CN101018502A - Non-invasive analyzer sampling probe interface method and apparatus - Google Patents

Abstract

The invention provides a method and apparatus for non-invasive sampling. More particularly, the methods and apparatus relate to controlling the action of an optical sampling probe interface relative to a tissue sampling point. The dynamic probe interface is used to acquire spectra of a target sample, control positioning of the sampling probe relative to the tissue sample according to at least one of the x, y, and z axes, and/or control sample tissue displacement to minimize spectral changes resulting from the sampling process and increase analyte property estimation accuracy and precision.

Description

Noninvasive analyzer sample probe interface method and device

Technical field

The present invention relates to the non-intrusion type sampling, specifically, the present invention relates to a kind of sample probe interface method and device, be used for using based on optical Noninvasive analyzer.Particularly, the present invention relates to a kind of dynamic probe interface, wherein move to be controlled in the sampling process with a kind of mode relative organization sample of control to the small part sample probe because the spectrum change that the displacement of the sample probe of tissue samples causes.

Background technology

Be transported to external energy in the volume (volume ofthe human body) of specific sample point, zone or human body with the form of light based on spectrographic Noninvasive analyzer, photon and tissue samples interact there, thereby survey chemistry and physical characteristic.A large amount of incident photons by direct reflection, diffuse-reflectance, scattering or send to they detected external.Based on the information of incident photon and detected photon, can infer the chemistry and/or the architecture basics of sample point.The remarkable advantage of Noninvasive analyzer is the analysis of the chemistry of health and constituent is carried out and do not produced biohazard in painless mode with limited consumption.In addition, Noninvasive analyzer allows to determine simultaneously a plurality of analytes or architectural feature.Concentrate on the non-intrusion type concentration of glucose in this example and estimate, but this principle is applicable to other non-intrusion measurement of other blood or fabric analysis thing characteristic.

Diabetes

Diabetes are a kind of chronic diseases, and it causes the generation of insulin and utilizes unusually, and insulin is that a kind of glucose absorption that promotes is advanced the hormone of cell.Though the accurate reason of diabetes or the unknown, inherited genetic factors, environmental factors and obesity all work to the generation of diabetes.Diabetics increases in the danger of three broad aspect: cardiovascular heart disease, retinopathy, and neuropathy.Diabetes have following one or more complication usually: heart disease and stroke, hypertension, nephropathy, neuropathy (sacred disease and amputation), retinopathy, diabetics ketoacidosis, dermatosis, gum disease, sexual impotence and fetus complication.Diabetes are that world wide causes dead and disabled first cause.In addition, diabetes only are a kind of among the glucose metabolism imbalance series, and it also comprises glucose tolerance attenuating and hyperinsulinism, and it is also referred to as hypoglycemia.

Sampling method

Technology can be used for analyzing the chemistry formation of human body widely.These technology broadly are divided into two classes, intrusive mood and non-intrusion type.At this, obtain any biological specimen as a Technology Need from human body and demarcate to be used for analysis, to surpass, if perhaps any part transdermal skin of measuring device enters human body, then this technology is called as intrusive mood.The multiple non-intrusion type method employing spectrophotometry that is used for determining the biological specimen concentration of glucose.These technology comprise: Raman method and fluorescence method, and adopt from ultraviolet to ultrared light (ultraviolet (200 to 400 nanometer), visible light (400 to 700 nanometer), near infrared ray (700 to 2500 nanometers or 14,286 to 4000 centimetres^-1), infrared ray (2500 to 14,285 nanometers or 4000 to 700 centimetres^-1)) technology.

The non-intrusion type concentration of glucose is estimated

Existing in the multiple non-intrusion type method that is used for estimating or determining the concentration of glucose of tissue or blood.These methods have nothing in common with each other, but have two common step at least.The first, utilize a kind of device to obtain photometric signal from human body.The second, utilize a kind of algorithm being this conversion of signals the concentration of glucose estimated value.

One class non-intrusion type concentration of glucose analyser is a kind of system that carries out the concentration of glucose estimation from spectrum.Typically, a kind of non-intrusion type device wave spectrum of utilizing certain form is with from human body picked up signal, for example spectrum.The non-intrusion type concentration of glucose of diffuse-reflectance pattern is estimated that effective particular range is positioned near infrared range, about from 1100 to 2500 nanometers or therebetween one or more scopes, the thesis for the doctorate that is entitled as " Glucose Determination in Biological Matrices Using Near-InfraredSpectroscopy (adopting near infrared spectrum to determine glucose) " referring to K.Hazen with biological matrix, Iowa university (1995). these technology and traditional invasive and other intrusive mood technology are completely different, because the sample of inquiring in the technology of these traditional invasive and other intrusive mood is the part of human body body original position (bodyin-situ) rather than the biological specimen that obtains from human body.

Typically, utilize one of following various modes, comprising: transmission, penetrate through reflective (transflectance) and/or diffuse-reflectance to gather non-intrusion type spectrum.In estimating based on the concentration of transmission, the signal of being gathered is typically light or spectrum, the human region of penetrable for example finger tip.At this, penetrate through reflective is meant that the collection of signal is not at incidence point or incident area (diffuse-reflectance), neither be at the reverse side (transmission) of sample, but on the human body between transmission and the diffuse-reflectance pickup area certain a bit on.For example,, finger tip or the forearm of the light of penetrate through reflective from a zone enters, and according to employed wavelength, generally comes out from 0.2 to 5 millimeter of distance or another farther zone.Diffuse reflection spectrum produces from the zero photon to several millimeters of position radial propagation that incident photon penetrates into skin in the skin surface effusion by catching at least some usually.Typically, by the strong absorbed light of human body, reaching peaked wavelength as the water absorptance is near 1450 or 1950 nanometers light, and the path in the diffuse-reflectance pattern is collected after dispersing.The light that is absorbed on a small quantity, the wavelength that reaches minima as the absorptance of water is near thelight 1300,1600 or 2250 nanometers, is collected in bigger radial distance, and is known as penetrate through reflective light or diffuses.Be called as specular light at its light of collecting again after outermost surface ejects from skin.

Calibration

Need calibration based on optical concentration of glucose analyser.This is for for example traditional invasive, and all types of concentration of glucose analysers of other intrusive mood, non-intrusion type and implantable analyser all are such.A basic feature of non-intrusion type glucose analyser is that they are accessory in itself, that is, and and their not direct measuring blood concentration.Therefore, need a kind of basic skills of these devices that be used to calibrate with the correct measurement blood sugar concentration.There are many calibration steps.

A kind of non-intrusion type technology, near infrared spectrum need be set up the mathematical relationship between interior near infrared spectrum of body and the actual blood glucose concentration.This relation can have that the near infrared ray measured value obtains in the body of corresponding blood sugar concentration by collection, and described blood sugar concentration is by using the measuring device as traditional invasive or other intrusive mood reference unit directly to obtain.

For based on spectrophotometric analyser, exist multiple single argument and multivariable method to be used to set up mathematical relationship between measured signal and the actual blood glucose concentration.Yet the basic equation that is used to solve is lambert Bill (Beer-Lambert) law.The metric intensity of this law regulation absorptance/reflection coefficient is directly proportional with the concentration of measured analyte, as equation 1,

A＝εbC (1)

Wherein, A is the absorptance/reflection coefficient tolerance at setted wavelength, and ε is the molar absorption coefficient that is associated with molecule (s) of interest under identical setted wavelength, and b is the distance that light is propagated, and C is the concentration of molecule (s) of interest.

The stoichiometry collimation technique extracts glucose signals or the relevant signal of glucose by the multiple signal processing of one or more mathematical modeies and the Calibration Method of comprising from the spectrum of measuring.The foundation of described model is by to realize as one group of the calibration group exemplary optical spectrum instrumentation and one group of calibration process based on the blood sugar concentration reference value of the analysis of capillary blood or venous blood being associated.General multivariant method, its each sample spectrum all needs exemplary concentration of glucose reference value in calibration, comprises partial least square method (PLS) and principal component regression (PCR).

The report of existing a plurality of non-intrusion type glucose technology.Wherein some relate to all purpose instrument structure that the non-intrusion type concentration of glucose is estimated needs, and other relate to sampling technique.Those technology related to the present invention are done concise and to the point review at this:

All purpose instrument

R.Barnes, J.Brasch, D.Purdy, W.Lougheed, the U.S. Patent No. 5 that is entitled as " Non-invasivedetermination ofanalyte concentration in body ofmammals (non-intrusion type of mammalian body inner analysis substrate concentration is determined) ", described a kind of non-intrusion type concentration of glucose in 379,764 (January 10 nineteen ninety-five) and estimated analyser, its method that adopts the data pretreatment to combine with multiple analysis is determined blood sugar concentration.

P.Rolfe, the UK Patent Application serial number No.2 that is entitled as " Investigating substances in a patients ' bloodstream (the material investigation in patient's blood flow) ", 033, in 575 (on Augusts 24th, 1979) a kind of device has been described, this device is used to import light in the body, detect weakened backscattering light, and adopt the signal of collecting to determine in the blood flow or near concentration of glucose.

C.Dahne, D.Gross, the U.S. Patent No. 4 that is entitled as " Spectrophotometric method and apparatus for thenon-invasive (spectrophotometric method and the device that are used for non-intrusion type) ", 655, in 225 (on April 7th, 1987) a kind of method and apparatus has been described, it is used to import light into the intravital of patient, collects transillumination or backscattering light, and determines concentration of glucose from the near infrared ray wavelength range of selecting.Wavelength comprises 1560 to 1590,1750 to 1780,2085 to 2115 and 2255 to 2285 nanometers, has the additional reference signal of at least one from 1000 to 2700 nanometer.

M.Robinson, K.Ward, R.Eaton, D.Haaland, the U.S. Patent No. 4 that is entitled as " Method and apparatusfor determining the similarity of a biological analyte from a model constructedfrom known biological fluids (determining the method and apparatus of biological analyte similarity by the model of known organism fluid structure) ", described in 975,581 (nineteen nineties December 4 days) and a kind ofly be used to adopt infrared spectrum to measure method and apparatus such as the concentration of the biological analyte of glucose in conjunction with multivariate model.This multivariate model is configured to by multiple known biological fluid sample.

J.Hall, T.Cadell, the U.S. Patent No. 5 that is entitled as " Method and device for measuring concentrationlevels of blood constituents non-invasively (being used for other method of non-invasive measurements of blood related constituent concentration level and device) ", a kind of polychromatic light, wavelength separated device and matrix cymoscope non-intrusion type Apparatus and method at the definite analyte concentration of live subject that is used for adopting was described in 361,758 (on November 8th, 1994).This device adopts the receptor that is suitable for receiving finger tip, comprises the device that is used to stop irrelevant light.

S.Malin, G Khalil, the U.S. Patent No. 6 that is entitled as " Method and apparatus for multi-spectral analysis oforganic blood analytes in noninvasive infrared spectroscopy (being used for method and apparatus) " at the organic blood analyte of the multispectral piecewise analysis of non-intrusion type infrared spectrum, having described a kind of being used in 040,578 (on March 21st, 2000) adopts multispectral piecewise analysis to estimate the method and apparatus of organic blood analyte near infrared ray.A plurality of obvious non-overlapping wavelength region may incide sample surface, and irreflexive light is collected, and determine the concentration of this analyte by chemical technology.

Specular reflectivity

R.Messerschmidt, D.Sting, the U.S. Patent No. 4 that is entitled as " Blocker device for eliminating specularreflectance from a diffuse reflectance spectrum (eliminating the blocking device of direct reflection from diffuse reflection spectrum) ", having described in 661,706 (on April 28th, 1987) by mechanical devices reduces specular reflectivity.The device of blade shapes was skimmed it before specular light bump cymoscope.A shortcoming of this system is that it is collected irreflexive light not yet in effectly and proofreaies and correct also existing problems.

R.Messerschmidt, M.Robinson, the U.S. Patent No. 5 that is entitled as " Diffuse reflectance monitoringapparatus (diffuse-reflectance monitoring arrangement) ", a kind of one group of reflection of employing of diffuse reflection spectrum and minute surface control device of open cross-sections of being used for described in 636,633 (on June 10th, 1997).

R.Messerschmidt, M.Robinson, the U.S. Patent No. 5 that is entitled as " Diffuse reflectance monitoringapparatus (diffuse-reflectance monitoring arrangement) ", 935, in 062 (on August 10th, 1999) and R.Messerschmidt, the U.S. Patent No. 6 that is entitled as " Diffuse reflectance monitoringapparatus (diffuse-reflectance monitoring arrangement) " of M.Robinson, 230, described a kind of diffuse-reflectance control device in 034 (May 8 calendar year 2001), it can be distinguished from diffusing that the degree of depth of selecting reflects.This control device also arrives detector as obstacle to stop specular light extraly.

The Malin pro-described use be positioned at high zone of receiving the water rate as 1450 and 1900 nanometers diffuse the peripheral spectrographic existence of labelling, wherein fully do not reduce specular light.

K.Hazen, G.Acosta, A.Abul-Haj, R.Abul-Haj, the U.S. Patent No. 6 that is entitled as " Apparatus and methodfor reproducibly modifying localized absorption and scattering coefficients at atissue measurement site during optical sampling (organizing measurement point to repeat to revise the apparatus and method of local absorption and scattering coefficient in the optical sampling process) ", described in 534,012 (on March 18th, 2003) a kind of make device fully with can repeatedly contact the mechanical devices that sampling medium minimizes direct reflection.In addition, this device allows to repeat to exert pressure and in the temperature of sample point to sample point.

Temperature

K.Hazen, the thesis for the doctorate that is entitled as " Glucose Determination in Biological Matrices UsingNear-Infrared Spectroscopy (adopting near infrared spectrum to determine glucose) " with biological matrix, the adverse effect of temperature in estimating based near infrared concentration of glucose has been described by Iowa university (1995).Physiology's composition has near-infrared absorbing spectrum, and according to size and position, it is responsive to partial temperature, and this sensitivity influences the estimation of non-intrusion type concentration of glucose.

Coupled fluid (coupling fluid)

Multiple raw data is described the coupled fluid that has important sampling parameters.

Refractive index match between sampler and the sample medium is well-known.Glycerol is a kind of common index-matched fluid of light to skin that be used for.

R.Messerschmidt, the U.S. Patent No. 5 that is entitled as " Method for non-invasive blood analytemeasurement with improved optical interface (being used for method) " with improved optical interface non-invasive measurements of blood related analyte, 655,530 (on August 12nd, 1997) and R.Messerschmidt, the U.S. Patent No. 5 that is entitled as " Method for non-invasive blood analyte measurement withimproved optical interface (with the method for improved optical interface non-invasive measurements of blood related analyte) ", in 823,951 (on October 20th, 1998) a kind of index-matched medium that uses has been described between sensor probe and skin surface.This index-matched medium is the synthetic that comprises full fluorocarbon and chloride fluorocarbon.

M.Robinson, R.Messerschmidt, the U.S. Patent No. 6 that is entitled as " Method for non-invasive bloodanalyte measurement with improved optical interface (with the method for improved optical interface non-invasive measurements of blood related analyte) ", 152, in 876 (on November 28th, 2000) and M.Rohrscheib, C.Gardner, M.Robinson, the U.S. Patent No. 6 that is entitled as " Method and apparatus fornon-invasive blood analyte measurement with fluid compartment equilibration (utilizing the fluid method and apparatus of balance non-invasive measurements of blood related analyte at interval) ", a kind of index-matched medium that improves the interface between sensor probe and the skin surface in spectrum analysis was described in 240,306 (Mays 29calendar year 2001).Preferably a kind of synthetic that comprises chloride fluorocarbon (chlorofluorocarbon) of this index-matched medium has optionally added full fluorocarbon (perfluorocarbon).

T.Blank, G.Acosta, M.Mattu, S.Monfre, (July 2 to be entitled as the U.S. Patent No. 6,415,167 of " Fiber optic probe guideplacement guide (fiber optics probe guider place guide) ", 2002) describe a kind of coupled fluid that contains one or more perfluorochemicals (perfluoro compound) in, the some of them coupled fluid is placed on the seam of optical probe and measurement point.The toxicity that perfluorochemical does not have chloride fluorocarbon to have.

The location

The T.Blank pro-has been described and has been used in combination guider and non-intrusion type concentration of glucose analyser to increase the accuracy of sampling interlacing point position, has increased correctness and accuracy that the non-intrusion type concentration of glucose is estimated thus.

J.Griffith, P.Cooper, T.Barker, the U.S. Patent No. 6 that is entitled as " Method and apparatus fornon-invasive blood glucose sensing (being used for the method and apparatus that the non-intrusion type blood-glucose is measured) ", 088, described a kind of analyser of the patient's of having forearm interface in 605 (on July 11st, 2000), patient's forearm moves with the longitudinal axis of a kind of progressive mode along patient's forearm in this interface.On average considered in the variation of skin biotic component at the spectrum that progressive distance is gathered.Roller is used to lift arm between measuring, and moves arm relative to device, reduces arm by separating solenoid, causes thus that skin-lifting mechanism is reduced to arm with sensor head to carry out new contacting.Do not advise between forearm sample point and sampling head, adopting the pressure of control in the literary composition of Griffith.In addition, in the period that relatively moves between sample and the analyser, do not gather spectrum.

Pressure

E.Chan, B.Sorg, D.Protsenko, M.O ' Neil, M.Motamedi, A.Welch, be entitled as " Effects of compression on soft tissue optical properties (compression is to the influence of soft tissue optical characteristics) ", IEEE Journal of Selected Topics in Quantum Electronics, Vol.2, no.4, pp.943-950 (1996) (IEEE quantum electronics selected topic magazine, volume 2, no.4,943-950 page or leaf (1996)) from 400 to 1800 nanometer pressure have been described to absorptance and the influence that reduces scattering coefficient.Most example illustrates by the compression scattering coefficient have been increased.

K.Hazen, G.Acosta, A.Abul-Haj, R.Abul-Haj, the U.S. Patent No. 6 that is entitled as " Apparatus and methodfor reproducibly modifying localized absorption and scattering coefficients at atissue measurement site during optical sampling (being used for organizing measurement point to repeat to revise the apparatus and method of local absorptance and scattering coefficient) " in the optical sampling process, 534, describe a kind of non-intrusion type concentration of glucose estimation unit 012 (on March 18th, 2003) in the first embodiment, be used for by along the mobile sample probe of Z axle on vertical sampling point surface with a kind of controlled and repeatably mode change pressure that is applied to sample point or the pressure that remains unchanged at a sample point.In the embodiment of another description, improve or reduce the sampling carrying platform by relative analyser probe pinpoint, make arm sample point platform along being moved perpendicular to the planar Z axle that limits by the sampling surface.Should ' 012 patent further specify, be suitably contact when specular light is approximately zero in ripples section 1950 and 2500 nanometers.

M.Makarewicz, M.Mattu, T.Blank, G.Acosta, E.Handy, W.Hay, T.Stippick, B.Richie, the United States Patent (USP) no.6 that is entitled as " Method and apparatus for minimizing spectralinterference due within and between sample variations during in-situ spectralsampling of tissue (in the process of former address spectrum sample of tissue, minimize because in the sample and the method and apparatus of the spectral interference that produces of the variation between the sample) ", a kind of sample connection of temperature and pressure control was described in 839,584 (on January 4th, 2005).Pressure controlled device is one group of holder that is used to take a sample, the natural place of the relative sample of its control sample probe.

Up to now, also do not have the FDA device to be checked and approved and be used for the estimation of non-intrusion type concentration of glucose for individual or medical professional.In addition, the non-intrusion type concentration of glucose analyser version of report does not produce concentration of glucose estimation accurately always in patient's test at present.Concentration of glucose is estimated in greater than 90% test population accuracy is compared with hemanalysis and need be higher than 15% and just think success.The key reason of concentration of glucose estimation difference is relevant with probe design and patient interface, rather than spectrogrph unit or algorithm design.The key parameter that will control is the power that applies, displacement or the pressure that is applied to the tissue volume that is detected or sample point by sample probe.The sample connection of power and/or displacement control is of value to the reproducible sample spectrum of generation, and this sample spectrum uses to produce acceptable replicability and acceptable concentration of glucose with Noninvasive analyzer and algorithm to be estimated.

Obviously, the needs that have the load that control applies to measurement point as the time function sample probe.

Summary of the invention

The present invention relates to the non-intrusion type sampling.Especially, the present invention relates to interface method and device with the sample probe that uses based on optical Noninvasive analyzer.Especially, the present invention relates to a kind of dynamic instrumentation interface, wherein at least a portion relative organization sample of sample probe moves in a controlled manner and is controlled in the sampling process spectrum change that the displacement by the sample probe of sample of tissue produces.

Description of drawings

Fig. 1 provides the block diagram that comprises the Noninvasive analyzer of basic module, communication bundle and sampling module according to of the present invention, and wherein move along the Z axle with respect to sample the position of sample probe;

Fig. 2 shows a kind of according to Noninvasive analyzer of the present invention, and it comprises elementary cell, communication bundle and by the sample probe of algorithm controls;

Fig. 3 A and 3B show a kind of controller according to driving activator of the present invention, and this activator moves sample probe with respect to sample;

Fig. 4 A and 4B show a kind of according to the present invention the sample probe of sampling module, its be positioned at first period not displacement (Fig. 4 A) and second period to sample displacement (Fig. 4 B);

Fig. 5 A is to draw (Fig. 5 A) according to the present invention by the non-intrusion type near infrared ray single beam spectrum of the different displacements of tissue samples of sample probe collection with at the function (Fig. 5 B) of 1450 nanometer intensity as displacement with 5B;

Fig. 6 represents the different non-intrusion type near infrared ray absorptance spectrum that are shifted of the sampling tissue of being gathered by sample probe according to the present invention;

Fig. 7 is plotted in the function of the absorptance variation of chemical characteristic under the multi-wavelength as tissue displacement according to the present invention;

Fig. 8 is plotted in the function of the absorptance variation of chemical characteristic under three kinds of wavelength as tissue displacement according to the present invention;

Fig. 9 represents skin texture;

Figure 10 A and 10B represent the schematic diagram of the hydraulic system according to the present invention;

Figure 11 A-11D represents two dimension 7 views according to excitation system of the present invention;

Figure 12 represents the 3-D view that is connected with the excitation system that sample probe can move along the Z axle according to of the present invention;

Figure 13 represents according to the present invention the intensity spectrum of gathering with respect to the diverse location of the sample probe Z axle of sample;

Figure 14 represents according to the present invention the absorptance spectrum gathered with respect to the diverse location of the sample probe Z axle of sample;

Figure 15 represent according to the present invention when the position of sample probe when the axial sample of Z moves, the intensity of the suction wave band of the specific sample of specific objective;

Figure 16 represent according to the present invention when the position of sample probe when the axial sample of Z moves, the intensity in the second harmonic zone of the specific sample of specific objective;

Figure 17 represents according to the present invention for the specific sample of specific objective, the concentration of glucose of estimating for all gratings of the variation Z shaft position of the sample probe of sample relatively;

Figure 18 represents to be used for according to the present invention the reference of nine individualities and the glucose concentration curve that non-intrusion type is estimated;

Figure 19 represents the concentration relationship figure of the non-intrusion type glucose estimator concentration relative reference concentration of glucose according to the present invention, and it covers on the Clarke Error Graph;

Figure 20 A and 20B represent to be connected with along the drive system of Z axle mobile probe according to the present invention;

Figure 21 represents to have according to the present invention the motor machine embodiment of dynamic control sample probe;

Figure 22 represents to drive sample probe according to cam of the present invention;

Figure 23 represents to be used for according to the present invention the fluid regulation drive system of the displacement of sample probe;

Figure 24 represents the rate curve according to sample probe of the present invention;

Figure 25 represents according to the present invention at the grating intensity spectrum of sample probe to the variation distance of sample;

Figure 26 represents according to the present invention at the grating absorptance spectrum of sample probe to the variation distance of sample;

Figure 27 represents according to the present invention for the single grating intensity that is replicated in 1450 and 1290 nanometers; And

Figure 28 represents the derivative according to grating intensity ratio of the present invention.

The specific embodiment

Summation

The invention provides a kind of Noninvasive analyzer sample probe (sampling probe), it uses the displacement of controlled sample probe with respect to sample.One or more shift components of sampling module are controlled along perpendicular to the planar z axle of x, y, this x, y plane and sample point surperficial tangent.The control of the z axle of the displacement sample probe element of sampling module provides tissue samples to have the displacement of specifying or the spectrographic collection of non-intrusion type of not having a displacement has with the nominal plane that the relative sample tissue surface of sample is provided and changes the spectrographic collection of non-intrusion type that applies displacement.

Move the ability permission dynamic organization measurement of sample probe as the function relative organization sample of time.Dynamic organization's measurement is designed to collect the time series spectroscopic data of the dynamic organization's response that comprises tissue samples when sample probe contacts with tissue samples.In this measuring process,, sample probe contacts with tissue samples or randomly continuous or semicontinuous collection spectrum raster scanning when being used for displacement tissue when moving to.For example, when apparatus needed signal, sample probe slowly was reduced to the target measurement point under the situation that has or do not have the optical probe orientation direction.

Sample probe moves randomly by algorithm controls.In one embodiment, this algorithm adopts the motion of instructing sample probe relative organization sample from the feature and the control parameter of the extraction of non-intrusion type spectrum.A feature is spectrographic any derivative, its processed special nature in order to strengthen helping controlling.A feature is in order to control the information of extraction.Feature Extraction typically reduced to probe move control deleterious interference.The example of Feature Extraction Technology comprises the employing derivative, multivariate analysis, or be used for the spectral intensity analysis of chemistry or physical signalling.

Instrument

Following detailed description should be read with reference to accompanying drawing, and element similar among the wherein different figure uses identical Reference numeral.Described accompanying drawing is unnecessary proportional, has described schematic embodiment, and it is not limited to scope of the present invention.

Referring now to Fig. 1, show an analyser.Analyser comprises at least one source, a sample connection, at least one detector and related algorithm.Typically, all assemblies of this analyser are included in the single unit, but this is not necessary.Among Fig. 1,analyser 100 is expressed as basic module 101, communication bundle 102 and sampling module 103.This sampling module and a sample orreference material 104 are connected by interface.In this article, basic module 101, communication bundle 102, sampling module 103, and the combination of algorithm is called as spectrometer and/oranalyser 100.

Whenanalyser 100 was comprised in the single unit, basic module 101, communication bundle 102 and sampling module 103 were integrated in together and are comprised in or are integrated in the single accommodating unit.As selection, basic module 101 is separated with sampling module 103.There is communication between sampling module 103 and the basic module 101 and schematically is expressed as communication bundle 102 at this.In different embodiment, this communication bundle is wireless, transmits electric energy, transmits data, transmission of power or motion and/or transmits fluid.For example this communication bundle 102 transmits feedback control signal, temperature sensing data, coupled fluid, light, data and/or comprises hydraulic fluid.

There is multiple possible configuration in the analyser element in basic module, communication numeral and sampling module.In first example, the source element is integrated in the basic module, and the communication bundle is sent to sample with the incident illumination energy.In second example, the source element is integrated in the sampling module.In these two examples, photon all is by as the sample probe of sampling module part guiding tissue samples.In the 3rd example, be sent to basic module from the signal of sample collection by communication Shu Zuowei data or light by sampling module.Basic module preferably comprises detector and is used to implement the blood processor of algorithm.This algorithm is used for the collection of deal with data and/or control data.If the collection broadband light, then this basic module typically also comprises the wavelength separated device.The embodiment of other that U.S. Patent Application Serial Number No.10/472856 (lawyer's case SENS0011) describes, at this as a reference in conjunction with its full content.

Referring now to Fig. 2, schematically show the example ofanalyser 100, its basic module that is separated from each other 101 is connected by communication bundle 102 with sampling module 103.In this example, the major part of analyser on stayed surface, for example desktop or wall or be installed in unit on the floor.A littler sampling module and a sample, the skin histology as the people is connected by interface.This separation allows to use more flexibly and/or lighter sampling module is used for individual sampling.In addition, according to the management of power, weight and heat, basic module can realize separating ccontaining requirement with sampling module.In an example, experimental subject is seated, its sample point, and arm for example is supported on that go up on a surface and sampling module is brought to this sample point.

Referring now to Fig. 3 A and 3B, show the principle schematic that sample probe control and sample probe move with respect to sample.Sampling module 103 comprises sample probe 303.The activator 302 of the mobile sample probe 303 of controller 301 controls.Signal processing method produces control signal, and it typically is transferred to sample probe 303 by activator 302 slave controllers 301.The sampling module 103 that this control signals transmitted is used to be controlled to small part moves with respect to the Z axle of tissue samples 104 or reference material.Sampling module 103 can be called sample probe or sample probe 303 along the part that Z axle at least moves.In one case, controller sends control signals to the sampling module activator from algorithm, and is preferred by the communication bundle.Under second kind of situation, controller 301 receives the input of sample probe or other pick off and uses this to import mobile activator 302.Like this, in each embodiment, the diverse location of controller in analyser is for example in sampling module 103 or in basic module 101.In these cases, activator 302 relative organization's sample points 104 continuous mobile sample probes 303.Under the third situation, do not adopt controller or activator and sample probe response external force and moving, for example manually-operated or owing to gravity.Sample probe 303 controlled usually along the Z axle never position contacting and optionally move to having position contacting to move to the position of tissue samples displacement with tissue samples.Show the sample probe 303 of first instantaneous time (Fig. 3 A) and second instantaneous time (Fig. 3 B),, wherein, in the very first time sample probe is shown and does not contact with sample point.In second time sample probe that the sample tissue has minimum or nominal displacement is shown.Sample probe at random shift to sample, from sample remove or as the function hereinafter discussed as the time keep static.Optionally guide block 304 is connected on this sample and/or the reference material.Explanation or the input of pick off, for example pressure transducer, optical pickocff or the heat sensor of the spectroscopic data that the input of controller 301 comprises predetermined profile, gather from sample probe 303.

The effect of tissue spectrum displacement

There has been research to carry out the effect that non-intrusion type spectrum is produced with the tissue displacement that determines to produce by sample probe.Employing has the non-intrusiontype glucose analyser 100 of basic module 101, communication bundle 102 and sampling module 103 and gathers spectrum.The applicant has determined to cause corresponding variation by the tissue displacement that sample probe produces in the non-intrusion type spectrum that is associated.This effect will prove hereinafter.

Referring now to Fig. 4 A and 4B, schematically show the removable sample probe 303 that is included in the sampling module 103 and be in and the discontiguous primary importance of sample (Fig. 4 A) at Time1 (very first time).In this example, sample probe 303 passes through T.Blank, G.Acosta, M.Mattu, S.Monfre is entitled as the United States Patent (USP) no.6 of " Fiber optic probe guide placement guide (fiber optics probe guide block place guide) ", 415,167 2002 on July 2) and the Application No. no.10/170 that submitted on June 12nd, 2002, optional guide block 304 elements of describing in 921 are directed into the sample position, at this in conjunction with its full content as a reference.The replaceable sample point 104 that is connected to of guide block element.Cause being connected of sample point and guide block in the opening of guide block, forming the meniscus 401 of skin.This meniscus is generally from the tissue part of the nominal rat of skin histology, but be flat or recessed in some individuality, for example older individuals or have the little individuality of less collagen density at sample point.Meniscal size depends on object, changes every day according to given object, and changes in one day according to object.The a series of pads 402 that are placed on the guide block top sample probe along Z axially down vertical skin surface provide the space to stop (Fig. 4 B) for sample probe 303 when sample of tissue 104 moves.When individual pad was removed, sample probe began to contact sample.The probe that causes deformable tissue samples that removes of extra pad is shifted.

Along with the space stops 402 successive and multiple being removed, spectrum is collected. and Fig. 5 A shows from 1100 to 1930 nanometers of gathering when adopting 1.2,1.1,1.0,0.9,0.8 and 0.7 millimeters pad and produces the single beam spectrum.This is a sample probe 303 along the Z axle with respect to the relatively moving of tissue samples 104, and its size with respect to pad is very important.When pad be moved out of and tissue displacement after the intensity of observing when producing contact reduce.Observe two main spectral signatures: the second harmonic zone is the light of about from 1450 to 1900 nanometers of light and first harmonic zone of from 1100 to 1450 nanometers approximately.In the minimizing of these area light intensity is because chemistry and physical effect comprise the big flood absorptance wave band during in 1450 and 1930 nanometers described below.Fig. 5 B has further analyzed the minimizing of intensity when 1450 nanometers.0.116 volt of intensity of observation and 1.2 millimeters pad mean that sample probe 303 does not also have contact tissue sample 104.Along with the sample probe height from 1/10^ThMillimeter is reduced to 1.1 millimeters the declining to a great extent of observed strength, and expression has been set up and contact skin.This point is confirmed by the single variable effect maximum of pad height by observation in the minimizing of all wavelengths place intensity, and this means that specular light significantly reduces and the spectrum that produces now by the absorptance and the scattering decision of tissue samples.In the U.S. Patent number No.6040578 of S.Malin, this basic role has been described, in conjunction with its full content as a reference at this.Pad subsequently remove the further displacement that causes by the sample of tissue of sample probe.The displacement of the increasing sample of tissue by tissue probe causes the variation of the observed strength of the spectral band relevant with physical characteristic with chemistry.

Referring now to Fig. 6, the function that the single beam of collection spectrum is shifted as tissue samples utilizes intensity reference spectrum to be converted to absorptance spectrum in succession and shows.The absorptance spectrum that produces has shown the chemistry and the physical characteristic of sample.Observe two big flood absorptances (water absorbance) wave band, one concentrates on about 1450 and another concentrates on about 1930 nanometers.Observe a little bit smaller fat and protein absorptance wave band in the first and second harmonic wave SPECTRAL REGION.Observe scattering effect at whole spectrum, but it is more general in spectrographic more high-energy zone.Especially, from about 1100 to 1300 nano collimations to bigger scattering properties and from 1300 to 1930 nanometers produce the absorptance controlled characteristic.That utilizes between the pickup area of incident illumination and skin surface that the sampling spectrum of the pad collection of 1.2 millimeters radiuses causes sample probe and tissue samples insufficiently contacts and manually causes because the specular light of gathering enters the spectrographic low absorptance of crossing that the optically detecting of sample probe causes.In order to strengthen the chemical characteristic of in the first and second humorous wave spectrum forms, observing, utilize 13 second dervatives of Savitsky-Golay at first that spectrum is smoothed across the time, smoothed across wavelength subsequently.Figure 7 shows that and handle the spectrum that the back produces.Second dervative has reduced scattering properties and has allowed observation to chemical characteristic.Control by the absorptance of water, protein and fat respectively in the spectrographic minima that about 1152,1687 and 1720 nanometers are observed.

The variation of the spectral characteristic of the absorptance of water, protein and fat is drawn in Fig. 8 as the function change of displacement.In this example, the absorptance of observing all three kinds of chemical features reduces along with the increase of the displacement of the sample probe that enters tissue samples.The absorptance of individual chemistry and physical features depends on series of factors as the function of tissue displacement.These factors comprise:

● the physical size of the sample probe point that is connected by interface with tissue samples;

● the size of guide block mesopore and the chemical constituent of tissue samples;

● the relative and absolute thickness of skin layer, for example corium;

● the speed that the sample probe displacement enters tissue; And

● the in advance hysteresis effect of contact of external object on sample point.

The displacement of the tissue samples that is produced by sample probe causes the compression of sample point.Described displacement causes a series of variations, comprise following one of at least: because the partial water concentration change that the liquid displacement causes, there is not the variation of local concentration of the chemical substance of displacement, for example the associated change of the variation of the local concentration of collagen and local scattering concentration.In addition, the physical features of sample point is changed.These variations comprise: the compression of epidermis protuberance, and the compression of corium projection, blood compression capillaceous, the distortion of skin collagen matter, and/or skin is embedded in relatively moving of composition.

In this example, the displacement that enters tissue samples along with sample probe observes chemistry and physical change.Concrete chemical characteristic under three kinds of wavelength has been described.Yet this example has proved the spectrum of the broad range of shift affects from 1100 to 1930 nano wave lengths of organizing.Extra spectroscopic data shows that these pressure effects present at the infrared spectral range that expands to 2500 nanometers at least.The variation of scattering mainly from 1100 to 1300 nanometers is remarkable.In addition, the more chemistry of effect representative of special chemistry of the minority of description and physical arrangement displacement and the displacement effect of physical features.The displacement of tissue also influences additional skin chemistry more shown in Figure 9, physics and architectural feature.

Dynamic organization measures

As discussed above, the displacement of the tissue samples that is caused by sample probe causes the spectrographic variation of non-intruding.The displacement of sampling tissue is relevant with the pressure that imposes on the sampling tissue.Yet, when metaplasia, change to the return force that sample probe applies by tissue samples.Therefore, the interaction of sample/tissue preferably is discussed according to displacement rather than pressure.

Response signal

When sample probe moves to sampling, contact sampling, during moving tissue sampling then, the distortion of tissue samples causes many variations, comprises the variation of scattering and absorption.Displacement and applied pressure make the distortion of skin histology layer cause the variation of the optical scattering characteristic of tissue samples.The variation of scattering causes a transient phenomenon of probe contact and sees through the variation of the optical path length of tissue.The variation of sample causes the variation of the absorptance observed, and in some cases, it estimates it is disadvantageous to the non-intrusion type analyte concentration.Absorptance changes the displacement of going back owing to the sample that is caused by the sample probe tissue, and it causes that fluid causes the different optics sample of gathering of photon sampling from the displacement of photo measure volume.These of optics sample deviate from has increased the complexity that concerns between spectral response and the chemical concentrations.

Tissue displacement's control

By the displacement of the tissue of sample probe sampling by suitable being controlled between insufficient and the superfluous displacement or pressure.Sample probe is deleterious with inadequate contact of sample of tissue.The surface of skin is coarse often and irregular.Insufficient contact causes the surface reflectance of a part of incident illumination.Contact minimum air capsule between sample probe and the sample of tissue also reduces the optical interface reflection, and it comprises limited useful chemical information.Light contact need abundance enters capillary fringe so that good light source transmission to be provided, and has analytic signal there, minimizes the reflection from skin surface simultaneously, and it shows as noise.This is helped by selectable light fluid, for example fluorocarbon or FC-40.U.S. Patent Application Serial Number No.10/170 has described the fluid that is used for coupling light to tissue samples, at this in conjunction with its full content as a reference among 921 (the lawyer's case IMET0045CIP).The displacement of too much tissue samples by sample probe is disadvantageous.The main region-of-interest that is used for the measurement of blood propagation analyte is the capillary fringe of dermal zone, its under epidermis 0.1 to 0.4 millimeter greatly.Capillary fringe is compressible zone and to pressure, moment of torsion and anamorphic effect sensitivity.The accurate expression of the blood propagation analyte that is used by the time by health, for example glucose relies on blood to flow into and flow out the transmission of capillary fringe, does not therefore preferably limit this fluidic moving.Therefore, contact pressure is preferably too not high so that too limit in the time cycle of expansion or part limit blood and slit flow direction of flow sampling tissue regions.

The present invention's first illustrative embodiments

In first embodiment of the invention,sample probe 303 is that the part of sampling module 103 and sample probe are controlled probably along Z axle at least, and it is the planar coordinate axes of x, y that is vertically limited by the incisal plane of sample point.

In the first embodiment, basic module kind, the sampling module kind of particular type and the bundle kind of communicating by letter have been adopted.Therefore, the given and described diverse labelling of labelling of the basic module type in this example, sampling module type and the bundle type of communicating by letter.

Tissue samples

In first embodiment of the invention, analyte concentration adopts the sample point at the forearm back side to determine.Yet other zone of health or the volume that are subjected to non-intrusion measurement comprise: hands, finger tip, palm area, the thumb palm refer to, forearm, palm one side of forearm, the outside, upper arm, head, ear-lobe, eyes, tongue, thoracic cavity, trunk, abdomen area, thigh, shank, foot, plantar foot area and the toe of forearm.

Use instrument

In this first embodiment of the present invention, adopt hydraulic pressure roughly to move sample probe relative to sample along the Z axle.In general, this embodiment adopts controller to drive activator, and the mobile sample probe of activator.Referring now to Figure 10 A and 10B, schematically provide the detailed example of embodiments of the present invention.Basic module 1001 is connected to sampling module 1002 by communication bundle 1007.Basic module has a drive system, and it moves hydraulic fluid by communication bundle 1007.In this example, electromotor 1003 is connected to the driving screw 1004 that drives first bellows 1005.Because first bellows are compressed, hydraulic fluid is compressed by the communication bundle and second bellows 1008 are expanded by composite force.When second bellows 1008 expanded, sample probe 1009 moved along theaxial sample 104 of Z.In this example, optionally linear bearing 1010 is used to guide sample probe along the Z axle.The drive system of analyser is in 2 demonstrations of time.In the time 1, (Figure 10 A), sample probe does not contact sample.At time 2 (Figure 10 B), electromotor 1003 compression first bellows 1005, the first bellows second bellows 1008 that expand, and second bellows advance sample probe 1009contact samples 104 gradually.In one optionally disposes, drive system, for example electromotor 1003, directly or indirectly append to sample probe 1009.

In first embodiment shown in Figure 10 A and the 10B, adopt motor driven to be connected to first bellows of second bellows by hydraulic tube.The weight that critical aspects of this design is a drive system is not in the sampling module of contact sample.Preferred sample point is the back side of forearm.As mentioned above, impose on the sampling tissue volume pressure cause spectrographic variation.Determined that heavier sample probe weight applied pressure changes spectrum.This design is the example of class design, and wherein the weight of drive system removes from sampling module.In order to make sampling module littler, making drive system generally also is preferred away from sampling module.Yet, generally acknowledged the drive system may adopt very near sampling module.Selectable drive system is described hereinafter.

Even the inventor only has been found that kidney weight also can cause the variation of spectrum along with the time on the sample probe.For example, if the arm sample is placed on the sample probe, the weight of probe last arm causes the variation of sample point and causes spectrum to become the function of time.If do not solve, these variations have adverse effect to the concentration of glucose estimated result.Selectively adopt the distribution of weight system, it is with the weight transmitting of sample probe around sample point rather than on the sample point.For example, sample probe to the physical interface of sample point around sampling.In first kind of situation, the flexible film that adopts the shape meet sample point and curvature with distribution of weight around sample point.In second kind of situation, adopt pillar, the film of full of liquid or one group of foot (feet), weight is assigned to around the sample point.In another kind of situation, the weight of sample probe is supported by anchor clamps or elementary cell.In this case, the dynamic part of Z axle mobile probe is controlled in one way, causes the contact of sample probe or displacement to enter the sample point minimum, causes imposing on weight, displacement or the pressure minimum of sample point.

Referring now to Figure 11 A to 11D, represented second example of the present invention's first hydraulic pressure embodiment.The driver unit of having represented long-range driving sample probe mobile system among Figure 11 A to 11D.In this example, the hydraulic tube (not shown) from long-range driving and control system is the input of hydraulic fittings.Hydraulic fluid expands or compression bellows 1102 come mobile sample probe, represents that for clear excitation system is not shown.Sample probe slides up and down along the center of Z axle at activator 1103.Probe and mechanical system, for example probe supports 1104 and is directed along the Z axle.The excitation system of representing among Figure 12presentation graphs 11A to 11D is in conjunction with the 3-D view of sample probe.Sample probe by activator along the Z axle towards and/or keep away sample point and move.

Sampling is reproduced

The inventor has determined that the control of sampling reduces the error that the non-intrusion type analyte concentration is estimated.Embodiments of the present invention control parameter, for example photon path, stabilized fiber are qualitative, sample probe/tissue samples interface, coupled fluid, thermal control and the x that sample probe is placed and sample probe limits with respect to the surface by tissue samples, the Z shaft position of y plane sample probe.These parameter influences detect spectral characteristic result's signal to noise ratio and explanation hereinafter.

Photon path

In yet another embodiment of the present invention, adopt the sample probe that has the transmission form and be installed in the collection optical fiber of form, described collection optical fiber roughly flushes with the outmost surface of form.The tip of sample probe, it shifts to and/or removes sample, comprises a detection fiber and transmission form, and incident photon passes described transmission form.In this example, window dimension is configured to allow photon penetrating into sample under the restriction of the minimum and maximum radial distance of gathering the light external dimensions.Minimum range has the buffer and the shell control of the collection optics of pad.Ultimate range in a preferred embodiment is 1.65 millimeters.The selectable embodiment of the present invention adopts and reaches 10 millimeters maximum radial diffusion.The definite many photons of inventor can not cause actual signal greater than a few mm distance radial propagations, consequently change effectively and measure in tissue.

In another embodiment of the present invention, sample probe comprises one or more collection optical fiber with the pad that centers on given collection optical fiber, and given collection optical fiber limits the smallest radial scattering by the sample photon of tissue samples.Pad helps to reduce specular light and is used for obtaining distribution of photons figure with average depth of penetration, and the signal to noise ratio grade of generation enough is used for the non-intrusion type concentration of glucose and estimates.In preferred implementation of the present invention, the depth capacity that photon penetrates surpasses spacer thickness.In an embodiment of the present invention, adopt single collection optical fiber, its fiber core diameter is approximately 100 to 500 microns and preferred approximately diameter is 300 microns.

Stabilized fiber is qualitative

In another embodiment of the present invention, one or more collection optical fiber optical devices are used for direct light from the sample directed toward detector.The spectrum change of the transmissison characteristic of optical fiber optical device causes spectrum change under the situation of various bendings and warpage, for example loss of strength, the spectrographic transmutability that its proof is gathered.Gather optical fiber optical device by communication Shu Yidong and therefore be subjected to the motion artifacts influence.The bending and the mobile loss of propagating by coating from light are big sources of this variation.Light is launched into coating in the termination of optical fiber, and it contacts with tissue samples or reference material there.In addition, when being subjected to strain or doing anxious turning, between optical fiber coating and fibre core, launches optical fiber.Therefore preferably removing the light that passes coating by one or more mechanisms propagates.First mechanism is by stoping light to enter optical fiber for the most advanced and sophisticated coating of the coating of optical fiber reflectingly.Second mechanism provides the fiber stress of optical fiber to eliminate.Use stress relieving in one of multiple at least mode.At first optical fiber is formed ring by loosely.The second, optical fiber moves being subjected on the medium of stress, and described medium is assigned to the strain of optical fiber on the bigger zone.Fiber stress release allows the sample probe tip to move and does not force the radius of curvature of optical fiber curvature too tight, allows the low profile sampling pattern like this.Tight radius of curvature causes the micro-crack on coating, and it allows light to leave fibre core and enter coating, and it is propagated by the communication bundle there.The 3rd mechanism is to a kind of mould detacher of fiber optic applications.The padded coaming of coating is peelled off by the 4th kind of mechanism, and is preferred near the end of optical fiber.Index-matching material is joined then and is coated on optical fiber, and preferred index-matched epoxy allows coating light effusion optical fiber.In example of the present invention, utilizing the outlet port to make optical fiber run out of sampling module in sampling module provides the photostress of optical fiber optical device to discharge, and described outlet port has flexible member, and for example a slice rubber surrounds optical fiber at its exit point.In addition, a kind of mould detacher is used to communicate by letter near the interface between bundle and the basic module.

Sample probe/tissue samples interface

The tip of sample probe contacts with tissue samples.Tissue samples does not have flat fully surface.The natural curvature of people's external surface produces range of curvature radius several inches from about 1 inch (2.54 centimetres) of wrist to thigh or trunk.In addition, in some examples, sampling module or guide block are used to cause the tissue surface shape.For example, the guide block with center bore causes meniscus.The common radius of curvature of meniscus has only several millimeters.Different sample probe tip design adapt to these interfaces.First selects to make the sample probe point that adopts coupling human body curvature.Second selection is to make the softish curved surface distortion of tissue samples up to its unanimity with hard probe pinpoint.The 3rd selects to make the probe pinpoint that adopts little surface area, and by tissue samples relatively flat on than small size, it needs the minimum concordance of tissue samples.The 4th selection is that positive curvature is provided on the tip of sample probe, and first of contact sampling tissue is the center of sample probe point like this.The example radius of curvature of probe pinpoint comprises about 1.0,1.5,2,3 and 4 inches.In one example, the tip of preferred sample probe is very little, less than one square centimeter, and smooth.

Coupled fluid

In another embodiment of the present invention, between sample probe tip and tissue samples, use optional coupled fluid.One of below coupled fluid is used at least: thermal control minimizes the air of sample probe/tissue samples interface, and increases the light that is coupled into decoupling skin.The accurate addition of coupled fluid volume has increased the spectrographic accuracy of result, defeats the gradient of power and makes the tissue samples distortion because the trapping of coupled fluid under sample probe increases hydrostatic.In addition, the homogeneous film thickness of coupled fluid minimizes the angular distribution of sample probe relative organization sample and the film thickness of generation minimizes from the detection of skin surface direct reflection.The coupled fluid scope of using preferably is applied as 20 microlitres from about 5 to 100 microlitres.Coupled fluid is applied to sample point with manual or automatic mode.Automatic transmission system allows to use more accurate volume, uses the heat energy control of coupled fluid, and is simply used by object.U.S. Patent Application Serial Number No.11/031 has described in 103 (submissions on January 6th, 2005) and has adopted optional donkey pump transmission coupled fluid by algorithm controls.In an automatic coupled fluid transmission system, coupled fluid is the storage cylinder from sampling module, container preferably, perhaps carries by the intrafascicular pipe of communication.Optionally, coupled fluid approximately had been the sample point temperature by thermal control before being transferred to sample point, so that minimize the temperature effect in the sampling.In one example, about 20 milliliters coupled fluid, for example FC-40 is applied to sample point before the sampling.Do not use coupled fluid in certain embodiments.

In alternative embodiment, the coupled fluid between group sample probe and the tissue samples forms a beach fluid of the part of about 1,2,3,4 or 5 millimeters thick.The inventor determines, adopts focused light to allow light to penetrate coupled fluid and enters sample.This allows not take a sample under the sample probe tip contacts the situation of sample.Has the quantity that increases the photon on transdermal surface greater than the refractive index of air.

In another embodiment, as mentioned below, circular sample probe tip is used in conjunction with coupled fluid.When sample probe near to or in contact with sample, excessive coupled fluid away from the center of sample point by radial displacement.The fluid that this prevention is caught is delivered to tissue samples with pressure from sample probe movably.

Heat

In another embodiment, sample probe interface is subjected to thermal control.The importance of the thermal control of sample probe has several reasons, comprise food and FAD (FDA) article processing needs, along with the volume of production stability of time series analysis instrument, and sample probe is to the influence of the thermal properties of the sample interface that comprises the most advanced and sophisticated and tissue samples of sample probe.

A kind of technology of thermal management is to adopt one or more optical fiber to reduce to the photon volume of production that does not need wavelength of tissue samples.Adopting optical fiber to reduce photon output causes owing to wave filter is heated in the conduction and/or the radiation heating effect of lamp.Preferably, the sample probe tip before contact by thermal control in about tissue sample surface temperature to be minimized in the thermograde that causes the interface that spectrum moves aspect wavelength and the intensity.Special control temperature approximately is 93,94,95,96,97 and 98 degrees Fahrenheits.The heat temperature controlling of wave filter reduces the variation of sample temperature when sample probe touches tissue samples.Coupling sample probe tip temperature and tissue sample surface temperature reduce because or the Fast Heating of the sample probe optics or the tissue of taking a sample or the spectrum change that cooling causes.

The surface skin temperature is dynamic.In an embodiment of the present invention, coupled fluid by thermal control at target temperature.Target temperature is from 85 to 98 degrees Fahrenheits, preferred 90 ± 2 degrees Fahrenheits.The coupled fluid of controlled target temperature is applied to the tissue samples point then.This hull-skin temperature with skin is adjusted to known temperature.Preferably, target temperature is a little less than human body temperature.Optionally the tip of sample probe also is controlled in target temperature.Therefore, when sample probe contact tissue sample point, there is a little temperature difference between sample probe tip and the tissue samples point.Optionally, with reference to be subjected to temperature controlled.

Have black-body resource, after the source and the wave filter before the fiber optic tip preferably be used to remove wavelength, if described wavelength be unnecessary to measurement and incide skin, cause the photon heating of tissue samples.An example is to use the U.S. Patent Application Serial Number No.10/472 of above K.Hazen, the silicon of describing in 856.The material of sample contact optical device influences heat and transfers to tissue samples from the sampling probe tip.Some optics caloric restriction is delivered to tissue, for example heat resistant glass or vitreous silica, and its pyroconductivity is respectively 1.15 and 1.38W/m-K.These optics restrictions are delivered to tissue samples to heat from the sampling probe tip, restriction tissue samples variation of temperature.Other materials, for example pyroconductivity is the silicon of 150W/m-K, conducts heat easily, conducts stronger and makes tissue sample surface reach the temperature of setting easily.On generalized meaning, the control on the surface of the selection of the material of contact skin by considering tissue samples will be controlled or the degree of leaving its oneself internal heat adjusting for be determined.In one example, preferably adopt two wave filter.First wave filter remove the heat that is derived from the source photon and second wave filter with the heat passage sample of tissue point that is limited in.

Sample probe is placed

Human body is a dynamical system.The sampling interlacing point also is dynamic.Along with the time, the sample point alteration of form.For example, when guide block is attached to skin and/or selecteed sample of tissue o'clock among one day during retest, the meniscus that forms is with respect to the Level Change of reference position, and this is because the causing one of at least of the physiological change of the hysteresis of sampling and human body.At fixed height setting sample probe point, cause the difference displacement that the sample probe tip enters tissue samples in one day time then, cause different samplings.A kind of sample probe of algorithm controls moves permission and enters tissue samples with continuous sampling even contact or even displacement.

Polyalgorithm is used to control sample probe and moves, and comprising: adopt direct reflection, adopt chemical information, adopt physical message, adopt sensing data, and pattern recognition.These methods are discussed below.

Adopt direct reflection to be used to control the sample probe displacement and allow to determine sample probe contact tissue sample, and before at the U.S. Patent number No.6 of K.Hazen, part is introduced in 534,012, at this in conjunction with its full content as a reference.Direct reflection is used in real time or spectrum or the grating of post processing exceptional value detecting pattern to determine whether when the contact tissue sample of sample probe tip to obtain to select, or the relative distance between definite sample probe and the sample.As arriving at height sampling absorptance regional observation, contact is represented in the basic removal of specular light, and the signal that detects in these wavelength region may is the indication of the air gap between sample probe tip and the tissue samples simultaneously.

As selection, with continuous or semicontinuous collection of data acquisition model or analysis spectrum.In first kind of situation, gather spectrum according to predefined agreement.For example, after destination organization point initial movable, collect one group of spectrum at sample probe in predetermined interval.In second kind of situation, adopt in real time or semireal time analysis and guidance based on the data acquisition of sensor reading.Pick off is optional a kind of aiding sensors, a kind of touch sensor, or from the reading of analyser.For example, analyser is gathered spectrum and spectrum or one or more spectral characteristic are used to be determined to the distance of sample, contact, displacement, pressure, and/or direct reflection.The example of spectral characteristic comprises absorption bands, scattering properties, the signal of extraction, pre-processed spectrum reading, or abstract feature.Feature is analyzed and be used to instruct afterwards data acquisition by analyser.For first example,, guide analyser to continue to move so and periodically gather spectrum if do not obtain contact between sample probe and the sample.In second example, tell analyser to stop mobile sample probe and collection.In the 3rd example, algorithm detects direct reflection in real time and uses this information to remove to control activator, and this activator is positioned to the sample probe tip to contact with the tissue samples nominal.Obtain spectrum at this point, after the sample probe tip further entered tissue samples, perhaps sample probe was moved to approaching position, and for example about 0.11 to 2 millimeter, spectrum is gathered once more.When needs, repeat this circulation.In general, adopt signal or feature to control follow-up data acquisition step in the algorithm.

Selectable, adopt sample probe displacement chemical information to determine contact and displacement.The chemical feature absorptance, for example water, fat and protein are determined by algorithm.Because these features are pressure sensibilities, mathematics relatively, or the operation of absorptance is used to determine that displacement is minus, nominal, or positive.

Selectable, in the sample probe displacement, adopt physical message to determine that sample probe point relative organization sample is minus, nominal or positive displacement.For example, adopt above-described direct reflection.In addition, adopt scattered information to determine pressure.Scattered information in the second harmonic zone of about in thisrespect 1100 to 1400 nanometers is to be particularly useful.

In the sample probe displacement, pick off is also useful to the relative position of sample of tissue to determining the sample probe tip.For example, adopt pressure and/or temperature sensor to determine approximation.

Optionally, algorithm sample probe displacement method, for example intelligence system or pattern recognition also is used to control the position of the most advanced and sophisticated relative organization of sample probe sample.Typically, the input of these systems is spectrum and represents chemistry discussed above and physical message.

In all these sample probe displacement control algolithms, the sample probe point is determined the relative position of tissue samples.A kind of sample probe of algorithm controls is from nominal position, electromechanical stop for example, or, be used to control the displacement minimum of the tissue samples between the sample that is displaced in the tissue samples or allows to cause by probe pinpoint from the moving of nominal contact.Because the tissue samples external surface shape is dynamic, is different between the individuality, and between the different sample every day change, so this is important.In one example, adopt a kind of algorithm to determine and the position of controlling the most advanced and sophisticated relative sample point of sample probe, as described below.

Chemistry that above example adopted and physical features are exemplary.Sample probe moves available relevant information or the combination of minute surface, chemistry, physics and algorithm extraction feature or technology is controlled.For example, adopting the algorithm information that obtains from chemistry and scattered information to control sample probe moves.

Instance data group and analysis

Pass through to use instrument collection and analysis example data described herein according to the present invention.

Experiment

Instrument

Glucose analyser based on diffuse reflectance is used for gathering calibration and estimates (prediction) near infrared spectrum.As mentioned above, the concentration of glucose analyser comprises sampling module and the basic module that is connected by the communication bundle.Sampling module comprises source, rear reflector and optics.The communication bundle transmits energy, hydraulic fluid and optical signalling.Basic module comprises grating and linear array detector.Wavelength and intensity benchmark are gathered and are used.In this case, wavelength standard is that polystyrene and intensity benchmark are politef (polytetrafluoroethylene).Sample is the human body forearm.With stationary probe and floating probe collection calibration and monitor data.Has Dan Shu (bundlet) at the palmar aspect collection of forearm calibration and monitoring spectrum and probe.In top-down fiber probe structure, with the movable floating probe collection prediction of z axle spectrum with the back side of single collection fiber sampling forearm.When example is for concrete analysis during instrument, the present invention is applicable to from the data matrix of a large amount of correlation analysis instrument and sample point generation, for example in the 10/472nd, No. 856 (lawyer's case SENS0011) middle those disclosed of U.S. Patent application, described application is all quoted with for referencial use at this.

Data set

Analyser in this example is used for gathering the spectrographic calibration of the non-intrusion type with relevant concentration of glucose, monitoring and independent estimations (prediction) group.Calibration, monitoring and independent estimations data set use with following processing method.Calibration matrix representative is at 1109 spectrum that use two analysers to gather on six objects altogether during eight weeks.The monitor data group be included in 20 weeks during use two analysers on six objects altogether, to gather 1547 spectrum.Estimate the representative of (prediction) matrix come comfortable many weeks during 126 samples of nine different objects on nine visitors altogether, gathering of two analysers of use.

Data analysis

With respect to the different z shaft position collection of the sample probe of sample, be meant grating or grating spectrum with generating the single a plurality of spectrum that duplicate at this.Referring now to Figure 13, show the relevant intensity grating spectrum of given sample with the given object that is used for estimating (prediction) single concentration of glucose.Z axle rate travel collection with 32.5um/ second is used for producing these grating spectrums that single concentration of glucose is estimated, wherein when sample probe when sample moves through total projection distance of sample probe of 0.95mm, per 0.2 second collection spectrum.Figure 13 illustrates each the tenth spectrum of on first sample, gathering.Along with sample probe contacts near sample and with sample, the intensity in second harmonic spectral regions (overtone spectral region) (about 1100 to 1450nm) and first harmonic spectral regions (about 1450 to 1900nm) is observed amplitude and reduces.On behalf of sample probe, higher-strength do not contact with sample.On behalf of sample probe, intermediate intensity contact with the fluorocarbon contacting with fluid (fluorocarbon contact fluid) of for example FC-40.Represent sample probe to contact than small intensity with sample.The sample displacement that the intensity representative of gathering is at last caused by sample probe.

Referring now to Figure 14, the time-based intensity spectrum of the grating of the given sample of the given object shown in Figure 13 is converted into absorptance.Observe absorptance along with sample probe moves and reduces to sample.This mainly is the removal of spectral reflectance light.For example, light intensity near zero, there along with sample probe moves to contact with sample to sample, has big water absorptance wave band at 1450nm.

For this sample, figure 15 illustrates each grating intensity reading at 1450nm.Intensity is observed along with sample probe descends fast near sample, thereby has spike (spike) when reaching the fluorocarbon fluid or when sample probe contacts with sample, and flattens whole along with sample probe minimum level ground displacement sample.The speed of sample probe is fast more, and spike is confirmed as big more.Sample probe enters displacement in the sample when increasing, and usually observed observation intensity increases.This is the pressure effect of displacement water.Usually, the wavelength from about 1400nm to 1900nm is arranged by absorptance, and is opposite with scattering, and relevant with the absorptance of sample in the intensity of the big flood absorptance wave band of 1450nm.

Referring now to Figure 16, show intensity at each grating spectrum of this sample of this object of 1271nm.In the second harmonic district, the intensity reading has and the bonded big scattering parameter of absorptance.Observe along with sample probe moves to sample, intensity descends at the beginning fast, observes spike then, and intensity can fast rise or continuation decline then.Spectrum is represented the complex interactions of sample probe and tissue.In the initial decline of the intensity in 1271nm and near for example 1150 to 1350nm the zone it is owing to along with sample probe reduces to the collection that sample moves the spectral reflectance light that causes.Spike is because at least one of several phenomenons.Spike partly is because sample probe contacts with fluorocarbon fluid on the sample.Along with probe moves in the fluid and excessive fluid is extruded from sample path, form pressure.At this moment and the time afterwards, sample probe is exerted pressure to sample, causes the stretching, extension of collagen and causes the increase of scattered light.And some water are shifted from sample, cause relative concentration in the scattering object to increase and the increase of scattered light.In addition, determine that the amount of the collagen in scattered quantum and the sample path is relevant.Therefore, the elderly woman that for example has a less collagen has the littler variation of the observed scattered light in the second harmonic district.

For each grating spectrum of the given sample of given object, the module that use produces with calibration and monitor data is carried out concentration of glucose and is estimated.Figure 17 illustrates the result.Observing the concentration of glucose of wide region estimates to cause from about scope of 100 to 300mg/dL.This is the spectrographic expression that does not drop in the space that is covered by calibration module.For example, the low concentration of glucose of initial spectrum prediction that spectral reflectivity is strong.In addition, the accuracy of concentration of glucose estimation is poor for given grating.Solid line represent from data acquisition two seconds moving windows, estimate in the average glucose concentration of ten gratings of 5Hz acquisition rate.This has increased the accuracy that concentration of glucose is estimated significantly.In addition, along with sample probe arrives sample, concentration of glucose begins to flatten whole.Then, along with sample probe contacts with the initial of sample, produce metastable concentration of glucose estimated result.Common increase scanning afterwards causes competent signal to noise ratio to be estimated to allow clinical accurate and accurate concentration of glucose.Therefore, it is important estimating to select the different grating spectrums of suitable z axle for concentration of glucose.The general method of making this selection is to be used for determining that by use the threshold value of acceptable grating selects to have the spectrum of the high absorptance that water absorbs.Alternatively, use the ratio of the intensity of two wavelength that have threshold value.First wavelength that this ratio uses expection to have the high absorptance of very little response intensity, and expection has high-intensity second wavelength, for example about first or the centre in second harmonic district.Below show a plurality of methods that are used to select grating.

On the data of the given sample of the given object that reduces spectrum quantity, carry out a series of pre-treatment step.Typically, data by spectrographic be chosen in quantitatively to reduce and to learn a skill by the stoichiometry of for example dividing equally (averaging) and meansigma methods centralization (mean centering) handle to reduce spectrographic quantity.In this example, for using 1455 and each raster scanning calculating strength ratio of the intensity of 1255nm.Subsequently, scan the logarithm of ratio calculated for each z shaft position of given sample.Selection according to this logarithm ratio corresponding to preceding 20% sample of sample and divide equally spectrographic group as a result.Pretreatment afterwards is identical with processing with the pretreatment of calibration data set with processing.Produce pretreatment and processing method with calibration that is independent of any data estimator and monitor data group.Preprocess method has three steps:

Step 1: carry out 27 first derivative Savitsky-Golay convolution;

Step 2: select and the relevant data matrix of 1150 to 1850nm spectral regions; And

Step 3: meansigma methods centralization.

By use 44 factors and principal component regression (principal componentregression, PCR) models treated matrix of consequence.(standard error of prediction, results estimated standard deviation SEP) is 32.2mg/dL to the prediction standard deviation that is also referred to as on new samples.Utilize this processing, analyze the independent prediction data set.Figure 18 illustrates each glucose concentration curve figure of nine tested objects being used for the independent prediction group.Glucose concentration curve figure is shaped as: on/down, down/on/down and on/down/on, breaking the mutual relation with the time dependent variable of for example room temperature and humidity, and break and other human body component correlations.Calibration data also similarly changes.The concentration of glucose as a result of nine individualities is estimated to cover on the benchmark concentration curve chart.Observe the non-intrusion type concentration of glucose and estimate to meet (track) benchmark glucose concentration curve figure.Figure 19 illustrates concentration of glucose estimation as a result with the graph of a relation between concentration and the benchmark concentration of glucose.Clarke error form covers in this drawing.69.8 of glucose estimation, 30.2,0.0,0.0 and 0.0% A, B, C, D and the E zone that drops into Clarke error form respectively as a result.A and the concentration of glucose in the B zone at Clarke error form estimate it is accurately with accurate clinically.Therefore, 100% concentration of glucose estimates it is clinical acceptable.Result's F value is 4.37.

Optional embodiment

Optional instrument

Motion control system

Optional embodiment of the present invention has been shown in Figure 20 A and 20B.In the first embodiment, drive motors is away from sample probe.Yet, in sampling module, place drive system and allow system more simple.In this embodiment, the parts that are used to drive sample probe are extremely approaching, and are directly connected to sample probe, or are connected to sample probe indirectly.In the exemplary embodiment,driver part 2001 is connected to sampleprobe 2003 by the such moving-member 2002 of for example driving screw.Show the operation of this embodiment in time 1 (Figure 20 A) and time 2 (Figure 20 B).

As shown in figure 21, in another embodiment of the present invention, electromagnet/permanent magnet is to driving by controller.Magnet is to moving sample probe along the z axle with respect to tissue samples.In this embodiment, tip and the sample interface form of gathering optical fiber are displaced to tissue samples, and are displaced in the tissue samples alternatively.Alternatively, all move by activator with for example relevant optics of rear reflector, optical filter and sample probe point in the source.Mobile together sampling module optics has reduced the impact of optical coupling and the light that incides on the tissue samples distributes.In two embodiments (Figure 20 A/20B and 21), gather optical fiber penetrate alternatively the interface form and with the impact of the flush of sample interface form with the direct reflection that reduces skin.

Moving of sample probe element preferably surpasses limiting distance, for example from about 0 to 10mm.This magnet moves less than 0.1mm making sample probe.Use encoder, mechanical brake or dynamo-electric assembly (mechano-electrical components) to carry out the positioning control of sample probe alternatively.Magnet right active half be permanent magnet or electromagnet.In the preferred version of present embodiment, permanent magnet is subjected to the electric current in the electromagnet and moves.

As shown in figure 22, in another embodiment of the present invention, cam is used for the mobile of driver and sample probe linked together.For example, the cam with eccentric outstanding (eccentric lobe) is used for spinning movement with driver part and is converted to linear sample probe and moves.

In another embodiment of the present invention, the fluid regulation drive system is used for moving sample probe along the z axle with respect to tissue samples.As shown in figure 23, fluid pressure is used for mobile sample probe.The fluid regulation drive system comprises: fluid container, valve or hole controller and bellows.System can work under the pressure of wide region.Yet optimum system choosing ground is at high pressure operation, thereby the displacement of sample probe and time are linear, allows closely control sample probe position.The advantage of fluid regulating system is that it is passive system alternatively.

In another embodiment of the present invention, sampling module be positioned on the sample point and at least a portion sampling module, sample probe for example is because gravity is pulled to sample point.The sample point applied pressure is distributed to whole zone by the weight with sampling module and is alleviated.Alternatively, the most advanced and sophisticated detachable tip of using of sample probe with different table area.Make the weight of probe tip be disperseed like this and produce the different pressures on the sample point and the different displacements of tissue samples.

In additional embodiment of the present invention, the tip of sample probe is the tip that comprises single collection optical fiber, surrounds the fibre bundle of pad and the lighting fiber around pad of gathering fiber or the ring that throws light on.In this embodiment, be deep into the greatest optical degree of depth in the sample greater than the pad cross section.

In yet another embodiment of the present invention, dynamically the z axle moves mobile combination the one of at least that is used for along x and/or y axle.In this embodiment, the freedom of movement of sample probe is not limited to the z axle.Probe uses one or more driving mechanisms control sample probes along any one of x, y and z axle or all move, thereby sample probe is along the line, plane or move as time function in three dimensions.Give analyser (measuring system) with sighting system or by operational analysis instrument signal aiming sample with direction.Therefore, dynamically the z axle moves and points to given sample position.In No. the 60/656th, 727, the U.S. Provisional Patent Application of on February 25th, 2005 application, further described the use of the sighting system that is used in combination with analyser, described application at this all in conjunction with for referencial use.

In another additional embodiment, only nominal ground moves with respect to sample along z axle control sample probe, makes it about reasonably controlled but do not controlled by strictness with the vertical central shaft of skin.This is called as about vertical relatively, the swing in the moving of central vertical shaft or tilt (slop).This action is specially designed or as not obtaining the result of perfect manufacturing tolerance.

Also there is the additional embodiment a large amount of of the present invention that is used for moving sample probe along the axial sample point of z.These comprise:

Permanent magnet/electromagnet is right;

Hand crank;

The motor gear group;

Lever arm;

The jack of cultrating;

Worm-drive;

Counterweight;

Spring control system;

Air pressure;

Fluid regulating system;

Hydraulic system;

Bellows;

Driving screw;

Linear electric machine;

Motor;

Cam;

The GRAVITY CONTROL system;

Controlled potential energy discharges;

The rotating screw line;

Wedge;

Swing pinion;

Rotary-piston;

Mechatronic Systems;

Memory metal;

The magnetorheological logical system;

Controlled viscosity system;

Magnetic system;

Cable drive;

Air bag;

Air rammer; And

The for example expansion of the material of wax and contraction.

Other system is conspicuous for those skilled in the art.Middle device comprises machinery, electromechanics and hydraulic system, and the system that is connected to the parts that are used for traveling probe in logic.

In the above-described embodiment, sample probe is the part of sampling module.Alternatively, sample probe is the part of analyser, and described analyser is not separated into basic module, sampling module and the bundle of communicating by letter.In this embodiment, sample probe is that a part and the sample probe of analyser moves to sample along arbitrary axis.For example, analyser on the table and sample be placed on the analyser.Sample probe moves up along the direction of axial contact of z and displacement sample.

Lock control

In additional embodiment, z axle moving curve is predetermined.Thereby, system does not have the z axle of sample probe to move with open loop mode work feedback control.In optional embodiment of the present invention, sample probe passes through algorithm controls with respect to the mobile of sample with closed loop mode.In this embodiment, algorithm uses input to move with the z axle of controlling probe.Input comprises the output of spectrum and/or heat input or aiding sensors alternatively.For example, observed chemistry and physical characteristic are used for controlling moving of sampling module in the spectrum of auxiliary base or sample.An example is to use the zone that comprises high water absorptance to determine via direct reflection when probe fully contacts near sample or with sample.Another example uses spectral signature ratio to make suitable optics contact to determine when.For example, ask the ratio in zone of high and low absorptance and this ratio to be used to priori threshold value (a-priori threshold) and stop mobile sampling module to indicate analyser.On wide significance, the benchmark of determining at one or more wavelength or absorption, intensity or the scattering signatures of sample offer the algorithm that the control sampling module moves with respect to sample with input.Alternatively, the input source in the spectrum outside of gathering is used as the input of algorithm.Several examples comprise the pressure transducer on the skin, break the plane (plain) of laser or optical signalling on sample point, and electrically, magnetically or dynamo-electricly finish contact.

Though describe embodiment individually at this, the permutation and combination of element described here, embodiment and system also can be used for the Kinematic Positioning of sample pick off and/or along with the data acquisition of sample optics sensor tip end with respect to the analyser that moves of skin histology sample point.For example, closed loop system is applicable to many open-loop design.In addition, each appliance design is herein used with the one or more algorithms that illustrate below.

Optional probe moves

Preferably, sample probe nominal ground during sample obtains and/or between move along the axial sample of z.Alternatively, sample probe moves or moves away sample point with speed different or that change to sample point.Usually, sample probe is mobile preferably controlled and/or reproducible.The position that it is desirable to respect to skin is known, but is not necessary.And, preferably know z axle speed as time function, but not necessarily.Usually preferably sample probe is moved to very and contact near sample or with sample surface.Usually, do not expect with the sample probe sample that is shifted.Yet, be preferred sometimes with sample probe displacement sample.For example, also extracting probe subsequently out with sample probe displacement sample tissue can cause fluid to flow in the sample point.This has increased the sample volume that comprises analytical information and has helped balanced concentration of glucose between the human body fluid space.

Sample probe is possible towards sample or away from the certain limit of the at the uniform velocity rate travel of sample.First example is the sample probe that moves with at the uniform velocity.Typical velocity interval is in about 15 to 100um/ seconds.Yet, use slow and fast speeds, for example about 5 to 200um/ seconds.Two preferred rate travels are about 16 and 32.5um/ second.When beginning or stop when mobile or comprise when using the period that static probe moves use than jogging speed when the timetable (profile) that uses.Actual rate travel depends on other parameters, for example the cross-sectional area of hydraulic fluid transfer tube.Figure 24 illustrates the example of the fixedspeed rate travel 2401 of sample probe as time function.

The rate travel of sample probe needn't be fixed speed.The sample probe curve example of several exemplary is provided in Figure 24.Example is to have the probe tip of speed of minimizing or the probe of deceleration, for example shown in 2402.The probe speed of slowing down has initial velocity and slope.Initial velocity and slope cause arbitrarily given time point those at the uniform velocity the probe in the scope of probe move.Second example is to be interrupted rate curve, for example shown in 2403.Being interrupted rate curve is any moving curve with the fast-changing interruption of speed and cycle.An example of use unbroken curve moves quickly into sample probe with sample and closely contacts.Near determining, for example check the algorithm of spectrum contact or inspection pedestal effect by vision or with algorithm.Pedestal effect is spectral reflectance and is described in conjunction with in No. the 6th, 040,578, the U.S. Patent application for referencial use in front.Along with sample probe near sample, speed of displaying curve 2403 is slower.Yet the speed increase is possible.The 3rd example is the curve that changes speed in time, shown in 2404.The rate curve 2404 that changes is designed to probe the moving to sample of slowing down when the degree of closeness of sample probe and sample reduces.The 4th example of rate curve be before the sample spectra collection 2505 and/or during time period sample probe is moved stop.Curve as other sample speed of time function comprises sine curve, logarithm, quadratic equation or higher order polynomial.Also have other probe speed curve to comprise symmetry and skew curve.Arrangement and/or combination that other probe speed curves are above-mentioned curves.For example, probe circulates mobile towards sample with away from sample, wherein endless form generation one or many and begin and stop following intra-annular arbitrfary point.In the example that provides, what move is the most advanced and sophisticated or sampling module of probe tip, sampling.Alternatively, mobile sample point, thus obtain relative sample probe described here/sample point z axle moving curve by mobile sample.These move preferably along the z axle.Yet, be used for changing the sample position along x and/or y axle mobile.

In the example that as above provides, it is 0.95mm that sample probe moves towards total z axle of sample.The specific assignment sampling probe unit of describing in the example in the above has the movable projection distance of 1.3mm.Yet, realize big distance easily.For example, potential z axle moves and comprises submillimeter (sub-millimeter) or about 1,2,3,4,5 millimeter or above moving.

Usually advantageously sample probe is initially moved to sample.Yet, can be provided with that sample probe initially contacts under minimum pressure with sample or at the flexible sample of initial contact with the sample probe displacing part.Subsequently, after further being displaced in the tissue, sample probe moves away from sample alternatively.Loosen along with dermatological specimens like this and produce negative pressure.Typically, scattering reduces along with loosening.For example, scattering coefficient reduces in the second harmonic spectral regions of about 1290 ± 100nm.

Usually move and/or collection grating or spectrum when it stops when sample probe.Under first kind of situation, when moving, gathers sample probe raster scanning.Under second kind of situation, gather grating in the subclass of the time period that sample probe moves.The time subclass is successive or is separated into two or more time periods.Data or grating are gathered and are preserved, and perhaps data are compressed in real time or at one's leisure.Under the third situation, gather grating in speed of very first time section with in the second speed of second time period.For example, when probe is gathered grating during near sample not too continually, and when realizing correct placements of probe collection grating fast.The advantage of during the subclass of traveling time, gathering be the storage grating require less.In further storage save mode, in case algorithm is determined gathering acceptable grating, grating is divided equally or is calculated mathematic(al) manipulation, thereby only needs to be used to preserve the subclass of the space requirement of all gratings.An example is rolling average.Second example is data compression.

In yet another embodiment of the present invention, at first mobile sample probe is gathered all gratings simultaneously, and the grating of quantity is not perhaps gathered grating in the middle of gathering simultaneously.Stop to move of sample probe then.When stopping, gathering sample probe second group of grating.An example of this configuration is that mobile sample probe has been set up sample probe up to algorithm and contacted with the suitable of sample.Alternatively, algorithm uses first group of grating to stop to move of sample probe to determine when.Sample probe stops and gathering second group of grating subsequently.Second group of grating is used as the main data group processing of the grating of saying in this place.The optional mode of the halt that closed loop algorithm is determined is an open cycle system, and wherein sample probe moves on predetermined curve before stopping.Also can for example use the modification that move/stops/reading and repeat to move/stop/reading.

In other embodiments of the present invention, sample probe moves through multiple curve, for example sine wave pattern.Grating with the collection result in various degree that do not contact, contact and/or be shifted.Use lock algorithms (lock-in algorithm) to leach the function of undesired signal subsequently as displacement.

Optional algorithm

Usually, the grating of each sample provides spectral information and z axis information.Handle grating to produce the single beam intensity spectrum of one or more results with the different chemical metering unit.The single beam spectrum is to use the processing of Chemical Measurement to produce one or more analyte concentrations afterwards as a result.In U.S. Provisional Patent Application the 60/558th, the U.S. Provisional Patent Application the 60/599th of 610 (lawyer's case SENS0007PR) and application on August 6th, 2004, the example of pretreatment and processing unit is provided in No. 431 (lawyer's case SEN00053PR), and described application is all combined with for referencial use at this.

The information in the dynamic spectrum transition of being included in is used for selecting the scope of raster scanning, and the optical characteristics that has relation between grating response and chemical constituent has been represented in the perhaps sampling of the raster scanning of a period of time, described sampling best.This spectrum selects preferably representative to simplify the reproducible optics sample of quantitative optical spectral measurement.Alternatively, select by in given calibration bunch, selecting spectrographic intelligence system to carry out this spectrum.At U.S. Patent application the 09/664th, in No. 973 (apply for 2000 on JIUYUE 18) and by T.Blank, S.Monfre, T.Ruchti, the U.S. Patent application made from S.Thennadil the 6th that is entitled as " A multi-tier method ofdeveloping localized calibration models for non-invasive blood analyteprediction ", 512, further described calibration bunch in No. 937 (applying on January 28th, 2003), described application is all combined with for referencial use at this.Under any circumstance, the selection of one or more time windows (time window) permission is measured in the wide region of the sample probe displacement of the tissue samples that comprises the little displacement relevant with little applied pressure.This selection is important in many cases, comprises that optimum measurement pressure relates to the situation of given subject's skin characteristic and every day or skin hydration weekly and changes and cause by the situation of sample probe in the variation of the contact pressure of the specific displacement of tissue samples.

The collection of the continuous spectrum during the moving of optical probe provides the useful enhancing information of accuracy that the non-intrusion type concentration of glucose is estimated.The form of data is dual.The first, spectrographic time series is gathered and evenly or is discretely taken a sample by the time.The second, the time series of data about probe to the tissue in penetrate sampled.Two groups of time series datas provide the selection of the characteristic that comprises types of organization, best preprocess method, the detection of mistake measurement and the unique information of determining of optimum calibrating patterns.In addition, time series spectrum forms and closely similar matrix or the cube of image.The kinetics of this two-dimensional signal and types of organization and optical probe is got in touch.The chance that further solves clean analyte signal by the multimode data analysis is provided like this.The different purposes of multidimensional data be classified as wavelength to time, wavelength to the position and by wavelength to time and position and the image that forms.

Allow the classification of types of organization and interferential character in time with the character of the spectrum change that is shifted.And this allows to select optimum calibrating patterns to be used to make the non-intrusion type estimation of analyte attribute.In the past, types of organization was classified according to the character of observed spectrum change in time series is measured.Categorical data is used for producing the calibrating patterns relevant with each bunch.At last, select calibration and use it for non-intrusion type analyte estimation or definite based on the types of organization that shows by the time series measurement.For example, multivariate time series spectrum uses to determine the state of tissue with the Kalman filter of Kalman or extension.Alternatively, for example the key group of the spectral signature of the time correlation of water, fat and protein belt (protein bands) variation response is used for discerning types of organization and state.At last, the variation of the score of determining from abstract factor analysis is used for modeling and characterize the different tissues characteristic and can determine types of organization.

Two-dimensional time or shifted data and three-dimensional time provide big ability to come by image processing techniques and multichannel analysis (multiway analysis) the difference clean analyte signal relevant with analytic signal with the shifted data group.Contact Dynamics and tissue property by probe get in touch the high-order measurement.This contact can be used the higher-order method of the detection and the extraction of the clean analyte signal relevant with analyte.For example, following multichannel method is used with floating probe system and time series spectral information: subtract order factorial analysis, broad sense and subtract rank technique, parallel factor analysis (parallel factor analysis) and multichannel calibration.

It is important that the definite grating that will be used for the follow-up data analysis of inventor is selected.In some cases, select all gratings.For example, divide equally grating to increase signal to noise ratio.In another case, carry out time series analysis with definite exceptional value (outliers), thus and/or the grating of the selection of the difference in grating subsequent analysis.Under another situation, carry out exceptional value and detect to select to satisfy the grating of specification.For example, check single grating, for example signal to noise ratio or sample probe/tissue samples contact distance based on tolerance.Be combined into the data set of later process by metric grating.Metric example comprises signal to noise ratio, one or more intensity threshold and/or one or more absorption threshold value.In another example, one or more grating bands are used for subsequent analysis.For example, only select grating, select expression to be coupled to the grating of sample with sufficient signal to noise ratio, or the grating of selecting expression to contact with sample.The spectrum relevant with the grating of selecting is used for subsequent analysis subsequently.Some examples of pretreatment grating are provided at this.

The inventor has determined that the selection of grating and correlation spectrum thereof after sample probe contacts with sample is useful.Spike in the grating curve relevant with time or position with contact relevant.Therefore, having studied multiple technologies is used to use spike to determine contact.Use other technologies to be used for determining not use the contact of spike.Be several examples below.

Referring now to Figure 25, show and gather a plurality of intensity gratings that are used for the single sample on the single object.A kind of method of determining contact is to select spectrum, wherein preselected wavelength or alternatively one or more intensity of the absorptance of preselected wavelength drop on threshold value, ratio and the tolerance or under.For example, keep the intensity that has under the threshold value of 1450nm.Threshold value is general, customizes for object type, or for specific to liking.At 1450nm, example thresholds is about 0.05,0.1,0.15 or 0.2 volt.Similar threshold technology is used for having alternatively other wavelength of different threshold values.Also use from a plurality of wavelength, the combination of wavelength, ratio, bunch analysis is perhaps studied threshold value from the signal of the mathematic(al) manipulation of data.If a wavelength or a plurality of wavelength for test satisfy tolerance, be used for subsequent analysis with bunch relevant spectrum so.

Another method is by using one or more choice criteria to select window or the piece and the corresponding spectrum thereof of grating.For example, change by (time cutoff), based on the time period, based on the position of sample probe, based on spectral signature or based on signal based on the time and gather the function of grating as time or position.The intensity grating for the single sample collection on the single object shown in Figure 25 is analyzed at this by way of example by the combination of using these methods.Along with sample probe moves along the axial sample of z, concentrate on 1450 and the intensity of the ripples section of 1950nm be observed minimizing.This be and sample probe and sample between the result that changes of the efficient of optical coupling of relative distance.Intensity spectrum is converted to absorptance and shown in Figure 26, and it has proved is being longer than the wavelength of 1400nm, along with the mobile change of observing absorptance of z axle probe.These longer wavelengths are arranged by absorptance.At shorter wavelength, the change of absorptance exists, but it is not strong.From 1100 to 1400nm, scattering has than from 1400 to 1930nm bigger effects.Grating intensity at 1450nm and 1290nm is respectively that absorptance accounts for representative leading and that scattering has the intensity of relatively large effect.

Be used for determining for example time point that contacts of sample probe and sample at separately intensity, absorptance or the curve of the grating of wavelength.For example, 1450 and the grating intensity gathered of 1290nm be plotted as the function of the grating quantity among Figure 27.Intensity at 1450nm is observed minimizing and flattens whole subsequently.The variation of slope is the expression that sample probe contacts with sample.This ancon is used for the setting-up time point.Typically, at this moment between the point after grating be used for subsequent analysis.Yet, at this moment between before the point and afterwards grating be used for subsequent analysis alternatively.The elbow point is effective ways of setting up contact.Yet the improvement of sensitivity is possible.For example, in Figure 27, also drawn the intensity at 1290nm of each grating of given sample.Intensity is used for expression by skew.Intensity is observed and reduces and upwards form subsequently spike at the beginning.Usually, reduce up to making by sample probe and the contacting of sample in the intensity from 1100 to 1300nm zone.After contact, from 1100 to 1330 intensity increases usually.Therefore, the direction of intensity curve changes and to be the indication of contact and to be used for the setting-up time point.

Alternatively, the combination of the response of grating intensity is used for determining which spectrum relevant with the grating of selecting will be used for subsequent analysis.For example, use the ratio of grating intensity.Example is at each of the grating intensity of 1450nm and ratio at the skew grating intensity of 1290nm.Draw ratio and contact relevant clearly breakpoint with sample with sample probe with the time relation generation.The first derivative of 11 Savitsky-Golay is applied to 1450 to 1290nm ratio and at Figure 28 function as the time is shown.Big negative peak is represented contact.This is to be used for determining contacting the sensitivity of relevant grating with sample and sane technology with sample probe.Alternatively, this time period is as allowing between according to sample or grating quantity between the individuality is that the internal standard of consistent time period is selected.In this example, moving relevant spectrum with the z axle and be used for subsequent analysis after big negative derivative peak value.

In yet another embodiment of the present invention, the time series analysis of grating is used for determining that adopting above-mentioned technology when to make sufficient tissue according to for example scattering of water, fat and protein belt with absorption signal contacts.

In another embodiment of the present invention, make difference measurement (differential measurement) by using the spectrum or the part spectrum of being correlated with different z shaft positions or time period.Along with sample probe moves, enters sample, comes out or away from sample, produce different spectral responses from sample to sample.Differential technique thereby be applicable to the spectrum of gathering in different z shaft positions or time period.For example, sample is not compressed when initial contact.After further being displaced to sample probe in the sample, some skin layers begin to be compressed.This compression changes physical samples, thereby changes analytic signal.For example, along with the tissue volume of analyte from sampling is shifted, the capillary tube zone is compressed and glucose signals reduces.Similarly, use from the different gratings of same sample and make difference measurement.This analytical model can be used for being undertaken by sample probe the single or multiple displacement of tissue samples.

In another embodiment, adopt the Best Times sheet of pattern identification with the vector of definite non-intrusion type analysis measurement.Adopt the priori base set to come illustration destination organization state.Spectrographic tested time series and this base set compare to determine the optimum measurement data.

In another embodiment of the present invention, on grating, carry out exceptional value and determine.The character that grating in time changes makes it possible to determine invalid measurement.For example, significantly change the grating feature with the contact of relatively poor surface or fully the tissue distortion is consistent.Represent the key feature of surface contact and tissue distortion to compare to discern aforesaid invalid grating with the restriction of accepting in the past.

In these examples, used intensity.Be to be understood that spectrographic mathematic(al) manipulation also is available.For example, can carry out the false analysis that absorbs (pseudo-absorbance) or absorption spectrum with equivalence techniques.

In these examples, used specific wavelength.Be to be understood that a large amount of wavelength near infrared ray can carry equivalent information.The many technology that are applicable to here to be said at many wavelength of the spectral regions of whole collection.

The combination of analytical technology also can be used for selecting and analytical data.On wide significance, one or more chemometric techniques are used for selecting spectrum or the part spectrum relevant with respect to one or more z shaft positions of sample with processing and sampling module.

In the discussion in front, estimate to have described preferred implementation of the present invention with reference to concentration of glucose.Other analytes that concentration or threshold value are determined are found in human body, comprising: water, protein, fat and/or lipid, multi-form cholesterol, blood urea nitrogen (BUN), treatment and illicit drug and ethanol.

It will be appreciated by those skilled in the art that can be by except the multi-form proof the present invention the specific embodiment of this description and consideration.Can make under the situation without departing from the spirit and scope of the present invention in form and the change on the details.Therefore, the present invention only should be by following appended claim restriction.

Claims (61)

Translated fromChinese

1、一种组织样本属性的非侵入式估计方法，包括如下步骤：1. A non-invasive method for estimating properties of tissue samples, comprising the steps of:提供分析仪，其中所述分析仪包括：An analyzer is provided, wherein the analyzer comprises:连接到所述分析仪的取样探针，所述取样探针相对于所述分析仪是活动的，并且所述取样探针具有尖端；a sampling probe connected to the analyzer, the sampling probe is movable relative to the analyzer, and the sampling probe has a tip;用所述取样探针移位至少一部分所述组织样本；displacing at least a portion of the tissue sample with the sampling probe;至少在所述移位步骤期间采集所述组织样本的时间序列光谱数据组；acquiring a time-series spectroscopic data set of said tissue sample during at least said translating step;选择所述光谱组的子集，其中加强取样精确性；以及selecting a subset of the set of spectra wherein sampling accuracy is enforced; and用所述子集估计所述组织样本属性。The tissue sample properties are estimated using the subset.2、根据权利要求1所述的方法，其特征在于，所述移位所述组织的步骤包括所述取样探针的z轴移动，其中所述z轴垂直于与样本组织表面正切的平面。2. The method of claim 1, wherein the step of displacing the tissue comprises z-axis movement of the sampling probe, wherein the z-axis is perpendicular to a plane tangent to the surface of the sample tissue.3、根据权利要求2所述的方法，其特征在于，所述移位步骤作为时间函数改变所述组织样本的移位。3. The method of claim 2, wherein the displacing step varies the displacement of the tissue sample as a function of time.4、根据权利要求2所述的方法，其特征在于，所述移位步骤由于所述取样探针与所述组织样本的最接近的接触最小化镜面反射光的采集。4. The method of claim 2, wherein said displacing step minimizes the collection of specularly reflected light due to the proximate contact of said sampling probe with said tissue sample.5、根据权利要求1所述的方法，其特征在于，所述取样探针的移动速度在约0和约100微米/秒之间的范围内。5. The method of claim 1, wherein the speed of movement of the sampling probe is in a range between about 0 and about 100 microns/second.6、根据权利要求1所述的方法，还包括如下步骤：6. The method of claim 1, further comprising the steps of:将导块可代替地附加到所述组织样本。A guide block may alternatively be attached to the tissue sample.7、根据权利要求6所述的方法，还包括如下步骤：7. The method of claim 6, further comprising the steps of:使用所述导块控制所述取样探针相对于所述组织样本的径向放置。Radial placement of the sampling probe relative to the tissue sample is controlled using the guide block.8、根据权利要求1所述的方法，还包括如下步骤：8. The method of claim 1, further comprising the steps of:在所述组织样本和所述取样探针尖端之间分配耦合流体。A coupling fluid is dispensed between the tissue sample and the sampling probe tip.9、根据权利要求8所述的方法，其特征在于，所述移位步骤将在所述取样探针尖端和所述组织样本之间的过量的所述耦合流体挤出。9. The method of claim 8, wherein said displacing step squeezes excess of said coupling fluid between said sampling probe tip and said tissue sample.10、根据权利要求1所述的方法，其特征在于，所述移位步骤仅移动所述取样探针的一部分。10. The method of claim 1, wherein the displacing step moves only a portion of the sampling probe.11、根据权利要求1所述的方法，其特征在于，所述移位步骤沿下面任意之一移动所述取样探针：11. The method of claim 1, wherein said displacing step moves said sampling probe along any of the following:朝向所述组织样本的路径；a path towards said tissue sample;远离所述组织样本的路径；以及away from the path of the tissue sample; and朝向和远离所述组织样本。towards and away from the tissue sample.12、根据权利要求1所述的方法，其特征在于，所述移位步骤用包括下面任意之一的速度曲线移动所述取样探针：12. The method of claim 1, wherein said displacing step moves said sampling probe with a velocity profile comprising any of the following:固定速率；fixed rate;变化速率；rate of change;间断速率；Intermittent rate;加速率；acceleration rate;减速率；以及deceleration rate; and包括零速度成分的速率。Velocity that includes a zero velocity component.13、根据权利要求1所述的方法，其特征在于，所述选择步骤还包括下面步骤的任意之一：13. The method according to claim 1, wherein the selecting step further comprises any one of the following steps:去除至少一个异常值光谱；以及removing at least one outlier spectrum; and计算来自至少一个高吸收波长和至少一个低吸收波长的响应比。A ratio of responses from at least one high absorbing wavelength and at least one low absorbing wavelength is calculated.14、根据权利要求1所述的方法，其特征在于，所述选择步骤还包括如下步骤：14. The method according to claim 1, wherein the selecting step further comprises the following steps:从所述光谱组提取特征。Features are extracted from the set of spectra.15、根据权利要求14所述的方法，其特征在于，所述选择步骤基于来自所述光谱组的所述特征选择在最小组织压缩状态期间的所述组织样本的光谱表示。15. The method of claim 14, wherein said selecting step selects a spectral representation of said tissue sample during a state of minimal tissue compression based on said features from said set of spectra.16、根据权利要求14所述的方法，其特征在于，所述选择步骤基于来自所述光谱组的所述特征去除包含镜面反射光的至少一个光谱。16. The method of claim 14, wherein said selecting step removes at least one spectrum containing specularly reflected light based on said features from said set of spectra.17、根据权利要求14所述的方法，还包括步骤如下：17. The method of claim 14, further comprising the steps of:提供算法，所述算法与所述分析仪结合，其中所述算法重复使用所述特征以控制下面的至少之一：An algorithm is provided, the algorithm is combined with the analyzer, wherein the algorithm reuses the feature to control at least one of:所述移位步骤；以及said shifting step; and所述采集步骤。The collection step.18、根据权利要求1所述的方法，还包括如下步骤：18. The method of claim 1, further comprising the step of:提供算法，所述算法与所述分析仪结合，并且所述算法用来控制下面的至少之一：An algorithm is provided, the algorithm is integrated with the analyzer, and the algorithm is used to control at least one of the following:所述移位步骤；以及said shifting step; and所述采集步骤。The collection step.19、根据权利要求1所述的方法，还包括步骤如下：19. The method of claim 1, further comprising the steps of:预处理所述光谱的子集以产生预处理光谱组。A subset of the spectra is preprocessed to produce a set of preprocessed spectra.20、根据权利要求19所述的方法，其特征在于，所述估计步骤将多变量分析应用于所述预处理光谱组。20. The method of claim 19, wherein said step of estimating applies multivariate analysis to said set of preprocessed spectra.21、根据权利要求20所述的方法，其特征在于，所述组织样本属性包括葡萄糖浓度。21. The method of claim 20, wherein the tissue sample attribute includes glucose concentration.22、一种确定血液/组织分析物浓度的方法，包括如下步骤：22. A method of determining the concentration of an analyte in blood/tissue comprising the steps of:提供非侵入式分析仪，包括：Offers non-invasive analyzers including:取样探针，其中至少一部分所述取样探针相对于所述分析仪是活动的；a sampling probe, wherein at least a portion of said sampling probe is movable relative to said analyzer;以第一速率重复采集定位光谱；repeatedly acquiring localization spectra at a first rate;使用所述定位光谱的至少一部分以建立所述取样探针与所述组织的接触；using at least a portion of the localization spectrum to establish contact of the sampling probe with the tissue;以第二速率采集光谱组；以及acquiring sets of spectra at a second rate; and使用所述光谱组的至少一部分以估计所述分析物属性。At least a portion of the set of spectra is used to estimate the analyte property.23、根据权利要求22所述的方法，其特征在于，所述第二速率比所述第一速率快。23. The method of claim 22, wherein the second rate is faster than the first rate.24、根据权利要求23所述的方法，其特征在于，还包括如下步骤：24. The method according to claim 23, further comprising the steps of:从所述光谱组提取特征；extracting features from the set of spectra;基于所述特征去除任意异常值光谱；removing any outlier spectra based on the features;预处理所述光谱的子集以产生预处理光谱组；以及preprocessing a subset of the spectra to produce a preprocessed set of spectra; and连同所述估计步骤一起将多变量分析应用于所述预处理光谱组。A multivariate analysis is applied to the preprocessed set of spectra in conjunction with the estimating step.25、一种用于组织分析物属性的估计的非侵入式取样的方法，包括如下步骤：25. A method of non-invasive sampling for estimation of tissue analyte properties comprising the steps of:提供分析仪，其中所述分析仪包括：An analyzer is provided, wherein the analyzer comprises:连接到所述分析仪的取样探针；a sampling probe connected to the analyzer;相对于所述组织样本沿z轴平移所述取样探针的至少一部分；translating at least a portion of the sampling probe along the z-axis relative to the tissue sample;至少在相对于所述组织样本平移所述取样探针的所述步骤期间采集时间序列光谱数据组；acquiring time-series spectroscopic data sets during at least said step of translating said sampling probe relative to said tissue sample;从所述光谱数据组提取特征；以及extracting features from the spectral data set; and使用所述提取的特征正确估计组织样本。The tissue sample is correctly estimated using the extracted features.26、根据权利要求25所述的方法，其特征在于，所述提取特征的步骤包括使用下面的任意之一：26. The method of claim 25, wherein said step of extracting features comprises using any of the following:导数；Derivative;多变量分析；multivariate analysis;化学信号；以及chemical signals; and物理信号。physical signal.27、一种用于组织样本的分光镜非侵入式测量的装置，包括：27. An apparatus for spectroscopic non-invasive measurement of a tissue sample, comprising:非侵入式分析仪；Non-invasive analyzers;连接到所述分析仪的取样探针；a sampling probe connected to the analyzer;用于沿x、y和z轴的任意一个移动所述取样探针的至少一部分的部件；means for moving at least a portion of the sampling probe along any of the x, y and z axes;用于当所述取样探针移动时采集至少一个光谱的部件；以及means for acquiring at least one spectrum while the sampling probe is moving; and用于分析所述光谱的至少一个算法，其中所述至少一个算法提供用于移动的所述部件和用于采集所述光谱的所述部件的重复控制。At least one algorithm for analyzing said spectrum, wherein said at least one algorithm provides repetitive control of said means for moving and said means for acquiring said spectrum.28、根据权利要求27所述的装置，其特征在于，所述用于移动的部件包括下面任意之一：28. The device according to claim 27, wherein said means for moving comprises any one of the following:永磁体/电磁体对；permanent magnet/electromagnet pair;手动摇把；hand crank;电机齿轮组；Motor gear set;杠杆臂；lever arm;剪形千斤顶；scissor jack;蜗杆传动；Worm drive;平衡配重；balance weight;弹簧控制系统；spring control system;气压；air pressure;流体调节系统；Fluid regulation system;液压系统；Hydraulic system;风箱；Bellows;导螺杆；lead screw;线性电机；linear motor;电机；motor;凸轮；cam;限制重力系统；limited gravity system;受控势能释放；Controlled potential energy release;旋转螺旋线；rotating helix;活动楔；movable wedge;旋转齿轮；rotating gear;旋转活塞；rotary piston;机电系统；Electromechanical systems;记忆金属；Memory metal;磁致流变逻辑系统；Magneto-rheological logic system;受控粘性系统；Controlled viscosity system;磁系统；magnetic system;绳双动；rope double action;气囊；air bag;气动活塞；以及pneumatic piston; and材料的膨胀和收缩。Expansion and contraction of materials.29、根据权利要求27所述的装置，其特征在于，所述算法包括所述取样探针的预设移动曲线。29. The apparatus of claim 27, wherein the algorithm includes a preset movement profile of the sampling probe.30、根据权利要求27所述的装置，其特征在于，所述算法基于下面的任意之一调整所述取样探针的移动：30. The apparatus of claim 27, wherein the algorithm adjusts the movement of the sampling probe based on any of the following:从所述光谱导出的化学信息；chemical information derived from said spectrum;从所述光谱导出的物理信息；Physical information derived from said spectrum;从所述光谱提取的特征；features extracted from said spectra;智能系统；smart system;图案识别系统；以及pattern recognition systems; and辅助传感器读数。Auxiliary sensor readings.31、根据权利要求30所述的装置，其特征在于，所述化学信息包括从下面任意之一得到的吸收特征；31. The apparatus of claim 30, wherein the chemical information includes absorption characteristics derived from any of the following;水；water;脂肪；Fat;蛋白质；以及protein; and葡萄糖。glucose.32、根据权利要求30所述的装置，其特征在于，所述物理信息包括下面至少之一：32. The device according to claim 30, wherein the physical information includes at least one of the following:镜面反射；以及specular reflection; and散射信息。Scatter information.33、根据权利要求30所述的装置，其特征在于，所述辅助传感器读数包括下面任意之一：33. The apparatus of claim 30, wherein said auxiliary sensor readings include any of the following:压力；pressure;温度；temperature;电读数；以及electrical readings; and检测器输出。detector output.34、根据权利要求27所述的装置，其特征在于，所述取样探针集成到所述分析仪中以形成手持单元。34. The device of claim 27, wherein the sampling probe is integrated into the analyzer to form a handheld unit.35、根据权利要求27所述的装置，所述分析仪还包括：35. The apparatus of claim 27, said analyzer further comprising:基本模块；以及basic modules; and通信束，其中所述通信束将所述取样探针连接到所述基本模块，并且其中所述取样探针位于第一外壳中并且所述基本模块位于与所述第一外壳分离的第二外壳中。a communication harness, wherein the communication harness connects the sampling probe to the base module, and wherein the sampling probe is located in a first housing and the base module is located in a second housing separate from the first housing middle.36、根据权利要求27所述的装置，其特征在于，所述用于移动的部件至少一部分位于所述取样模块的外面以减少所述取样模块的重量。36. The device of claim 27, wherein at least a portion of said means for moving is located outside said sampling module to reduce the weight of said sampling module.37、根据权利要求27所述的装置，其特征在于，所述取样探针包括：37. The device of claim 27, wherein said sampling probe comprises:正曲型取样探针尖端。Forward curved sampling probe tip.38、根据权利要求27所述的装置，其特征在于，所述取样模块的所述部分的移动符合包含下面任意之一的移动曲线：38. The apparatus of claim 27, wherein movement of said portion of said sampling module conforms to a movement curve comprising any of the following:固定速度周期；Fixed speed cycle;加速周期；acceleration cycle;减速周期；deceleration cycle;间断周期；以及intermittent period; and零净速度周期。Zero net velocity cycles.39、根据权利要求27所述的装置，其特征在于，所述重复控制基于从所述光谱导出的度量。39. The apparatus of claim 27, wherein the repetition control is based on a metric derived from the spectrum.40、根据权利要求39所述的装置，其特征在于，所述度量从下面任意之一获得：40. The apparatus of claim 39, wherein the metric is obtained from any one of:高吸光率的区域；areas of high absorbance;从1100至1400nm的区域；以及the region from 1100 to 1400nm; and来自所述高吸光率的区域和从1100至1400nm的所述区域的响应比。Response ratios from the region of high absorbance and the region from 1100 to 1400 nm.41、根据权利要求27所述的装置，其特征在于，所述取样模块重量小于约100克。41. The device of claim 27, wherein said sampling module weighs less than about 100 grams.42、根据权利要求41所述的装置，其特征在于，所述取样模块重量小于约30克。42. The device of claim 41, wherein the sampling module weighs less than about 30 grams.43、根据权利要求27所述的装置，其特征在于，所述取样模块还包括：43. The device according to claim 27, wherein the sampling module further comprises:用于将所述取样模块的重量分配到所述组织样本周围的部件。means for distributing the weight of the sampling module around the tissue sample.44、根据权利要求43所述的装置，其特征在于，所述分配重量的部件包括下面任意之一：44. The apparatus of claim 43, wherein said means for distributing weight comprises any one of the following:一个或多个支柱；one or more pillars;一组脚；a set of feet;流体填充膜；以及a fluid filled membrane; and可变形膜，其中所述可变形膜适合于组织样本形状。A deformable membrane, wherein the deformable membrane conforms to the shape of the tissue sample.45、根据权利要求27所述的装置，其特征在于，限制沿所述x和y轴的移动以加强取样精确性。45. The apparatus of claim 27, wherein movement along said x and y axes is limited to enhance sampling accuracy.46、一种使用连接到分析仪的取样探针用于组织分析物属性的估计的非侵入式取样的方法，包括如下步骤：46. A method of non-invasive sampling for estimation of tissue analyte properties using a sampling probe connected to an analyzer comprising the steps of:相对于所述组织移动所述取样探针的至少一部分；moving at least a portion of the sampling probe relative to the tissue;使用所述取样探针和所述分析仪采集所述组织的非侵入式光谱；acquiring a non-invasive spectrum of the tissue using the sampling probe and the analyzer;分析所述光谱以产生下面的任意之一：The spectrum is analyzed to produce either of the following:特征；以及characteristics; and度量；measure;基于所述米制或所述特征的任意之一重复所述移动、采集和分析的步骤；或者使用至少一个所述光谱估计所述组织分析物属性。Repeating said moving, acquiring and analyzing steps based on any one of said metric or said characteristic; or estimating said tissue analyte property using at least one of said spectra.47、根据权利要求46所述的方法，其特征在于，所述移动所述取样探针的步骤包括在所述采集步骤期间的所述取样探针的净零速度。47. The method of claim 46, wherein said step of moving said sampling probe includes a net zero velocity of said sampling probe during said acquiring step.48、根据权利要求46所述的方法，其特征在于，所述移动所述取样探针的步骤包括如下步骤：48. The method of claim 46, wherein said step of moving said sampling probe comprises the steps of:在所述移动步骤期间提供所述取样探针的移动的第一速率；以及providing a first rate of movement of the sampling probe during the moving step; and在所述采集步骤期间提供所述取样探针的移动的第二速率。A second rate of movement of the sampling probe is provided during the collecting step.49、根据权利要求48所述的方法，其特征在于，所述移动的第二速率小于所述移动的第一速率。49. The method of claim 48, wherein the second rate of movement is less than the first rate of movement.50、根据权利要求46所述的方法，还包括如下步骤：50. The method of claim 46, further comprising the step of:在所述采集步骤之前停止所述取样探针相对于所述组织的移动。Movement of the sampling probe relative to the tissue is stopped prior to the collecting step.51、一种使用连接到分析仪的取样探针用于组织分析物属性的估计的非侵入式取样的方法，包括如下步骤：51. A method of non-invasive sampling for estimation of tissue analyte properties using a sampling probe connected to an analyzer comprising the steps of:以第一速率相对于所述组织移动所述取样探针的至少一部分；moving at least a portion of the sampling probe relative to the tissue at a first rate;以第二速率相对于所述组织移动所述取样探针的至少一部分；moving at least a portion of the sampling probe relative to the tissue at a second rate;使用所述取样探针和所述分析仪采集所述组织的非侵入式光谱，其中所述采集步骤至少部分发生在以第二速率移动所述取样探针的步骤期间；acquiring a non-invasive spectrum of the tissue using the sampling probe and the analyzer, wherein the acquiring step occurs at least in part during the step of moving the sampling probe at a second rate;重复所述在前步骤；或者使用至少一个所述光谱估计所述组织分析物属性。repeating said preceding steps; or estimating said tissue analyte property using at least one of said spectra.52、根据权利要求51所述的方法，其特征在于，所述第二速率包括净零速度。52. The method of claim 51, wherein the second velocity comprises a net zero velocity.53、一种组织样本的分析物属性估计的方法，包括如下步骤：53. A method of estimating an analyte property of a tissue sample comprising the steps of:提供分析仪，包括：Provides analyzers including:具有取样探针尖端的取样探针；a sampling probe having a sampling probe tip;将耦合流体分配在所述组织样本上；dispensing a coupling fluid over the tissue sample;重复控制所述取样探针尖端相对于所述组织样本的z轴移动以使所述取样探针尖端接触所述耦合流体；repeatedly controlling the z-axis movement of the sampling probe tip relative to the tissue sample to contact the sampling probe tip with the coupling fluid;使用所述取样探针和所述分析仪采集所述组织样本的至少一个非侵入式光谱；以及acquiring at least one non-invasive spectrum of the tissue sample using the sampling probe and the analyzer; and使用所述非侵入式光谱估计所述分析物属性。The analyte property is estimated using the non-invasive spectrum.54.根据权利要求53所述的方法，还包括如下步骤：54. The method of claim 53, further comprising the step of:使用所述光谱作为所述重复控制移动的步骤中的反馈。The spectrum is used as feedback in the step of repeating the control movement.55、根据权利要求53所述的方法，还包括如下步骤：55. The method of claim 53, further comprising the step of:从所述光谱提取特征；以及extracting features from the spectrum; and在反馈环中使用所述特征用于所述重复控制所述取样探针尖端的移动的步骤。Using said feature in a feedback loop for said step of repeatedly controlling movement of said sampling probe tip.56、根据权利要求53所述的方法，其特征在于，所述重复控制所述移动的步骤导致在所述取样探针尖端和所述组织样本之间没有直接接触。56. The method of claim 53, wherein said step of repeatedly controlling said movement results in no direct contact between said sampling probe tip and said tissue sample.57、一种用于组织样本的分光镜非侵入式测量的装置，包括：57. An apparatus for spectroscopic non-invasive measurement of a tissue sample, comprising:非侵入式分析仪；Non-invasive analyzers;连接到所述分析仪的取样探针；a sampling probe connected to the analyzer;用于延x、y和z轴的至少之一移动至少一部分所述取样探针的部件；means for moving at least a portion of the sampling probe along at least one of x, y and z axes;用于当所述取样探针移动时采集至少一个光谱的部件；以及means for acquiring at least one spectrum while the sampling probe is moving; and用于分析所述光谱的算法，其中所述算法提供所述用于移动的部件和所述用于采集所述光谱的部件的重复控制。an algorithm for analyzing said spectrum, wherein said algorithm provides repetitive control of said means for moving and said means for acquiring said spectrum.58、一种样本组织属性的估计的方法，包括如下步骤：58. A method of estimating a tissue property of a sample comprising the steps of:提供近红外线非侵入式分析仪；Provide near-infrared non-invasive analyzers;提供连接到所述分析仪的取样探针；providing a sampling probe connected to the analyzer;用所述取样探针移位所述组织；displacing the tissue with the sampling probe;在所述移位步骤期间采集所述组织样本的时间序列光谱数据组；以及acquiring a time-series spectral data set of said tissue sample during said shifting step; and使用在所述移位和采集步骤期间在所述光谱组中捕获的动态组织响应来估计所述组织属性。The tissue properties are estimated using dynamic tissue responses captured in the set of spectra during the translating and acquiring steps.59、根据权利要求58所述的方法，其特征在于，所述取样探针初始捕获在所述取样探针和所述样本组织之间没有接触的光谱表示。59. The method of claim 58, wherein the sampling probe initially captures a spectral representation with no contact between the sampling probe and the sample tissue.60、根据权利要求59所述的方法，其特征在于，所述移位所述组织的步骤包括所述取样探针的z轴移动，其中所述z轴垂直于与所述样本组织的表面正切的平面。60. The method of claim 59, wherein said step of displacing said tissue comprises z-axis movement of said sampling probe, wherein said z-axis is perpendicular to a surface tangential to said sample tissue plane.61、一种用于最小化组织分析物属性的非侵入式估计的取样误差的装置，包括：61. An apparatus for minimizing sampling error in the non-invasive estimation of a tissue analyte property, comprising:相对于所述组织在x、y和z轴的至少之一上可移动的动态探针；a dynamic probe movable relative to the tissue in at least one of x, y and z axes;用于当所述探针在所述轴的至少之一中移动时用所述探针测量组织的光谱的部件；以及means for measuring a spectrum of tissue with the probe as the probe moves in at least one of the axes; and用于使用所述光谱估计所述分析物属性的部件。means for estimating a property of the analyte using the spectrum.

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