CN101018502A - Noninvasive analyzer sample probe interface method and apparatus - Google Patents
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Abstract
A method and apparatus are provided for noninvasive sampling. More particularly, the method and apparatus relate to control of motion of an optical sample probe interface relative to a tissue sample site. A dynamic probe interface, is used to collect spectra of a targeted sample, control positioning of the sample probe relative to the tissue sample in terms of at least one of x-, y-, and z-axes, and/or control of sample tissue displacement to minimize spectral variations resulting from the sampling process and increase analyte property estimation precision and accuracy.
Description
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 the light 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 29 calendar 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 or reference 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/or analyser 100.
When analyser 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 of analyser 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-intrusion type 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 the axial 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 1009 contact 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 12 presentation 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 this respect 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 sample probe 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 fixed speed 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)
1, a kind of non-intrusion type method of estimation of tissue samples attribute comprises the steps:
Analyser is provided, and wherein said analyser comprises:
Be connected to the sample probe of described analyser, described sample probe is active with respect to described analyser, and described sample probe has the tip;
With the described tissue samples of described sample probe displacement at least a portion;
At least during described shift step, gather the time series spectral data groups of described tissue samples;
Select the subclass of described spectrum group, wherein strengthen the sampling accuracy; And
Estimate described tissue samples attribute with described subclass.
2, method according to claim 1 is characterized in that, the step of the described tissue of described displacement comprises that the z axle of described sample probe moves, wherein said z axle perpendicular to the plane of sample tissue surface tangent.
3, method according to claim 2 is characterized in that, described shift step changes the displacement of described tissue samples as time function.
4, method according to claim 2 is characterized in that, described shift step is because described sample probe and described tissue samples immediate contacts the collection that minimizes specular light.
5, method according to claim 1 is characterized in that, in the scope of the translational speed of described sample probe between about 0 and about 100 little meter per seconds.
6, method according to claim 1 also comprises the steps:
Guide block can instead be appended to described tissue samples.
7, method according to claim 6 also comprises the steps:
Use described guide block to control of the radially placement of described sample probe with respect to described tissue samples.
8, method according to claim 1 also comprises the steps:
Between described tissue samples and described sample probe tip, distribute coupled fluid.
9, method according to claim 8 is characterized in that, described shift step will be extruded at the excessive described coupled fluid between described sample probe tip and the described tissue samples.
10, method according to claim 1 is characterized in that, described shift step only moves the part of described sample probe.
11, method according to claim 1 is characterized in that, described shift step moves one of arbitrarily described sample probe along following:
Path towards described tissue samples;
Path away from described tissue samples; And
Towards with away from described tissue samples.
12, method according to claim 1 is characterized in that, described shift step is with comprising that following one of any rate curve moves described sample probe:
Fixed rate;
Rate of change;
Be interrupted speed;
Rate of acceleration;
The rate of deceleration; And
The speed that comprises the zero velocity composition.
13, method according to claim 1 is characterized in that, described selection step also comprises the one of any of following step:
Remove at least one exceptional value spectrum; And
Calculating is from the response ratio of at least one high absorbing wavelength and at least one low absorbing wavelength.
14, method according to claim 1 is characterized in that, described selection step also comprises the steps:
Extract feature from described spectrum group.
15, method according to claim 14 is characterized in that, described selection step is based on the spectral representation from the described tissue samples of described feature selection during minimum is organized compressive state of described spectrum group.
16, method according to claim 14 is characterized in that, described selection step is removed at least one spectrum that comprises specular light based on the described feature from described spectrum group.
17, method according to claim 14 comprises that also step is as follows:
Algorithm is provided, and described algorithm combines with described analyser, wherein said algorithm reuse described feature with control following one of at least:
Described shift step; And
Described acquisition step.
18, method according to claim 1 also comprises the steps:
Algorithm is provided, and described algorithm combines with described analyser, and described algorithm be used for controlling following one of at least:
Described shift step; And
Described acquisition step.
19, method according to claim 1 comprises that also step is as follows:
The described spectrographic subclass of pretreatment is to produce the pre-processed spectrum group.
20, method according to claim 19 is characterized in that, described estimating step is applied to described pre-processed spectrum group with multivariate analysis.
21, method according to claim 20 is characterized in that, described tissue samples attribute comprises concentration of glucose.
22, a kind of method of definite blood/tissue analyte concentration comprises the steps:
Noninvasive analyzer is provided, comprises:
Sample probe, wherein the described sample probe of at least a portion is active with respect to described analyser;
With first rate repeated acquisition location spectrum;
Use the spectrographic at least a portion in described location to set up contacting of described sample probe and described tissue;
Gather the spectrum group with second speed; And
At least a portion of using described spectrum group is to estimate described analyte attribute.
23, method according to claim 22 is characterized in that, the described first rate of described second speed ratio is fast.
24, method according to claim 23 is characterized in that, also comprises the steps:
Extract feature from described spectrum group;
Remove any exceptional value spectrum based on described feature;
The described spectrographic subclass of pretreatment is to produce the pre-processed spectrum group; And
Together with described estimating step multivariate analysis is applied to described pre-processed spectrum group.
25, the method for a kind of non-intrusion type of the estimation that is used for fabric analysis thing attribute sampling comprises the steps:
Analyser is provided, and wherein said analyser comprises:
Be connected to the sample probe of described analyser;
With respect to described tissue samples at least a portion along the described sample probe of z axle translation;
At least acquisition time sequence spectral data groups during with respect to the described step of the described sample probe of described tissue samples translation;
Extract feature from described spectral data groups; And
Use the feature of described extraction correctly to estimate tissue samples.
26, method according to claim 25 is characterized in that, the step of described extraction feature comprises one of any below using:
Derivative;
Multivariate analysis;
Chemical signal; And
Physical signalling.
27, a kind of device that is used for the spectroscope non-intrusion measurement of tissue samples comprises:
Noninvasive analyzer;
Be connected to the sample probe of described analyser;
Any one that is used for along x, y and z axle moves the parts of at least a portion of described sample probe;
Be used for when described sample probe moves, gathering at least one spectrographic parts; And
Be used to analyze described spectrographic at least one algorithm, described parts that wherein said at least one algorithm is provided for moving and the control that repeats that is used to gather described spectrographic described parts.
28, device according to claim 27 is characterized in that, the described parts that are used to move comprise following one of any:
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 restriction gravity system;
Controlled potential energy discharges;
The rotating screw line;
Movable 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 expansion of material and contraction.
29, device according to claim 27 is characterized in that, described algorithm comprises the default moving curve of described sample probe.
30, device according to claim 27 is characterized in that, described algorithm is based on following one of any moving of described sample probe of adjusting:
Chemical information from described spectrum derivation;
Physical message from described spectrum derivation;
Feature from described spectrum extraction;
Intelligence system;
The pattern identification system; And
The aiding sensors reading.
31, device according to claim 30 is characterized in that, described chemical information comprises the absorption feature that obtains one of arbitrarily from following;
Water;
Fat;
Protein; And
Glucose.
32, device according to claim 30 is characterized in that, below described physical message comprises one of at least:
Direct reflection; And
Scattered information.
33, device according to claim 30 is characterized in that, described aiding sensors reading comprises following one of any:
Pressure;
Temperature;
Electric reading; And
Detector output.
34, device according to claim 27 is characterized in that, described sample probe is integrated in the described analyser to form handheld unit.
35, device according to claim 27, described analyser also comprises:
Basic module; And
The communication bundle, wherein said communication bundle is connected to described basic module with described sample probe, and wherein said sample probe is arranged in first shell and described basic module is arranged in and isolating second shell of described first shell.
36, device according to claim 27 is characterized in that, described parts at least a portion that is used to move is positioned at the outside of described sampling module to reduce the weight of described sampling module.
37, device according to claim 27 is characterized in that, described sample probe comprises:
Positive bent type sample probe tip.
38, device according to claim 27 is characterized in that, the described part of described sampling module mobile meets and comprise following one of any moving curve:
The fixed speed cycle;
Acceleration period;
Deceleration periods;
The interruption cycle; And
Zero net velocity cycle.
39, device according to claim 27 is characterized in that, the described tolerance that repeats to control based on from described spectrum derivation.
According to the described device of claim 39, it is characterized in that 40, described tolerance obtains one of arbitrarily from following:
The zone of high absorptance;
Zone from 1100 to 1400nm; And
From the zone of described high absorptance with from the response ratio in 1100 to 1400nm described zone.
41, device according to claim 27 is characterized in that, described sampling module weight is less than about 100 grams.
According to the described device of claim 41, it is characterized in that 42, described sampling module weight is less than about 30 grams.
43, device according to claim 27 is characterized in that, described sampling module also comprises:
Be used for the distribution of weight of described sampling module is arrived described tissue samples parts on every side.
According to the described device of claim 43, it is characterized in that 44, the parts of described dispensed weight comprise following one of any:
One or more pillars;
One group of foot;
The fluid filled film; And
Deformable film, wherein said deformable film is suitable for the tissue samples shape.
45, device according to claim 27 is characterized in that, restriction is moved to strengthen the sampling accuracy along described x and y axle.
46, a kind of use sample probe of being connected to analyser is used for the method for non-intrusion type sampling of the estimation of fabric analysis thing attribute, comprises the steps:
Move at least a portion of described sample probe with respect to described tissue;
Use described sample probe and described analyser to gather the non-intrusion type spectrum of described tissue;
It is following one of any to produce to analyze described spectrum:
Feature; And
Tolerance;
Repeat the described step that moves, gathers and analyze based on the described metric system or described feature one of any; Perhaps use at least one described spectrum to estimate described fabric analysis thing attribute.
According to the described method of claim 46, it is characterized in that 47, the described step that moves described sample probe is included in the clean zero velocity of the described sample probe during the described acquisition step.
According to the described method of claim 46, it is characterized in that 48, the described step that moves described sample probe comprises the steps:
The first rate that moves of described sample probe is provided during described mobile step; And
Second speed that moves of described sample probe is provided during described acquisition step.
According to the described method of claim 48, it is characterized in that 49, the described second mobile speed is less than described mobile first rate.
50, according to the described method of claim 46, also comprise the steps:
Before described acquisition step, stop described sample probe moving with respect to described tissue.
51, a kind of use sample probe of being connected to analyser is used for the method for non-intrusion type sampling of the estimation of fabric analysis thing attribute, comprises the steps:
Move at least a portion of described sample probe with respect to described tissue with first rate;
Move at least a portion of described sample probe with respect to described tissue with second speed;
Use described sample probe and described analyser to gather the non-intrusion type spectrum of described tissue, during wherein said acquisition step to small part occurs in and moves the step of described sample probe with second speed;
Repeat described pro-step; Perhaps use at least one described spectrum to estimate described fabric analysis thing attribute.
According to the described method of claim 51, it is characterized in that 52, described second speed comprises clean zero velocity.
53, a kind of method of analyte attributes estimation of tissue samples comprises the steps:
Analyser is provided, comprises:
Sample probe with sample probe tip;
Coupled fluid is distributed on the described tissue samples;
Repeating to control described sample probe tip moves so that the described coupled fluid of the most advanced and sophisticated contact of described sample probe with respect to the z axle of described tissue samples;
Use described sample probe and described analyser to gather at least one non-intrusion type spectrum of described tissue samples; And
Use described non-intrusion type spectrum to estimate described analyte attribute.
54., also comprise the steps: according to the described method of claim 53
Use described spectrum as the described feedback that repeats to control in the mobile step.
55, according to the described method of claim 53, also comprise the steps:
Extract feature from described spectrum; And
In feedback loop, use described feature to be used for the described step that moves that repeats to control described sample probe tip.
56, according to the described method of claim 53, it is characterized in that, describedly repeat to control described mobile step and cause not directly contact between the most advanced and sophisticated and described tissue samples at described sample probe.
57, a kind of device that is used for the spectroscope non-intrusion measurement of tissue samples comprises:
Noninvasive analyzer;
Be connected to the sample probe of described analyser;
Be used to prolong the parts of one of at least described sample probe of mobile at least a portion of x, y and z axle;
Be used for when described sample probe moves, gathering at least one spectrographic parts; And
Be used to analyze described spectrographic algorithm, wherein said algorithm provides described parts that are used to move and the described control that repeats that is used to gather described spectrographic parts.
58, a kind of estimation approach of sample organizational attribution comprises the steps:
The near infrared ray Noninvasive analyzer is provided;
The sample probe that is connected to described analyser is provided;
With the described sample probe described tissue that is shifted;
During described shift step, gather the time series spectral data groups of described tissue samples; And
Use responds in the dynamic organization that catches in described spectrum group during described displacement and the acquisition step estimates described organizational attribution.
According to the described method of claim 58, it is characterized in that 59, described sample probe initial acquisition does not have the spectral representation of contact between described sample probe and described sample tissue.
According to the described method of claim 59, it is characterized in that 60, the step of the described tissue of described displacement comprises that the z axle of described sample probe moves, wherein said z axle perpendicular to the plane of the surperficial tangent of described sample tissue.
61, the device of the error of sampling estimated of a kind of non-intrusion type that is used to minimize fabric analysis thing attribute comprises:
With respect to described be organized in x, y and z axle one of at least on dynamic probe movably;
Be used for when described probe spectrographic parts with described probe measurement tissue during described axle one of at least mobile; And
Be used to use described spectrum to estimate the parts of described analyte attribute.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US56656804P | 2004-04-28 | 2004-04-28 | |
| US60/566,568 | 2004-04-28 | ||
| US60/605,017 | 2004-08-27 | ||
| US11/117,104 | 2005-04-27 |
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| Publication Number | Publication Date |
|---|---|
| CN101018502A true CN101018502A (en) | 2007-08-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200580013837 Pending CN101018502A (en) | 2004-04-28 | 2005-04-28 | Noninvasive analyzer sample probe interface method and apparatus |
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| Country | Link |
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| CN (1) | CN101018502A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103443609A (en) * | 2011-01-24 | 2013-12-11 | N·B·阿迪 | Device, system and method for extracting material from a material sample |
| WO2020029898A1 (en) * | 2018-08-10 | 2020-02-13 | Foshan Hl Science & Technology Limited | Method for non-invasive blood glucose monitoring |
| US10871425B2 (en) | 2015-01-31 | 2020-12-22 | Roche Molecular Systems Inc. | Systems and methods for meso-dissection |
| US10876933B2 (en) | 2016-11-09 | 2020-12-29 | Ventana Medical Systems, Inc. | Automated tissue dissection instrument and methods of using the same |
| US11125660B2 (en) | 2015-01-31 | 2021-09-21 | Roche Molecular Systems, Inc. | Systems and methods for meso-dissection |
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2005
- 2005-04-28 CN CN 200580013837 patent/CN101018502A/en active Pending
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103443609A (en) * | 2011-01-24 | 2013-12-11 | N·B·阿迪 | Device, system and method for extracting material from a material sample |
| CN103443609B (en) * | 2011-01-24 | 2016-01-20 | N·B·阿迪 | Apparatus, system and method for extracting material from a material sample |
| US10866170B2 (en) | 2011-01-24 | 2020-12-15 | Roche Molecular Systems, Inc | Devices, systems, and methods for extracting a material from a material sample |
| US10871425B2 (en) | 2015-01-31 | 2020-12-22 | Roche Molecular Systems Inc. | Systems and methods for meso-dissection |
| US11125660B2 (en) | 2015-01-31 | 2021-09-21 | Roche Molecular Systems, Inc. | Systems and methods for meso-dissection |
| US11181449B2 (en) | 2015-01-31 | 2021-11-23 | Roche Molecular Systems, Inc. | Systems and methods for meso-dissection |
| US11768136B2 (en) | 2015-01-31 | 2023-09-26 | Roche Molecular Systems, Inc. | Systems and methods for meso-dissection |
| US11860072B2 (en) | 2015-01-31 | 2024-01-02 | Roche Molecular Systems, Inc. | Systems and methods for meso-dissection |
| US10876933B2 (en) | 2016-11-09 | 2020-12-29 | Ventana Medical Systems, Inc. | Automated tissue dissection instrument and methods of using the same |
| US11971333B2 (en) | 2016-11-09 | 2024-04-30 | Ventana Medical Systems, Inc. | Automated tissue dissection instrument and methods of using the same |
| WO2020029898A1 (en) * | 2018-08-10 | 2020-02-13 | Foshan Hl Science & Technology Limited | Method for non-invasive blood glucose monitoring |
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