
A targeting system is used to position a measuring system, such as an optical probe of a noninvasive glucose concentration analyzer. A targeting system targets a tissue area or volume of a sample. For example, a targeting system targets a surface feature, one or more volumes or layers, and/or an underlying feature, such as a capillary or blood vessel. The measuring system preferably contains a sample probe, which is optionally separate from or integrated into the targeting system. The sample probe of the measuring system is preferably directed to the targeted region or to a location relative to the targeted region either while the targeting system is active or subsequent to targeting. A controller is used to direct the movement of the sample probe in at least one of the x-, y-, and z-axes via one or more actuators. Optionally the controller directs a part of the analyzer that changes the observed tissue sample in terms of surface area or volume. The controller communicates with the targeting system, measuring system, and/or controller. A targeting system is further described, infra.
SAMPLE PROBE PLACEMENT
Controlled positioning of a tip of an optical probe with a skin tissue sample site is required for precise and accurate noninvasive analyte property determination, such as determination of glucose or urea concentration in blood and/or tissue. In order to avoid detrimental stray light and further to avoid detrimental sampling induced errors resulting from displacement of a portion of the tissue sample by the optical probe, it is desirable to control the motion and/or position of the tip of an optical probe so that the optical probe is in proximate contact with the tissue sample. Ideally, the tip of the optical probe is positioned in a manner allowing both the amount of collected specularly reflected light and the degree of sample probe movement induced change in the optically sampled tissue volume to not degrade analytical performance of the analyzer beyond acceptable error limits. The effects of applied pressure to the tissue sample site are further described, infra.
Control of a portion of an analyzer, such as the tip of an optical probe, preferably uses a signal indicative of the relative distance between the optical probe tip and the skin tissue sample site. A variety of signals are optionally used separately or in combination in positioning the optical probe relative to the sample site, including use of any of:
• an electrical signal; • an optical signal; and
• a capacitive signal.
An example of an electrical signal is conductance and/or resistance between a voltage source and the skin tissue site, typically measured with a current flow. Examples of optical signals include use of the optical signal used by the analyzer in determination of the analyte property and/or use of a visualization system, such as a camera. Further descriptions of electrical, optical, and capacitive sensors are provided, infra.
POSITIONING
An algorithm controls the sample probe placement and/or orientation relative to a sample site in a dynamic and/or static fashion. In various embodiments, the sample probe tip relative to a sample site is controlled with respect to one or more of: • x-axis position; • y-axis position;
• z-axis position;
• rotational orientation; and
• tilt.
Precise and/or accurate positioning of a sample probe tip with a sample site is beneficial to analyte property determination. For example, x- and y- axis positioning is used to sample the same location on a sample. As a further example, z-axis positioning is used to position the probes to ensure minimal collection of spectrally reflected light and/or to provide any of:
• proximate contact of a sample probe tip with a sample site;
• contact of a sample probe tip with a sample site; and
• displacement of a sample probe tip into a deformable sample site.
Tilt control is used to prevent excessive skin stretch when a flat surface, such as a sample probe tip or a guide, is brought into contact with a deformable sample site, such as tissue where tissue is often irregular and has generally non-flat measurement topology. Tilt control allows the sensing portion of an sample probe, such as a center of an optical probe tip, to be brought into contact with a sample site without displacement and hence stretching of nearby skin by the edges of the optical probe as the sample probe tip is brought into contact at an angle normal to the irregular sample surface.
CONTROL
In one embodiment of the invention, a contact, positioning, and/or contact sensor is used in control or positioning of analyzer relative to a tissue sample site. Preferably, a sample probe tip of the analyzer is positioned into proximate contact with the tissue sample site. Referring now to Figure 1 , an example of a control loop 10 for an analyzer 11 is presented. The analyzer has at least one part, such as a sample probe, that is moved into proximate contact or contact with a skin tissue sample 12. One or more inputs 13 for controlling the position of the sample control include any of:
• a conductive sensor system 17;
• a vision sensor system 14 sensing a sample feature or sample topology;
• an optical sensor system 15;
• a capacitive sensor system 16;
• an electromagnetic effect sensed from the material itself;
• an accelerometer;
• a transducer, such as a mechanical to electrical transducer; • a second optical system, such as a laser distancing and/or ranging system;
• a partial vacuum;
• a measured pressure; and
• an ultrasound signal.
At least one of the sensor systems provides input to an algorithm 19 that directs an actuator 19 that moves the relative position of the skin tissue sample and the analyzer.
Each of contact or positioning sensors are optionally integrated into the analyzer or are external to the analyzer. Each of the contact or positioning sensors are further described, infra. QUALIFICATION
When the sample probe, also referred to as a sample sensor probe, is placed in mechanical contact with the tissue measurement site, optical contact is not guaranteed but must be qualified. Acceptable optical contact is ascertained on the basis of one or more contact sensors, which surround or are in close proximity to the detection optic. As the sample probe is placed in mechanical contact with the skin tissue, a signal is generated by the contact sensor which indicates a contact event. For example, a conductive contact is detected when the signal changes from its mean level by an amount greater than two times the standard deviation of the noise.
The contact event leads the controller into a new mode of operation involving collection of the spectroscopic information that is used to make the noninvasive measurement, which is used for analyte property determination. The determination of the point at which the change in modes occurs is an important aspect of the invention and leads to superior quality of measurement.
Preferably, two or more of the above named sensor types are used cooperatively in positioning the sample probe of the analyzer relative to the sample. For example, the various sensor systems are used in control of the motion of the sample probe at different distances between a tip of the sample probe and the tissue sample. In a particular example, a target/vision system is used to find a tissue sample site to move the analyzer probe head toward, a capacitive sensor system is used to orient the tilt of the probe head to nominally match that of the skin surface at the sample site, the capacitive sensor is further used in positioning the sample probe head close to the sample site, and a conductive sensor system is used in fine positioning of the tip of the sample probe headed to distances of less than a tenth of a millimeter and preferably about a hundredth of a millimeter from the tissue sample site. Referring now to Figure 2, an example of a system 20 using two or more sensor position readings to position a sample probe tip relative to a sample site is presented. Initially a sensor probe of an analyzer 31 is positioned manually or through use of an actuator 10. A sensor position reading 22 and/or a noninvasive optical reading 23 are collected. The sensor position reading is optionally collected before, concurrently with, and/or after the noninvasive optical reading. In an iterative manner, one or both of the sensor position reading and the noninvasive optical reading 24 are used to reposition the sensor probe using the actuator 19. Optionally, the noninvasive reading is qualified for use in any of: a calibration model 25 and used for predicting 25 and analyte property.
In one case, a vision system 14 provides gross alignment, a capacitive sensor system 16 provides fine alignment, and a conductive sensor system 17 output is used to control very fine positioning of the sample probe, such as at distances of less than about 0.1 millimeter.
CONDUCTANCE SENSOR / CONDUCTANCE PROBE CONTROL
In another embodiment of the invention, completion of an electrical circuit is monitored in order to determine contact between a tip of a sample probe of an analyzer and a skin tissue sample. Referring now to Figure 3, a conductive contact sensing system 30 is used that includes at least a power supply 31 , such as a voltage source, replaceably interfaced to a skin tissue sample 12.
The voltage source is preferably a low voltage source, such as a source providing about 1 , 3, 6, or 12 volts. The voltage is converted to a current carried over one or more electrical conduits 33, 34 through an power meter
35, such as an ammeter. In this example, the circuit is initially open and is closed when the electrical conduits 33, 34 are brought into contact with the skin tissue 12, such as through one or more connections 36, 37. For example, current flows from the power source 31 to the skin through a first electrical conduit 33 and through a contacting element 36, such as a tip of a sample probe of an analyzer. In a first case, current returns to the voltage source via a separate electrical conduit 34, such as a conducting line. In this case, the first and second contacting elements 36, 37 are optionally contained in one housing or in two housings. In a second case, the current entering the skin tissue sample 32 completes an electrical circuit by passing to ground from the skin, the power supply also being grounded. In use, a change in current is observed when the circuit is completed. For example, the circuit is completed when the relative distance between the contacting element 36 and skin tissue 12 is reduced to a contacting distance of less than about 0.1 millimeter and typically to a distance of less than about 0.01 millimeters.
Referring now to Figure 4, a second example of a conductive contacting system 30 is provided. In this example, the power supply 31 , such as a bias voltage of about six volts, is an input to an operational amplifier 41. The voltage is converted to current across a resistor 42, such as resistor of about 100 MOhm resistance. When the circuit is completed by contacting the arm, the current flows into the arm. The decreased resistance to current flow upon contact with the arm results in an increase in the observed signal. Preferably, the observed current is compared with the bias current using a differential amplifier 44 and the resulting signal is converted to a voltage at an analog to digital converter 45. Optionally, the bias current is filtered using a low pass filter 43, such as a 2.5 Hertz low pass filter.
Referring now to Figure 5, a flowchart of an example of use of a sample probe 40 is provided. In this example, a conductive sensor system is described, which is illustrative of any of the sensor systems described herein used individually or in combination. Initially, tissue movement 51 of the sample relative to the sample probe is performed. The sample probe is moved 41 and contact between the sample probe and tissue sample is sought 42 using a contact sensor, such as any described herein. This process is iterative or the sensing signal is sought while the sample probe is moved. Upon contact, acquisition of data commences. Alternatively, data is additionally acquired as contact between the sample probe and tissue sample is sought. At this point, the sample probe:
• continues toward the sample and minimally displaces tissue volume; • stops;
• in position controlled using a contact sensing feedback signal; and
• is iterative backed away and toward the tissue providing reestablished contact.
For example, a contact qualification monitoring system 50 is used to determine contact or proximate contact of the sensor system with a tissue sample. The conductive sensor provides a feedback signal to a controlling algorithm or actuator telling the analyzer when to stop moving the sample probe. Spectral data is acquired is acquired during the contact sensing process and/or after contact is established. The contact sensing process is also referred to herein as a hunt process. Optionally, once contact is determined, the conductive sensor system acts as a system for monitoring continued contact. If contact is lost, the analyzer is preferably directed to reestablish contact between the optical probe and the tissue sample. The spectral data acquisition system, conductive contact determination/monitoring system, and actuator movement system are optionally used serially, iteratively, and/or in parallel with each other.
Referring now to Figure 6, a current monitored contact event between an analyzer and a skin tissue sample is demonstrated. In this example, a sample probe of an analyzer is moved toward a skin tissue sample as a function of time. A response of a conductive contact sensor is provided as the sample probe moves. Initially, a bias voltage from an analog to digital converter is obtained, which is nominally flat as a function of time. As contact is achieved between the tip of the sample probe and the skin tissue, the observed voltage rises rapidly to a new level. Once full contact is made, the returned voltage stabilizes at a new level. Both the slope of the rising response curve and the difference between the initial and final observed voltages are indicative of the contacting event. The high slope between the bias and stabilized voltage is indicative of the contact event occurring over a short time period. The difference is indicative of the quality of the contact and also of the state of the skin tissue. For example, a fully hydrated skin sample will yield a larger difference than a poorly hydrated skin sample. The current magnitude also provides information about the contact event, such as a coupling fluid thickness between the skin and the probe. For instance, since FC-40 has a high resistance, the observed contact current increases as the thickness of the FC40 layer on the skin decreases.
Referring now to Figure 7, another example of a sample probe having both an optical sampling system and a electrical contact monitoring system is provided. Figure 7 illustrates the conductive contact event as a tip of the sample probe is moved into contact with skin tissue. In this example, the slope of the rising response curve is illustrative of conductive contact being made over a longer time period, such as occurs when the skin sample stretches as the tip of the sample probe hits the skin surface. As a result, the sample probe further displaces the tissue before a stabilized contact is obtained. Selection of later optical samples collected when the electrical contact is stabilizing with acceptable contact allows calibration and/or prediction using the optical samples where good contact between the sample probe and skin tissue sample is present. This process yields samples with smaller changes in optically sampled tissue volume as a function of time. The selection of samples based upon the electrical contact sensor response thus leads to selection of prediction samples bounded by calibration data, thereby leading to more robust, accurate, and precise analyte property estimations. The use of one or more contact responses in selection of corresponding optical samples for use in calibration and/or prediction is further described, infra. The use of the conductive contact response in selection of corresponding optical samples for use in calibration and/or prediction is beneficial. For instance, only optical samples having full contact are selected for calibration and/or prediction. Alternatively, samples are selected having any contact, such as samples having a conductive contact response greater than the initial bias voltage plus two times the noise of the initial non- contacting samples. The use of conductive contact is also useful data in determining validity of an optical contact metric, as described infra.
Referring now to Figure 8, yet another example of a conductive contact sensor response is provided. In this example, the tip of an optical sample probe, configured with a conductive contact sensor, is moved toward a skin tissue sample. Initially, no contact is made. At sample number eighteen initial contact is made; full contact is made within a few additional samples. The observed voltage response of the conductive contact sensor subsequently fell due to loss of contact. Falling contact voltages result from a number of scenarios, such as skin movement, skin slipping or sagging relative, or perturbation of the sample by the probe. Subsequently, the sample probe tip was repositioned and the conductive contact sensor indicates when contact is reestablished after moving the probe, such as by monitoring the response voltage until movement of the sample probe brings the response back up to a contact level meeting specification or to a full contact level. In this case, the sample probe was moved toward the skin to regain full contact.
In yet another example, a current-measurement contact sensor is placed adjacent to or surrounding an optical detection fiber. A metal tube can surround the optical fiber and the contact sensor uses the tube for its measurement interface. When the metal tube shows contact, it is determined that the tip of optical collection means, such as the end of a fiber optic, is also making contact and the measurement may be made. The tip of the sample probe is preferably driven into the tissue sample along the z-axis a small amount, such as about 25 to 200 μm, in order to ensure the probe is in contact with the skin throughout the duration of the measurement. In yet another example, sensors are placed at away from the center of the tip of the sample probe. The circumferentially distributed contact sensors are used to indicate when the probe comes down at an angle and a corner of the tip of the sample probe contacts the skin tissue before the center of the sample probe. These contact sensors are optionally in a ring that indicates contact at any point around the probe or are sensors that indicate contact at specific locations, such as at corners or edges of the tip sample probe. Alternatively, sensors are placed along each of the axial, y-axis, and longitudinal axis, x-axis of a body part so that the phasing of the sensors contacting in time may be analyzed to help interpret the geometry changes occurring during the contact event. A single circuit is preferably multiplexed with multiple sensors to minimize the amount of additional cabling required with additional sensors.
Preferably, a current reading from a given sensor is be taken before contact to establish a baseline. The current is periodically monitored during a measurement sweep and more frequently as the probe approaches the arm in order to prevent a crash into skin due the probe stopping too late. In a realtime hunting scenario, such as samples collected at about five Hz as the probe approaches the arm, the contact-current is compared to the intensity at about 1290 or about 1450 nm returning from the arm or to capacitance measurements to assess the approach of the probe to the arm and slow its descent as necessary.
In yet another embodiment of the invention, a conductive sensor around the perimeter of the optical detection fiber is used to identify measurements and scans within a dynamic measurement that have intimate contact between the skin and the optical detection fiber. Such a sensor is used to control the dynamics of probe contact and/or to select the scans with the most intimate contact for use in calibration and for qualifying prediction spectra.
CAPACITIVE SENSOR / CAPACITANCE PROBE CONTROL In yet another embodiment of the invention, capacitance sensors or touch sensors are used for determining any of:
• tilt of a sample probe relative to a sample site;
• distance of a sample probe tip to a sample site; • x,y-position of a sample probe tip relative to a sample site;
• relative distance of a sample probe tip to a sample site; and
• contact of a sample probe tip with a sample site.
A capacitive sensor is used to adjust tilt of the sample probe relative to the sample site tissue morphology and/or in positioning of the tip of the sample probe in close proximity to the tissue sample. Preferably, a conductive sensor, as described supra, is used for determining contact and/or for positioning of the tip of the sample probe from distances of -0.05 to 0.1 mm from the nominal position of the skin tissue surface.
Referring now to Figure 9, Figure 9A is a side view of a sample module having a sample probe 902 having a sample probe tip 903 illustrated relative to a tissue sample or sample site. The sample probe 902 is illustrated with an optional collection optic 904, and two halves of two separate capacitance conductors 905, 906. An end view of the sample probe 902 is illustrated in Figure 9B.
Referring now to Figure 10, a circuit 1001 used to determine proximity of a subject's sample site to the sample probe is presented. The circuit includes a capacitor 1002 and a first resistor 1003. Here the capacitance, C, is calculated according to equation 1 , a
where capacitance, C, is proportional to the area, A, of the capacitor divided by the distance, d, between the capacitor plates. The capacitor has two plates. The first capacitor plate 1004 is integrated or connected to the sample module, preferably the sample module sample probe tip. The second capacitor 1005 is the deformable material, such as a skin sample, body part, or a the tissue sample site. The assumption is that the person is a capacitor.
A typical adult has a capacitance of about 120 pF. Capacitance of different people or kids will vary. The time constant of the capacitor/resistor in Figure
10 is calculated according to equation 2,
T = RC (2)
where the time constant, T, is equal to the resistance, R, times the capacitance. Hence, the distance between the capacitor plates is calculated through the combination of equations 1 and 2 through the measurement of the circuit time constant. For example, the time constant is the time required to trip a set voltage level, such as about 2.2 volts, given a power supply of known power, such as about 3.3 volts. The time constant is used to calculate the capacitance using equation 2. The capacitance is then used to calculate the distance or relative distance through equation 1. For example, as a distance between a sample site, such as a forearm or digit of a hand, and the capacitor plate decreases, the time constant increases and the capacitance increases. The measure of distance is used in positioning the probe at or in proximate contact with the sample site without disturbing the sample site as described, infra.
Referring now to Figure 11 , an example of an enhancement of the circuit in Figure 10 is presented. A second circuit 1101 using the capacitance 1002 / resistor 1003 combination of the first circuit is enhanced to amplify the signal to noise using an operational amplifier 1102 and a second resistor 1103. The gain of the circuit is the ratio of the first resistor 1103 and the second resistor 1103. Optionally, the voltage between the wire leading to the operation amplifier and a surrounding tube/shell is held at or about zero to minimize parasitic capacitance of the long wire and/or to minimize changes in capacitance caused by changes in the environment. A microprocessor used to measure the time constant is attached to any of the circuits herein described.
In use, the distance or relative distance between the sample probe tip and the sample site is determined, preferably before the tip of the sample probe displaces localized sample site skin/tissue which, as described supra, can lead to degradation of the sample integrity in terms of collected signal-to-noise ratios and /or sampling precision. Examples are used to illustrate the use of the capacitance sensor in the context of a noninvasive analyte property determination.
In one example, the distance or relative distance between the sample probe tip and the sample site is determined using a single capacitor. The sample probe is brought into close proximity with the sample site using the time constant/distance measurement as a metric. In this manner, the sample probe is brought into close proximity to the sample site without displacing the sample site. Due to the inverse relationship between capacitance and distance, the sensitivity to distance between the sample site and the sample probe increases as the distance between decreases. The distance between the sample site and the tip of the sample probe is readily brought to a distance of less than about one millimeter. Capacitance sensors as used herein can also readily be used to place the sample probe tip with a distance of less than about 0.1 millimeter to the sample site. Optionally, a conductance sensor is subsequently used in positioning the sample probe tip at distances less than one-tenth of a millimeter from the undisturbed tissue sample site surface. In this example, multiple capacitors are optionally used to yield more than one distance reading between the sample probe tip and the sample site. Multiple capacitive sensors are optionally used to control tilt along x- and/or y- axes.
Sample Probe Orientation Control
Two or more capacitance sensors are optionally used for leveling the tip of the sample probe relative to the morphology of the sample site. The distance between the sample site and the probe tip is measured using two or more capacitor pairs. For example, Figure 11 shows a first and second capacitor plate in the sample probe tip. If one capacitor reads a larger distance to the sample site than the second capacitor, then the probe tip is moved to level the probe by moving the larger distance side toward the sample, the smaller distance side away from the sample, or both. The sample probe tip tilt or angle is either moved manually or by mechanical means, described infra.
Referring now to Figure 12, exemplary capacitance layouts on the tip of a sample probe are provided. Referring now to Figure 12A, four capacitance sensors 1201-1204 are used allowing for detection of tilt along the x-, y-, or x and y-axis by comparison of signal strength between two or more of the four sensors 1201-1204. Alternatively, signals from two or more capacitors are combined, such as via a summation or an addition. For example, signals from sensors 1201 and 1202 are combined and compared against the combined signals of sensors 1203 and 1204. The combined signals are used as a feedback to a controller controlling tilt, such as along the y-axis. Referring now to Figure 12B, four capacitance based sensors are placed at or near the surface of a probe tip. In this example, the sensors are placed along the x- and y-axis for ease in determining x- and y-axis level of the sensor probe. Referring now to Figure 12C, two capacitance sensors 1201 , 1203 are shown off axis on a round sample probe tip. Referring now to Figure 12D, five capacitance sensors 1201-1205 are shown that vary in position along a single direction, the x-axis as shown. As orientated, the five sensors are used to detect tilt of the sample probe relative to the sample site and/or proximity of the sample probe tip to the sample site. Generally, any number of capacitance sensors are used in any geometric configuration on, near, or within a sample probe tip of any geometry.
Capacitive sensors have multiple advantages including: cost, response time, weight, size, and sensitivity. In addition, for biomedical applications, the capacitance sensors are optionally embedded into the sample probe tip providing a dielectric barrier between the sensor and the subject, which is beneficial in terms of safety requirements, such as government regulatory requirements.
INFRARED SENSORS
In another embodiment of the invention, an optical sensor, such as an infrared sensor, is used to detect distance between a sample probe tip and a sample, tilt of a sample probe relative to a sample, and/or contact or proximate contact of a sample probe tip with a sample site. The optical sensors are optionally configured in the orientation of any of the above described orientations of the capacitance proximity sensors, such as at or near the edges of the sample probe tip. Each of the optical sensors includes an illumination source and a detector. The source is optionally independent for each sensors, such as through one or more light emitting diodes. Alternatively, two of more of the sensors share a common source, such as a single light emitting diode or an incandescent source, such as a tungsten halogen lamp. The detectors are optionally placed within the sample probe tip, near the sample probe tip, or at a distance from the sample probe tip. In the later case, light is coupled to the detector via optics, such as fiber optics. The optical sensors are preferably used to detect contact or near contact of the sample probe tip with the sample through the use of over absorbed wavelengths in human tissue, such as about 1450 nm where the surface reflection intensity dominates over signal returning via scattering from within the tissue sample. In one mode, the sample probe is moved down the z-axis until the specular light approaches zero. Movement of the sample probe is as described using the capacitance sensor and includes movement under manual control or automated control with or without the use of one or more actuators and with or without a feedback sensor and controller. In a second mode, as surface reflection intensity is known to be a function of distance, the surface intensities from two or more optical sensors are compared in order to determine relative tilt of the sample probe relative to the tissue sample and the information used to adjust tilt until near tangential contact is achieved. In yet another mode, the optical signal, from the source of the analyzer that is detected by the detector used to generate a signal for subsequent an analyte property determination, is used to determine proximity to or contact of the sample probe tip with the sample site. For instance, the spectrum determined using photons gathered by the collection fiber is used to determine proximity of or contact of the sample probe with the tissue sample site.
An illustrative example of an optical probe is provided. Photons from a source are reflected off of a backreflector through a first optic and through a second optic to a sample, such as skin. The first optic is optionally used to remove unwanted emanating photons from the source that would otherwise optically heat the sample. The second optic passes light and is optionally used to stabilize any of: sample site topology, sample site hydration, and to mechanically stabilize or locate a collection optic, such as a fiber optic. In this example, detectors are used to detect light from the sensor source in order to control tilt of the sample probe relative to the sample and/or distance between the tip of the fiber optic and the sample.
VISION / TARGETING SENSOR PROBE CONTROL SYSTEM
A machine vision system 14 is used in determining a sample site and/or in reproducibly targeting a sample site, such as a determined sample site.
There exist a large number of targeting and measuring system configurations. Several exemplar embodiments are provided, infra. Some features of the configurations are outlined here. The targeting system and measuring system optionally use a single source that is shared or have separate sources. The targeting is optionally used to first target a region and the measuring system subsequently samples at or near the targeted region. Alternatively, the targeting and measuring system are used over the same period of time so that targeting is active during sampling by the measuring system. The targeting system and measuring system optionally share optics and/or probe the same tissue area and/or volume. Alternatively, the targeting and measuring system use separate optics and/or probe different or overlapping tissue volumes. In various configurations, neither, one, or both of the targeting system and measuring system are brought into contact with the skin tissue at or about the sample site. Finally, permutations and combinations of the strategies and components of the embodiments presented herein are possible.
The targeting system targets a target. Targets include any of:
• a natural tissue component;
• a chemical feature;
• a physical feature; • an abstract feature;
• a marking feature added to the skin;
• a skin surface feature;
• a measurement of tissue strain;
• tissue morphology; • a target below the skin surface;
• a manmade target;
• a fluorescent marker;
• a subcutaneous feature;
• a dermis thickness within a specification; • capillary beds;
• a capillary;
• a blood vessel; and
• arterial anastomoses.
Examples of marking features added to the skin include a tattoo, one or more dyes, one or more reflectors, a crosshair marking, and positional markers, such as one or more dots or lines. Examples of a skin surface feature include a wart, hair follicle, hair, freckle, wrinkle, and gland. Tissue morphology includes surface shape of the skin, such as curvature and flatness. Examples of specifications for a dermis thickness include a minimal thickness and a maximum depth. For example, the target is a volume of skin wherein the analyte, such as glucose, concentration is higher. In this example, the measuring system is directed to image photons at a depth of the enhanced analyte concentration.
A targeting system targets a target. A targeting system typically includes a controller, an actuator, and a sample probe. Examples of targeting systems include a planarity detection system, optical coherence topography (OCT), a proximity detector and/or targeting system, an imaging system, a two-detector system, and a single detector system. Examples of targeting system technology include impedence, acoustic signature, ultrasound, use of a pulsed laser to detect and determine distance, and the use of an electromagnetic field, such as radar and high frequency radio-frequency waves. Sources of the targeting system include a laser scanner, ultrasound, and light, such as ultraviolet, visible, near-infrared, mid-infrared, and far- infrared light. Detectors of the targeting system are optionally a single element, a two detector system, an imaging system, or a detector array, such as a charge coupled detector (CCD) or charge injection device or detector (CID). One use of a targeting system is to control movement of a sample probe to a sampling location. Axsecond example of use of a targeting system is to make its own measurement. A third use is as a primary or secondary outlier detection determination. In its broadest sense, one or more targeting systems are used in conjunction with or independently from a measurement system.
Different targeting techniques have different benefits. As a first example, mid- infrared light samples surface features to the exclusion of features at a depth due to the large absorbance of water in the mid-infrared. A second example uses the therapeutic window in the near-infrared to image a feature at a depth within tissue due to the light penetration ability from 700 to 1100 nm. Additional examples are targeting with light from about 1100 to 1450, about 1450 to 1900, and/or about 1900 to 2500 nm, which have progressively shallower penetration depths of about 10, 5, and 2 mm in tissue, respectively. A further example is use of visible light for targeting or imaging greater depths, such as tens of millimeters. Still an additional example is the use of a Raman targeting system, such as in WIPO international publication number WO 2005/009236 (February 3, 2005), which is incorporated herein in its entirety by this reference thereto. A Raman system is capable of targeting capillaries. Multiple permutations and combinations of optical system components are available for use in a targeting system.
Controller
A controller controls the movement of one or more sample probes via one or more actuators. The controller optionally uses an intelligent system for locating the sample site and/or for determining surface morphology. For example, the controller hunts in the x- and y-axes for a spectral signature. In a second example, the controller moves a sample probe via the actuator toward or away from the sample along the z-axis. The controller optionally uses feedback from the targeting system, from the measurement system, or from an outside sensor in a closed-loop mechanism for deciding on targeting probe movement and for sample probe movement. In a third example, the controller optimizes a multivariate response, such as response due to chemical features or physical features. Examples of chemical features include blood/tissue constituents, such as water, protein, collagen, elastin, and fat. Examples of physical features include temperature, pressure, and tissue strain. Combinations of features are used to determine features, such as specular reflectance. For example, specular reflectance is a physical feature optionally measured with a chemical signature, such as water absorbance bands centered at about 1450, 1900, or 2600 nm. Controlled elements include any of the x-, y-, and z-axis position of sampling along with rotation or tilt of the sample probe. Also optionally controlled are periods of light launch, intensity of light launch, depth of focus, and surface temperature. In a fourth example, the controller controls elements resulting in pathlength and/or depth of penetration variation. For example, the controller controls an iris, rotating wheel, backreflector, or incident optic, which are each described infra.
A targeting system used in combination with the positioning systems herein is further described in U.S. provisional patent application no. 60/656,727, which is incorporated herein its entirety by this reference thereto.
TISSUE STRESS / STRAIN
The controller moves the targeting probe and/or sample probe so as to make minimal and/or controlled contact with the sample to control stress and/or strain on the tissue, which is often detrimental to a noninvasive analyte property estimation. Strain is the elongation of material under load. Stress is a force that produces strain on a physical body. Strain is the deformation of a physical body under the action of applied force. In order for an elongated material to have strain there must be resistance to stretching. For example, an elongated spring has strain characterized by percent elongation, such as percent increase in length.
Skin contains constituents, such as collagen, that have spring-like properties. That is, elongation causes an increase in potential energy of the skin. Strain induced stress changes optical properties of skin, such as absorbance and scattering. Therefore, it is not desirable to make optical spectroscopy measurements on skin with varying stress states. Stressed skin also causes fluid movements that are not reversible on a short timescale. The most precise optical measurements are therefore conducted on skin in the natural strain state, such as minimally or non-stretched stretched skin. Skin is stretched or elongated by applying loads to skin along any of the x-, y-, and z- axes, described infra. Controlled contact reduces stress and strain on the sample. Reducing stress and strain on the sample results in more precise sampling and more accurate and precise glucose concentration estimations.
Effect of Displacement on Tissue Spectra
The displacement of the tissue sample by the sample probe results in compression of the sample site. The displacement results in a number of changes including at least one of:
• a change in the localized water concentration as fluid being displaced;
• a change in the localized concentration of chemicals that are not displaced such as collagen; and • a correlated change in the localized scattering concentration.
In addition, physical features of the sample site are changed. These changes include at least one of:
• compression of the epidermal ridge; • compression of the dermal papilla;
• compression of blood capillaries;
• deformation of skin collagen; and
• relative movement of components embedded in skin. Chemical and physical changes are observed with displacement of the sample probe into the tissue sample. The displacement of tissue is observed in spectra over a wide range of wavelengths from 1100 to 1930 nm. The displacement of tissue also effects a number of additional skin chemical, physical, and structural features as observed optically.
An example of using light to measure a physical property, such as contact, stress, and/or strain, in tissue is provided. Incident photons are directed at a sample and a portion of the photons returning from the sample are collected and detected. The detected photons are detected at various times, such as when no stress is applied to the tissue and when stress is applied to the tissue. For example, measurements are made when a sample probe is not yet in contact with the tissue and at various times when the sample probe is in contact with the tissue, such as immediately upon contact and with varying displacement of the sample probe into the tissue. The displacement into the tissue is optionally at a controlled or variable rate. The collected light is used to determine properties. One exemplary property is establishing contact of the sample probe with the tissue. A second exemplary property is strain. The inventors determined that different frequencies of light are indicative of different forms of stress/strain. For example, in regions of high water absorbance, such as about 1450 nm, the absorbance is indicative of water movement. Additional regions, such as those about 1290 nm, are indicative of a dermal stretch. The time constant of the response for water movement versus dermal stretch is not the same. The more fluid water movement occurs approximately twenty percent faster than the dermal stretch. The two time constants allow interpretation of the tissue state from the resultant signal. For example, the interior or subsurface hydration state is inferred from the signal. For example, a ratio of responses at high absorbance regions and low absorbance regions, such as about 1450 and 1290 nm, is made at one or more times during a measurement period. Changes in the ratio are indicative of hydration. Optionally, data collection routines are varied depending upon the determined state of the tissue. For example, the probing tissue displacement is varied with change in hydration. The strain measurement is optionally made with either the targeting system or measurement system. The tissue state probe describe herein is optionally used in conjunction with a dynamic probe, described infra.
In another embodiment of the invention, a coupling fluid is applied between the tip of the sample probe and the tissue sample site. It is determined that highly viscous coupling fluid degrade the noninvasive analyte determination system. A highly viscous coupling fluid requires increased pressure to be applied between the tip of a sample probe and a tissue sample site in order to displace the viscous coupling fluid. For example, Fluorolube is a viscous paste that is not readily displaced. The pressure required for the tip of the sample probe to displace the Fluorolube results in tissue stress and strain that degrades the analytical quality of the noninvasive signal. Therefore, less viscous coupling fluids are required, such as FC-70 or FC-40. The viscosity of the coupling fluid should not exceed that of FC-70 and preferably the viscosity of the coupling fluid should not exceed that of FC-40.
ANALYZER
Several exemplary systems are described, that are used in placing a tip of an optical probe of an analyzer relative to a tissue sample site. An overview of an analyzer having one or more of the contacting systems or used in combination with one or more of the contacting sensing systems is described, infra.
Herein, an analyzer comprises at least a source coupled via optics to a detector. In one embodiment, the analyzer is handheld. In a second embodiment, the analyzer sits upon a supporting surface during use. In a third embodiment, the analyzer is split having a base module physically separated from the sample module, where the sample module interfaces with the sample site during operational use. In the third embodiment, the base module is connected to the sample module via wireless communication, is connected via a communication bundle, or is connected through a semi-rigid weight support system, where the weight support system serves to support at least a portion of the weight of the sample module during use. The weight support system preferably operates as an automated positioning system or an actuation system. In the third embodiment, the communication bundle preferably carries any of: optical signal, data signal, power, electrical control signal, and a fluid between the base module and the sample module. In the third embodiment, the weight support system carries any of:
• optical signal;
• data signal; • power;
• electrical control signal; and
• a fluid between the base module and the sample module.
In the third embodiment, the analyzer is preferably a split analyzer where the weight support system additionally operates as a communication bundle. In any case, optical components, such as a source; backreflector; guiding optics; lenses; filters; mirrors; a wavelength separation device; and at least one detector, are optionally positioned in the base module and/or sample module.
Optionally, the noninvasive analyzer contains a base module interfaced to a sample module. The base module is any of:
• integrated with the sample module;
• physically coupled to the sample module through a communication bundle; and
• physically separated from the sample module and coupled with the sample module through wireless communication. The sample module interfaces with a sample. Means for analyzing collected data, such as spectra and subject data are preferably contained within or coupled to the base module.
Additional description of instrumentation configurations, calibration transfers, and data analysis techniques usable with this invention are described in U.S. patent application no. 10/870,727, filed June 16 2004 and U.S. patent application no. 10/472,856, filed March 7, 2003, both of which are incorporated herein in their entirety by this reference thereto.
Any of the embodiments described herein are operable in a home environment, public facility, or in a medical environment, such as an emergency room, critical care facility, intensive care unit, hospital room, or medical professional patient treatment area. For example, the split analyzer is operable in a critical care facility where the sample module is positioned in proximate contact with a subject or patient during use and where the base module is positioned on a support surface, such as a rack, medical instrumentation rack, table, or wall mount.
In one embodiment of the invention, at least a portion of the sample module is movable with respect to a subject or patient sample site along any of the x-, y- , and z-axes, and/or in terms of rotation or tilt. For example, the sample site, such as a forearm remains stationary while at least a portion of the analyzer, such as the sample probe head, moves to interface with the sample in terms of an X-, y-, and/or z-axis and/or with respect to rotation or tilt.
In another embodiment of the invention the components defining the optical train of an analyzer are moved as a unit to reposition the sample probe tip relative to a sample site. Moving the optical units of an analyzer together allows for fixed optics or optics with tighter constraints in terms of movement than a fiber optic. For instance moving the sample probe head to the sample does not change the collection optic pathway so that collection optics can spatially fixed or controlled in terms of optically coupling the tip of the fiber bundle to the detection element. In one case, optics in the optical train from the sample to the detector are moved together in a controlled fashion.
In yet another embodiment of the invention the analyzer is held in a fixed position while the tissue sample site is moved relative to the analyzer by moving a body part, such as with an adjustable platform, along any of the x-, y-, and z-axes, and/or in terms of rotation or tilt.
In any of the embodiments, the movable portion of the sample module moves in an active or passive manner. When the movable portion of the sample module moves in an active manner, a controller is preferably used to position the tip of the sample probe relative to a tissue sample site. For example, a command input is sent to an actuator system within the analyzer, where the actuator system is preferably in the sample module. The actuator system controls the position of a probe system having a sensor. The position is relative to a sample site. The signal from the sensor is either used in the measurement of an analyte property value of the sample or is used as input for a controller that sends additional input to the actuator system to further control position or movement of the probe system via the actuator system. The actuator system preferably contains electronics used in conjunction with electro-mechanical conversion of the movable aspect of the analyzer, such as the tip of the probe system within the sample module in terms of one or more of: x-position, y-position, z-position, tilt, and rotation of the sample probe tip relative to the sample site.
Sample Probe Movement
Movement of the sample probe is preferably performed using an electro- mechanical converter. After an initial command input, an actuator system is preferably controlled using a controller provided with signal from the probe system sensor. For example, if a capacitance sensor indicates that the probe tip is too far from the sample, an electro-mechanical converter is used to translate the sample probe along the z-axis toward the sample site. Similarly, if two capacitance signals from opposite sides of the sample probe tip indicate that the sample probe tip is not normal to the sample site, then one or more actuators are used to adjust the tilt of the sample probe or the level of the sample probe tip relative to the sample site surface. In one case, one or more sensors are used in combination with one or more actuators to control sample probe position in terms of any of:
• x-position; • y-position;
• z-position;
• tilt; and
• rotation.
Partial Vacuum
In combination with sample probe movement, when the tip of the sample probe is in proximate contact with the tissue sample site, a partial vacuum is optionally applied at or near the sample site. The partial vacuum pulls the skin into full contact with the sample probe tip. One benefit of this system is ease of use. A second benefit is that it allows the skin to have twitching movement without altering the optical sample site.
Liquid Lensing
As skin is a fluid with viscoelastic properties, the probe contact event is complicated by fluid drag properties that include contact inconsistencies in the contact at the measurement interface. One potential is for the development of liquid lensing of the optical fluid in the low pressure area near the optical detection fiber.
Feature Extraction One optional feature of the algorithm implemented in the analyzer is feature extraction. Feature extraction is used to qualify optical contact between a tip of a sample probe of an analyzer and a tissue sample. For example, the contact event of the measurement process is difficult to determine using optical methods as an optical signal used is a mixture of light that has been diffusely reflected from the arm and light that has been reflected from the arm as a first-surface reflector. This, along with dynamic nature of the skin makes it difficult to assign an absolute threshold that designates when contact has occurred. However, noninvasive spectra of human tissue contain features related to chemical and physical structures of the sampled tissue. For example, as optical contact is made the response signal in a region that is scattering dominated, such as about 1290 nm, increases in magnitude while the response signal in a region that is absorbance dominated decreases in value, such as at about 1450 nm. Thus, the ratio of two features or the change in direction of a magnitude of a feature as a function of distance between the sample probe and the tissue sample is an indicator of sample contact and is used to qualify the invention.
SAMPLE TOPOLOGY The interface to the skin tissue and related deformation is dependent upon the orientation of the contact surface to the skin tissue and the approach angle of the device probe as it contacts and deforms the skin. The problem is related to the necessity for optical contact between the probe optics and the skin surface. This contact is achieved by moving the optical interface into contact with skin surface and optionally displacing skin tissue as the point of optical contact recedes in response to the presence of the probe.
When the probe surface is angled relative to the contact point of the skin, there is a greater probability for tissue distortion since a portion of the probe necessarily hits the skin surface prior to proper optical contact.
Consequentially, a portion of the probe is likely to displace a greater portion of the skin tissue than desired, leading to a change in the scattering and absorption properties of the targeted measurement site.
The displacement and/or stretch of the tissue caused by a mismatch of the tissue surface and optical interface may lead to a push of interstitial fluid away from the point of measurement and/or a plastic deformation of the skin tissue. Both effects increase the level of spectral interference and reduce the signal to noise ratio of the measurement system.
The problem is especially severe in the case of a probe system which controls the z-axis (movement to and from the skin) on the basis of optical contact. When an angled probe relative to the skin is present, the actuator system may displace a significant volume of tissue in an effort to achieve the desired optical contact. The problem is exacerbated with the angle between the probe surface and skin varies from sample to sample. In this case both the scattering properties of the skin are varied in addition to effects related to tissue displacement.
Adjustment of the angle between the probe surface and the skin tissue measurement site (the "measurement angle") is accomplished either through a change in the orientation of the subject's body position, an in particular, the orientation of their forearm to the probe surface, the adjustment of the probe itself relative to the surface of the targeted point of measurement, the determination of a point of contact possessing a parallel point relative to the optical interface of the probe surface, or the tissue measurement site.
In the first case, the probe is relatively stationary and the subject's forearm is adjusted to achieve a measurement angle that is within the desired limits (plus or minus one degree). This is accomplished by a rotation of the arm and height adjustments of the subject's hand/wrist and elbow support systems. In particular, a hand/wrist and elbow support system is set up for a subject in a manner that achieves a near tangent point of measurement. When subsequent samples are collected, adjustments to the measurement angle are made by changing the angle of the subject's hand/wrist support system. The adjustments are made either manually by the patient on the basis of a display providing directions or through an automated feedback control system which detects the measurement angle through proximity sensors and directs an actuator to modify the angle of the wrist/hand support system.
Secondly, when the point of measurement and the patient interface module are set, the probe itself is adjusted to achieve a small measurement angle. In this case, the desired point of measurement has been located using criteria other than the measurement angle and therefore necessitate an adjustment of the probe to . The measurement angle is reduced by changing the orientation of the measurement probe itself. For example, a targeting system is employed to achieve a reproducible measurement site using either an adjustable forearm support system or an adjustable probe positioning system.
The location of the measurement site, however, leads to an unpredictable measurement angle due to changes in the subject's posture and arm placement. In this case, actuators are used, on the basis of the estimated measurement angle, to change the orientation of the probe itself such that a tangent point of contact occurs and optionally a z-axis displacement that is perpendicular to the probe surface.
In the third case, a point of tangency (measurement angle close to zero) is used to set the point of measurement by using a search algorithm on the basis of forearm topology. Several embodiments for this system are disclosed.
• The topology of the forearm is determined using an imaging system and a point of tangency determined by locating the measurement point extremum. • The topology of the forearm is mapped in the vicinity of the desired measurement site using proximity sensors. The measurement site is again determined as that point in which the slope relative to the probe surface is zero. In particular, on the bottom of the forearm the lowest point is determined as the point of measurement. The forearm can be mapped by moving proximity sensors across the surface or hunted for by repeatedly mapping a small region.
• The point of measurement is hunted for using a feedback control system which adjusts the x-y position of the probe on the basis of the measurement angle. In this case, the error in the measurement angle is used to direct movement of the probe in either x and/or y directions until either a suitable measurement angle is achieved or a failure occurs (actuator moves beyond x-y bounds). For example, a proximity sensor can be moved closed to the skin surface in the vicinity of the desired measurement site. The measurement angle in both the x and y axis is determined. The probe is then repeatedly moved in the direction that is likely to reduce the measurement angle. Specifically, the probe is moved in the direction opposite of the measurement angle. Although the magnitude of movement may be fixed, it has been determined to be more efficient to adjust the movement step size on the basis of both the measurement angle and prior adjustments and/or measurement angles in a manner similar to a gradient descent or conjugate gradient descent optimizer or alternately, a proportional- integral-derivative (PID) controller. • The point of measurement is controlled in one dimension and hunted for in the other to achieve a low measurement angle. In this embodiment only the y-axis (across the arm) is controlled to achieve a low measurement angle.
In the final case, the tissue volume itself is mechanically controlled or constrained in a manner that achieves a low measurement angle. CALIBRATION
Optical spectroscopic measurements of living human skin are used to calibrate an instrument to measure blood glucose concentration noninvasively. As a result of the surface roughness of skin and the optical index of refraction, n, variation between dry stratum corneum (n=1.58) and wet skin (n=1.42), air (n=1.0), and the FC40 optical coupling fluid (n=1.29), surface reflections lead to the rise of nonlinear stray light type effects. That is nonlinear effects result from incident light that is reflected off the sample and measured instead of being transmitted into the sample and diffusely reflected and measured. It is desirable that minimal stray light effects in both a calibration set of data and in prediction spectra are minimized as the absence of nonlinearity resulting from stray light leads to less complex, more robust calibrations and prediction data. Optionally, calibration models are built using data of a specified sample probe / tissue contact level. For example, highly contacting samples are used in a first calibration, mid-level contacting samples are used in a second calibration, and low-level contacting samples are used in a third calibration. Prediction spectra are subsequently classified into a contacting specification and applied to the corresponding calibration model.
Additional examples of the invention are any combination and/or permutation of the embodiments, examples, and/or obvious variants of the examples provided herein.
Those skilled in the art will recognize that the present invention may be manifested in a variety of forms other than the specific embodiments described and contemplated herein. Departures in form and detail may be made without departing from the spirit and scope of the present invention. Accordingly, the invention should only be limited by the Claims included below.

Claims

1. A method for determing an analyte property of a deformable matrix, comprising the steps of: moving a noninvasive sample probe into proximate contact with the deformable matrix, wherein said sample probe comprises a sample probe tip; establishing initial contact between said sample probe tip and the deformable matrix by detection of an electrical signal, wherein said electrical signal results from contact of said sample probe tip with the deformable matrix closing an electrical circuit; collecting an optical signal with said noninvasive sample probe; and analyzing said optical signal to determine said analyte property.
2. The method of Claim 1 , wherein the deformable matrix comprises a human tissue sample, wherein said optical signal comprises a near-infrared optical signal having at least one response signal in the range of 1100 to 2500 nm, and wherein said analyte property comprises a glucose concentration.
3. The method of Claim 1 , wherein said electrical signal comprises a conductance signal.
4. The method of Claim 1 , further comprising the step of: maintaining applied force between said sample probe tip and said deformable matrix at less than about 0.02 pounds per square inch during said step of collecting.
5. The method of Claim 1 , further comprising the step of: conforming said deformable matrix to a shape of said sample probe tip during said step of collecting.
6. The method of Claim 3, further comprising a step of: dynamically moving said sample probe tip relative to the deformable matrix based upon feedback from said conductance signal.
7. An apparatus for analyzing a deformable sample, comprising: a noninvasive analyzer having a sample probe, said sample probe having a sample probe tip; at least one optical fiber terminating at said sample probe tip; at least one conductance sensor with a terminating electrical contact at said sample probe tip; and means for using a signal from said conductance sensor to determine contact of said sample probe tip with the deformable sample.
8. The apparatus of Claim 7, wherein during use a response of said conductance sensor deviates upon contact of said sample probe tip with the deformable sample.
9. The apparatus of Claim 7, further comprising: at least one capacitance sensor embedded in said sample probe.
10. A noninvasive analyzer for analyzing a deformable sample, comprising: a noninvasive spectrometer comprising: a sample probe tip constituting a portion of said spectrometer; and an actuatorfor mechanically controlling position and attitude of said sample probe tip relative to the deformable sample based upon a first control signal that provides a first distance reading between said sample probe tip and the sample and a second control signal that provides a second distance reading between said sample probe tip and the sample,
11. The apparatus of Claim 10, said first control signal comprising an optical signal and said second control signal comprising a capacitive signal.
12. The apparatus of Claim 10, said first control signal comprising an optical signal and said second control signal comprising a conductance signal.
13. The apparatus of Claim 10, said first control signal comprising a capacitive signal and said second control signal comprising a conductance signal.
14. The apparatus of Claim 10, said first control signal comprising a machine vision signal and said second control signal comprising an optical signal.
15. The apparatus of Claim 10, said first control signal comprising a machine vision signal and said second control signal comprising a conductance signal.
16. The apparatus of Claim 10, said first control signal comprising a machine vision signal and said second control signal comprising a conductance signal.
17. The apparatus of Claim 13, said first distance comprising a distance greater than one-tenth of a millimeter and said second distance comprising a distance less than two-tenths of a millimeter.
18. The apparatus of Claim 17, said noninvasive spectrometer comprising an analyzer using at least four wavelengths in the region 1100 to 2500 nm.
19. The apparatus of Claim 18, said deformable sample comprising a skin/tissue matrix and wherein said apparatus yields an estimated glucose concentration.
20. A method of noninvasive analysis of a sample, comprising the step of: an actuator mechanically controlling position and attitude of a sample probe tip of an analyzer relative to the deformable sample based upon a first control signal and a second control signal, wherein said sample probe tip constitutes a portion of a noninvasive spectrometer, said actuator first using a first control signal that provides a first distance reading between said sample probe tip and the sample, and said actuator later using a second control signal that provides a second distance reading between said sample probe tip and the sample.
21. The method of Claim 20, said first control signal comprising an optical signal and said second control signal comprising a capacitive signal.
22. The method of Claim 20, said first control signal comprising an optical signal and said second control signal comprising a conductance signal.
23. The method of Claim 20, said first control signal comprising a capacitive signal and said second control signal comprising a conductance signal.
24. The method of Claim 20, said first control signal comprising a machine vision signal and said second control signal comprising an optical signal.
25. The method of Claim 20, said first control signal comprising a machine vision signal and said second control signal comprising a conductance signal.
26. The method of Claim 20, said first control signal comprising a machine vision signal and said second control signal comprising a conductance signal.
27. The method of Claim 23, said first distance comprising a distance greater than one-tenth of a millimeter and said second distance comprising a distance less than two-tenths of a millimeter.
28. The method of Claim 27, said noninvasive spectrometer comprising an analyzer using at least four wavelengths in the region 1100 to 2500 nm.
29. The method of Claim 28, said deformable sample comprising a skin/tissue matrix, said method yielding an estimated glucose concentration.
30. A method of qualifying a noninvasive spectrum of a skin tissue/blood sample collected with a noninvasive analyzer having a sample probe tip, comprising the steps of: iteratively collecting a sensor position reading; controlling with said sensor position reading position and attitude of said sample probe tip to achieve proximate contact of said sample probe tip with the sample; collecting an optical noninvasive signal; and qualifying adequacy of said noninvasive signal based upon said sensor position reading.
31. The method of Claim 30, said sensor position reading comprising a conductance signal.
32. The method of Claim 31 , said conductance signal deviating upon contact of said sample probe tip with the sample.
33. The method of Claim 30, said sensor position reading comprising a capacitance reading.
34. The method of Claim 30, said sample probe tip displacing into the sample a distance of less than one-tenth of a millimeter.
35. A method of noninvasively determining a glucose concentration from a skin tissue/blood sample using a noninvasive analyzer having a sample probe tip, comprising the steps of: iteratively collecting a sensor position reading; controlling said sensor position reading position and said sample probe tip attitude to achieve proximate contact of said sample probe tip with the sample; collecting an optical noninvasive signal; and qualifying said noninvasive signal for any of: use in a calibration; and use in prediction of said glucose concentration.
36. An apparatus for controlling distance between an analyzer and a skin tissue sample, comprising: an optical probe having a tip; means for moving said optical probe relative to the skin tissue sample; and means for determining electrical contact between the sample and said tip of said sample probe.
37. The apparatus of Claim 36, said means for determining electrical contact comprising: a voltage source; an ammeter electrically connected to said source; and an electrical conductor connecting said source to said tip of said optical probe.
38. The apparatus of Claim 36, said analyzer comprising any of: a noninvasive glucose concentration analyzer; and a urea concentration analyzer.
39. A method for controlling relative positioning of an analyzer with a skin tissue sample, comprising the steps of: moving an optical probe having a tip toward the skin tissue sample; measuring electrical resistance as a function of time during said step of moving; controlling said moving based on said electrical resistance; and determining electrical contact between said tip of said optical probe and the skin tissue sample.
40. The method of Claim 1 , wherein said step of moving moves said optical probe at least along a z-axis, said z-axis comprising an axis orthogonal to an x, y-place tangential to the skin tissue sample.
EP07863843A 2006-11-03 2007-11-02 Method and apparatus for noninvasive probe/skin tissue contact sensing Withdrawn EP2077750A4 (en)

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