I IIIII
`
`1111111111111111111111111111111111111111111111111111111111111
`US007848605B2
`
`c12) United States Patent
`Ridder et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 7,848,605 B2
`Dec. 7, 2010
`
`(54) METHOD OF MAKING OPTICAL PROBES
`FOR NON-INVASIVE ANALYTE
`MEASUREMENTS
`
`(75)
`
`Inventors: Trent Ridder, Tucson, AZ (US); Ben
`ver Steeg, Redlands, CA (US); Mike
`Mills, Tijeras, NM (US)
`
`(73) Assignee: TruTouch Technologies, Inc.,
`Albuquerque, NM (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 305 days.
`
`(21) Appl. No.: 12/185,224
`
`(22) Filed:
`
`Aug. 4, 2008
`
`(65)
`
`Prior Publication Data
`
`US 2009/0003764 Al
`
`Jan. 1, 2009
`
`1111998 Wang eta!.
`5,830,112 A
`9/1999 Watch eta!.
`5,953,477 A
`12/1999 Alfano et al.
`6,006,001 A
`12/2000 Thomas eta!.
`6,157,041 A
`4/2001 Cupp et al.
`6,219,565 B1
`6/2002 Garside et a!.
`6,411,373 B1
`9/2003 Robinson eta!.
`6,622,032 B1
`112004 Durkin eta!.
`6,678,541 B1
`112004 Ridder eta!.
`6,684,099 B2
`3/2005 Faupel et al.
`6,870,620 B2
`6,939,313 B2 * 9/2005 Saadat eta!. ................ 600/587
`7,139,076 B1
`1112006 Marbach
`7,348,786 B2 * 3/2008 Thacker eta!. .............. 324/754
`
`* cited by examiner
`Primary Examiner-Jennifer Doan
`(74) Attorney, Agent, or Firm-V. Gerald Grafe
`
`Related U.S. Application Data
`
`(57)
`
`ABSTRACT
`
`(63) Continuation-in-part of application No. 11/305,964,
`filed on Dec. 19,2005, now Pat. No. 7,756,558, which
`is a continuation-in-part of application No. 10/852,
`415, filed on May 24, 2004, now Pat. No. 7,403,804.
`
`(51)
`
`Int. Cl.
`(2006.01)
`G02B 6144
`(52) U.S. Cl. ....................... 385/114; 385/100; 3851115;
`385/901
`(58) Field of Classification Search ................. 385/100,
`385/114, 115, 901
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,975,581 A
`
`12/1990 Robinson eta!.
`
`An optical probe for non-invasively measuring an analyte
`property in a biological sample of a subject, comprises a
`plurality of illumination fibers that deliver source light from
`an optical probe input to a sample interface, a plurality of
`collection fibers that deliver light returned from the sample
`interface to an optical probe output, and wherein the illumi(cid:173)
`nation and collection fibers are oriented substantially perpen(cid:173)
`dicular to the sample interface and the illumination and col(cid:173)
`lection fibers are stacked in a plurality of linear rows to
`provide a stack of fibers arranged in a rectangular pattern. The
`optical probe is amenable to manufacturing on a scale con(cid:173)
`sistent with a commercial product. Methods of making such
`probes are described.
`
`20 Claims, 42 Drawing Sheets
`
`Direction of light propagation
`
`To sample
`interface
`
`Input of optical probe
`
`Illumination or
`Spectrometer
`Subsystem Output
`
`Light homogenizer
`
`/
`
`Aperture
`
`Page 1
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`

`

`200
`
`300
`
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`
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`
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`
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`
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`
`Figure 1
`
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`
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`1+-------1
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`Page 3
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`

`U.S. Patent
`
`Dec. 7, 2010
`
`Sheet 3 of 42
`
`US 7,848,605 B2
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 4 of 42
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`US 7,848,605 B2
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 5 of 42
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`US 7,848,605 B2
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`Direction of light propagation
`
`•
`
`To sample
`interface
`
`•
`
`Illumination or
`Spectrometer
`Subsystem Output
`
`Light homogenizer 1
`
`Aperture
`
`Figure 6
`
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`
`Page 7
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`Large NA
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`Small NA
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`0 Degrees
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`30 Degrees
`
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`Fibers
`
`Optical
`Fibers
`
`Source
`Fibers
`
`Receiver
`Fibers
`
`IUumJin.ation-Collection
`Separation
`
`Numerical
`Aperture
`
`llllumination-CoJIIection
`Angl:e
`
`Figure 7
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`Page 8
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`U.S. Patent
`
`Dec. 7, 2010
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`Sheet 8 of 42
`
`US 7,848,605 B2
`
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`Page 9
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`

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`Symmetric
`
`Asymmetric
`
`Top View
`
`Sample Interface ---,.---~---~-
`
`Side View
`0 Collection Optical Fiber 0 Illumination Optical Fiber
`
`Figure 9
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`Page 10
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`U.S. Patent
`
`Dec. 7, 2010
`
`Sheet 10 of 42
`
`US 7,848,605 B2
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 11 of 42
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`US 7,848,605 B2
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 12 of 42
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 13 of 42
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`US 7,848,605 B2
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`Page 15
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`U.S. Patent
`
`Dec. 7, 2010
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`Sheet 15 of 42
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`US 7,848,605 B2
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`Page 16
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 16 of 42
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`US 7,848,605 B2
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 17 of 42
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`US 7,848,605 B2
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 18 of 42
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`US 7,848,605 B2
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`Cross Sections
`
`Side View
`
`+
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`Light homogenizer f
`
`Optical Probe Output
`
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 21 of 42
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`US 7,848,605 B2
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`Page 22
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 22 of 42
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`US 7,848,605 B2
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`Page 23
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`Fiber Ribbon
`Verification
`
`Verification of Sample
`Interface Geometry
`
`Verification of Final
`Sample Interface
`Surface
`
`Pass
`
`Fiber Ribbon
`Fabrication
`
`Fabrication of Sample
`Interface Geometry
`
`Rejec-t Part
`
`Formation of Final
`Sample Interface
`Surface
`
`Reject
`Assembly
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`Reject
`Assembly
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`Optical Probe
`Input
`
`Verification of
`Optical Probe
`Output
`
`Accept
`Optical
`Probe
`
`Formation of Illumination
`and Collection
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`
`)
`Reject
`Assembly
`
`Verification of Final
`Optical Probe
`
`Fabrication of
`Optical Probe
`Input
`
`Fabrication of
`Optical Probe
`Output
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`Figure 23
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`Page 24
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`Light Source W
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`Figure 24
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`Page 25
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`U.S. Patent
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`Dec. 7, 2010
`
`Sheet 25 of 42
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`US 7,848,605 B2
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`U.S. Patent
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`Dec. 7, 2010
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`U.S. Patent
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`Dec. 7, 2010
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`Photon Paths
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`Dec. 7, 2010
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`Sheet 29 of 42
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`U.S. Patent
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`Dec. 7, 2010
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`U.S. Patent
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`Dec. 7, 2010
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`Dec. 7, 2010
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`Dec. 7, 2010
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`Dec. 7, 2010
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`Sheet 38 of 42
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`U.S. Patent
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`Dec. 7, 2010
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`U.S. Patent
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`Dec. 7, 2010
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`Sheet 41 of 42
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`US 7,848,605 B2
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`1
`METHOD OF MAKING OPTICAL PROBES
`FOR NON-INVASIVE ANALYTE
`MEASUREMENTS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims priority under 35 U.S.C §120 as a
`continuation-in-part of U.S. patent application Ser. No.
`11/305,964, entitled "Apparatus and Methods for Mitigating
`the Effects of Foreign Interferents onAnalyte Measurements
`in Spectroscopy," filed Dec. 19, 2005, which application was
`a continuation-in-part of U.S. patent application Ser. No.
`10/852,415, entitled "Noninvasive determination of alcohol
`in tissue," filed May 24, 2004, now U.S. Pat. No. 7,403,804,
`each of which is incorporated herein by reference.
`
`FIELD OF THE INVENTION
`
`The present invention generally relates to optical probe 20
`designs for the measurement one or more analytes of interest
`Ill VIVO.
`
`2
`model that is empirically derived from a set of spectra of
`biological samples of known characteristic values. The
`above-mentioned characteristic is generally the concentra(cid:173)
`tion of an analyte, such as alcohol, but also can be any chemi(cid:173)
`cal or physical property of the sample. The method of Rob(cid:173)
`inson et a!. involves a two-step process that includes both
`calibration and prediction steps.
`In the calibration step, the infrared light is coupled to
`calibration samples of known characteristic values so that
`10 there is attenuation of at least several wavelengths of the
`infrared radiation as a function of the various components and
`analytes comprising the sample with known characteristic
`value. The infrared light is coupled to the sample by passing
`the light through the sample or by reflecting the light off the
`15 sample. Absorption of the infrared light by the sample causes
`intensity variations of the light that are a function of the
`wavelength of the light. The resulting intensity variations at a
`minimum of several wavelengths are measured for the set of
`calibration samples of known characteristic values. Original
`or transformed intensity variations are then empirically
`related to the known characteristics of the calibration samples
`using multivariate algorithms to obtain a multivariate calibra(cid:173)
`tionmodel.
`In the prediction step, the infrared light is coupled to a
`25 sample of unknown characteristic value, and a multivariate
`calibration model is applied to the original or transformed
`intensity variations of the appropriate wavelengths of light
`measured from this unknown sample. The result of the pre(cid:173)
`diction step is the estimated value of the characteristic of the
`30 unknown sample. The disclosure of Robinson eta!. is incor(cid:173)
`porated herein by reference.
`A further method ofbuilding a calibration model and using
`such model for prediction of analytes and/or attributes of
`tissue is disclosed in commonly assigned U.S. Pat. No.6, 157,
`35 041 to Thomas et a!., entitled "Method and Apparatus for
`Tailoring Spectrographic Calibration Models," the disclosure
`of which is incorporated herein by reference.
`In U.S. Pat. No. 5,830,112, Robinson describes a general
`method of robust sampling of tissue for non-invasive analyte
`40 measurement. The sampling method utilizes a tissue-sam(cid:173)
`pling accessory that is pathlength optimized by spectral
`region for measuring an analyte such as alcohol. The patent
`discloses several types of spectrometers for measuring the
`spectrum of the tissue from 400 to 2500 nm, including
`45 acousto-optical tunable filters, discrete wavelength spectrom(cid:173)
`eters, filters, grating spectrometers and FTIR spectrometers.
`The disclosure of Robinson is incorporated hereby reference.
`Although there has been substantial work conducted in
`attempting to produce commercially viable non-invasive
`50 spectroscopy-based systems for determination of attributes in
`humans and human samples, several challenges remain. It is
`believed that the systems described in the prior art have had
`limited success because of the challenges imposed by the
`spectral characteristics of tissue which make the design of a
`55 commercially viable measurement system a formidable task.
`Thus, there is a substantial need for a commercially viable
`device which incorporates subsystems and methods with suf(cid:173)
`ficient accuracy and precision to make clinically relevant
`determinations of biological attributes in human tissue. The
`60 present invention is primarily concerned with the optical
`probe, which is one of the system components that influence
`commercial viability of a non-invasive measurement system.
`In U.S. Pat. No. 5,953,477, Wach eta!. disclose embodi(cid:173)
`ments of optical fiber treatments that serve to improve the
`65 efficiency of optical probes. The treatments include reflective
`surfaces coatings applied to fibers that have been ground or
`shaped to alter the light output or collection properties of the
`
`BACKGROUND OF THE INVENTION
`
`The present invention predominantly deals with non-inva(cid:173)
`sive determination of attributes in humans or human samples
`by quantitative spectroscopy. Spectroscopy offers the poten(cid:173)
`tial of completely non-invasive measurements for a variety of
`applications such as alcohol monitoring, glucose monitoring,
`diagnostic medicine, quality control, and process monitoring.
`Non-invasive measurements that use quantitative spectros(cid:173)
`copy are desirable because they are painless, do not require a
`fluid draw from the body, carry little risk of contamination or
`infection, do not generate any hazardous waste, and can have
`short measurement times. Quantitative spectroscopy can
`measure a variety of attributes of interest including, as
`examples, analyte presence, analyte concentration (e.g., alco(cid:173)
`hol or substance of abuse concentration), direction of change
`of an analyte concentration, rate of change of an analyte
`concentration, disease presence (e.g., alcoholism or diabe(cid:173)
`tes), disease state, and combinations and subsets thereof.
`Several approaches have been proposed for the non-inva(cid:173)
`sive determination of attributes in humans or human samples.
`These systems have included technologies incorporating
`polarimetry, mid-infrared spectroscopy, Raman spectros(cid:173)
`copy, Kromoscopy, fluorescence spectroscopy, nuclear mag(cid:173)
`netic resonance spectroscopy, radio-frequency spectroscopy,
`ultrasound, transdermal measurements, photo-acoustic spec(cid:173)
`troscopy, and near-infrared spectroscopy. Many of these
`approaches share a common need to deliver light to and
`collect light from the sample of interest. The sample of inter(cid:173)
`est can be skin tissue of a subject, biopsied tissue, internal
`tissues accessed by an endoscope, blood, saliva, urine, or any
`other biological tissue of interest. In the context of non(cid:173)
`invasive measurements, the part of a system that delivers and
`collects the light is often referred to as an optical probe or an
`optical sampler. One skilled in the art recognizes that other
`terms may exist that refer to a system component that serves
`this purpose.
`Many systems for non-invasive measurement of analytes
`are known in the art, several of which describe embodiments
`of optical probes for measuring analytes in biological
`samples. As an example, Robinson et a!. in U.S. Pat. No.
`4,975,581 disclose a method and apparatus for measuring a
`characteristic of unknown value in a biological sample using
`infrared spectroscopy in conjunction with a multivariate
`
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`4
`tiple pathlengths through a sample using a multi-channel
`probe can provide insight into the pathlengths of each channel
`that might be obfuscated if only a single channel measure(cid:173)
`ment were performed. Furthermore, all independent claims
`incorporate the explicit step of using algorithms or equations
`to process the measured channels in order to cancel surface
`effects. None of the embodiments of the present invention
`involve algorithms or equations to explicitly cancel surface
`effects.
`
`SUMMARY OF THE INVENTION
`
`25
`
`3
`fiber at the sample interface. Wach et a!. also disclose the
`application of optical filtering materials directly to the ends of
`the optical fibers at sample interface. All of the embodiments
`involve a central fiber surrounded by a circular arrangement
`of additional fibers with at least one having a shaped end or
`internally reflective surfaces to bend or steer the emitted or
`collected light paths from its longitudinal axis (e.g., the axis
`parallel to the optical fiber and perpendicular to the sample
`interface). None of the embodiments disclosed in the present
`invention involve circular arrangements at the sample inter- 10
`face, shaping the ends of any fibers, or internally reflective
`surfaces to steer or bend light paths.
`In U.S. Pat. No. 6,006,001 Alfano eta!. disclose embodi(cid:173)
`ments of optical probes suitable for endoscopy. All disclosed
`embodiments are comprised of illumination and collection 15
`fibers encased in a tubular structure and include a narrow band
`filter between the illumination and collection fibers. None of
`the embodiments disclosed in the present invention involve
`tubular encasing structures or narrow band filters.
`In U.S. Pat. No. 6,219,565 Cupp eta!. discloses optical
`probes for measuring glucose. All independent claims are
`limited to glucose and ring geometries (illumination fibers
`surround each collection fiber in a circular pattern). None of
`the embodiments of the present invention involve ring illu(cid:173)
`mination/collection geometries.
`In U.S. Pat. No. 6,411,373, Garside eta!. disclose fiber
`optic illumination and detection patterns for use in spectro(cid:173)
`scopic analysis. They disclose a design process for determin(cid:173)
`ing the illumination-detection pattern at the sample interface.
`The ratio of the illumination to detector fibers in the disclosed 30
`embodiments is restricted by the size of the fiber bundle at the
`detector. The embodiments of the present invention are not
`subject to this restriction. Furthermore, Garside eta!. disclose
`optical probe embodiments incorporating hex-packed fibers.
`None of the embodiments disclosed in the present invention 35
`involve hex-packed optical fibers at the sample interface.
`Garside et a!, further disclose a design method that states
`"fabrication constraints should be ignored whenever pos(cid:173)
`sible", and as such, is a starkly contrasting approach to that of
`the present invention.
`In U.S. Pat. No. 6,678,541, Durkin eta!. disclose optical
`probe geometries for measuring optical properties, such as
`the scattering coefficient of a sample. A single illumination
`channel is used to sequentially measure the sample at mul(cid:173)
`tiple collection channels at different separations relative to 45
`the illumination channel. A function relating the change in
`signal to illumination/collection separation is then used to
`determine the optical property of interest. No embodiments of
`the present invention involve determining properties by
`examining signals as a function of illumination/collection 50
`separation.
`In U.S. Pat. No. 6,870,620, Faupel et a!. disclose optical
`probe embodiments that are predominantly suited to fluores(cid:173)
`cence spectroscopy. All of the embodiments involve translat(cid:173)
`ing, rotating, or repositioning the optical probe during a mea- 55
`surement or a sample interface surface that conforms to the
`shape of the sample being measured. None of the embodi(cid:173)
`ments of the present invention involve rotating, translating, or
`otherwise moving the optical probe. Furthermore, none of the
`embodiments of the present invention involve sample inter- 60
`faces that conform to the sample shape. In the embodiments
`of the present invention, the sample interface is polished flat.
`In U.S. Pat. No. 7,136,076, Marbach discloses multi-chan(cid:173)
`nel optical probes for cancelling out surface effects of
`samples. Marbach does not disclose the advantages of or 65
`motivations for using multi -channel optical probes other than
`compensating for surface effects. For example, inducing mul-
`
`Any design of an optical probe suitable for non-invasive
`measurements must consider several variables such as the
`efficiency of coupling or throughput of light into and out of
`the sample, depth of penetration into the sample, quality of
`interface with the sample (e.g., effects of hair and wrinkles),
`spatial and angular homogeneity of the light introduced and
`collected from the sample, the wavelengths of light under
`20 consideration, and the surface quality of the optical probe.
`Each of these variables contributes to the overall performance
`of the probe. However, the performance of the optical probe is
`only one consideration for a commercially viable non-inva(cid:173)
`sive measurement system.
`The optical probe design must also be amenable to manu(cid:173)
`facturing on a scale consistent with a commercial product.
`This aspect of optical probe design has generally not been
`considered in the art despite the fact it is a critical enabling
`aspect of a non-invasive measurement system. The present
`invention discloses a family of optical probes that optimize
`the trade between performance and manufacturing objec-
`tives. This balance provides optical probes that offer suffi(cid:173)
`cient measurement performance while enabling reproducible
`and scalable high volume manufacturing.
`A significant requirement for a manufacturable design is
`the ability to cost-effectively measure and verifY subassem(cid:173)
`blies earlier in the manufacturing process, thereby reducing
`failure rates during final assembly. The current invention
`offers a significant improvement over designs disclosed in the
`40 art that are labor intensive to fabricate and difficult to verify
`prior to completion. The optical probes of the present inven(cid:173)
`tion also offer improved physical robustness to contamination
`from the envirouments encountered in non-invasive measure-
`ments. In addition, some embodiments within the family of
`disclosed designs are comprised of optical materials that offer
`substantial performance advantages relative to commonly
`available optical fibers typically used in optical probe fabri(cid:173)
`cation.
`The subsystems of the non-invasive monitor are highly
`optimized to provide reproducible and, preferably, uniform
`illumination of the tissue, low tissue sampling error, depth
`targeting of the tissue layers that contain the property (ana(cid:173)
`lyte) of interest, and efficient collection of diffuse reflectance
`spectra from the tissue.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The accompanying drawings, which are incorporated in
`and form part of the specification, illustrate the present inven(cid:173)
`tion and, together with the description, describe the invention.
`In the drawings, like elements are referred to by like numbers.
`FIG. 1 is a diagram of a non-invasive analyte measurement
`system showing an illumination, optical probe, and spectrom(cid:173)
`eter subsystem orientation.
`FIG. 2 is a diagram of a non-invasive analyte measurement
`system showing an illumination, spectrometer, and optical
`probe subsystem orientation.
`
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`6
`FIG. 30 is a diagram of the non-invasive skin tissue spectra
`in the near-infrared region obtained using the linear stack of
`three ribbons optical probe on the forearm.
`FIG. 31 is a diagram of a linear stack 8:1 optical probe
`comprising 25 ribbons of 25, 0.37 NA fibers.
`FIG. 32a, 32b, 32c (collectively referred to herein as FIG.
`32) comprises a diagram of the non-invasive skin tissue spec(cid:173)
`tra in the near-infrared region obtained using the linear stack
`8:1 of25, 0.37 NA fiber ribbons optical probe on the forearm.
`FIG. 33 is a diagram of a linear stack 8:1 optical probe
`comprising 25 ribbons of 25, 0.22 NA fibers.
`FIG. 34 is a diagram of the non-invasive skin tissue spectra
`in the near-infrared region obtained using the linear stack 8:1
`of 25, 0.22 NA fiber ribbons optical probe on the forearm.
`FIG. 35a, 35b, 35c (collectively referred to herein as FIG.
`35) comprises a diagram of a linear stack 8:1 optical probe
`comprising 19 ribbons of 19, 0.37 NA fibers.
`FIG. 36a, 36b, 36c (collectively referred to herein as FIG.
`36) comprises a diagram of a linear stack 8:1 optical probe
`20 comprising 17 ribbons of 17, 0.44 NA fibers.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`5
`FIG. 3 is a diagram showing the key aspects of an optical
`probe.
`FIG. 4 is a diagram of an optical probe known in the art.
`FIG. 5 is a magnified view of the sample interface of the
`known optical probe shown in FIG. 4.
`FIG. 6 is a diagram of an arrangement for coupling an
`illumination or spe