CN101263388A - Method and apparatus for the non-invasive sensing of glucose in a human subject - Google Patents
Method and apparatus for the non-invasive sensing of glucose in a human subject Download PDFInfo
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Abstract
An apparatus for a non-invasive sensing of biological analytes in a sample includes an optics system having at least one radiation source and at least one radiation detector; a measurement system operatively coupled to the optics system; a control/processing system operatively coupled to the measurement system and having an embedded software system; a user interface/peripheral system operatively coupled to the control/processing system for providing user interaction with the control/processing system; and a power supply system operatively coupled to the measurement system, the control/processing system and the user interface system for providing power to each of the systems. The embedded software system of the control/processing system processes signals obtained from the measurement system to determine a concentration of the biological analytes in the sample.
Description
Technical field
Present invention relates in general to in the capillary and the Noninvasive of the biological analyte in the interstitial fluid detect.More specifically, the present invention relates to continuously or determine with the short time interval of rule as requested the method and apparatus of blood sugar, blood fat and/or alcohol concentration.
Background technology
Diabetes are to be characterized as by the defective of insulin generation aspect, the defective of insulin action aspect or the high gang's disease of blood sugar level that two aspects together cause.Diabetes control is selected (DCCT) with complication, one has been carried out the clinical research in 10 years by national diabetes and digestive system and kidney trouble research institute between nineteen eighty-three to 1993 year, has proved that high average blood sugar level (being commonly called as hyperglycaemia) has direct positive quantity related with the development of the crushing complication of this sickness influence kidney, eyes, nervous system, blood vessel and the circulation system.Methods of treatment comprises injection of insulin, oral medication, diet control and exercise.The work and rest rule of regulating the user by the doctor controls that hyperglycaemia requires to do three times every day or the customary self-monitoring of more times glucose level.At present, the people who suffers from diabetes measures their glucose level by using invasive blood sugar instrument, the higher disposal type test strip measurement glucose of this invasive blood sugar instrument cost of use will be used on test-strips from the small blood sample of pointing or forearm obtains.This process is pain and cause the damage of chronic nerve endings through regular meeting very.This is that a lot of diabetics are emitting the risk of severe complication development and a reason abandoning monitoring.
A lot of existing systems utilize the blood sugar concentration of diffuse feflectance spec-troscopy in determining to organize.For example, authorize equipment and the method that people's such as Petrovsky United States Patent (USP) discloses the non-invasively measuring blood sugar concentration No. 6097975.This equipment projects a branch of light (2050-2500nm) on the euangiotic selection area in human body somewhere, such as interior wrist or ear-lobe.The light pulse transdermal, tissue and the blood vessel that are throwed, a part by the structural scattering that is shone, diffusion with reflect, is passed blood vessel, tissue and skin by the glucose absorption in the blood and a part.Collect catoptrical luminous energy by receiving detecting device then, convert thereof into subject blood in the proportional electric signal of concentration of glucose and analyzed.The wavelength coverage of disclosed preferred implementation has adopted the wavelength coverage of 2050-2500nm in this piece list of references.
The United States Patent (USP) of authorizing people such as Maruo discloses a kind of device of non-invasively determining concentration of glucose in the subject blood for No. 6016435.This device comprises light source, as the diffraction grating unit of the optical splitter of light that this light source provides and the anglec of rotation that is used to control diffraction grating the stepping motor unit that has from the near infrared ray of 1300 to 2500nm continuous wavelength is provided.This device comprises fibre bundle in addition, and this fibre bundle has and is used near infrared ray is projected a plurality of second optical fiber that a plurality of optical fiber and being used on the subject skin receive the ray as a result that sends from skin.Light receiving unit is connected with second optical fiber, and spectroscopy unit is determined concentration of glucose in the blood by using based on the spectral analysis of carrying out from the information of light receiving unit.This invention and difference of the present invention are that it utilizes continuous lamp and has the diffraction grating of mechanical moving element.
The United States Patent (USP) of authorizing people such as Koashi discloses a kind of equipment of non-invasive measurement blood sugar level for No. 5533509.This equipment comprises wavelength variable semiconductor laser and integrating sphere, semiconductor laser near interested wavelength among a small circle in regulate, produce light beam, this light beam is divided into two light paths by beam splitter, after integrating sphere is collected and to be advanced along a light path transmission or reflection and be incident on skin and examined laser on the part, determine that by the derivative of investigating absorption spectrum this is examined the interior blood sugar level of part.The difference of the present invention and this list of references is, seeks and visits skin in having the gamut of a plurality of wavelength, rather than only seeks and visits skin with specific wavelength, and use absorption spectrum to determine concentration of glucose, rather than use the derivative of absorption spectrum.
The U.S. Patent Application Publication of people such as Takeda application discloses the equipment of the concentration of light absorption material in a kind of definite blood for No. 2005/0250997.This equipment comprises a plurality of optical transmitting sets, and these optical transmitting sets have light beams of different wavelengths towards the living tissue emission.Optical receiver is suitable for receiving the light beam that passes living tissue or reflect from living tissue.But, preferred implementation of the present invention only needs two light emitting diodes; The optical wavelength of a light emitting diode is 680nm, and the optical wavelength of another light emitting diode is 940nm.
The U.S. Patent Application Publication of people such as Walker application discloses a kind of non-invasive glucose sensor No. 2005/0256384, comprise at least one laser instrument (vertical cavity surface emitting laser (VCSEL) or edge emitter laser) and at least one photodetector, this photodetector constitutes the emission light that is used for detecting from transmitter.Glucose sensor comprises controller in addition, and this controller drives one or more transmitters by the transmitter wavelength skew 1-2nm that will choose from the selected wavelength of one group of centre wavelength with 1060nm, 980nm, 850nm, 825nm, 800nm, 780nm and 765nm.This can realize the measurement that absorbs under a plurality of wavelength and derive the measurement result of concentration of glucose according to the absorptiometry value.The wavelength coverage of this operation of equipment has exceeded wavelength coverage of the present invention.
The United States Patent (USP) of authorizing Rosenthal discloses a kind of method of carrying out near infrared (NIR) quantitative test for No. 5703364.The method comprising the steps of: provide a plurality of NIR rays with different wave length (600-1100nm) to shine the subject that will be analyzed, change the time quantum of the radiation exposure subject under each wavelength with output level, thereby provide substantially similar detection data resolution for each wavelength in a plurality of wavelength according to ray under each wavelength.The wavelength coverage of this operation of equipment has exceeded wavelength coverage of the present invention.
The United States Patent (USP) of authorizing Grubisic discloses a kind of solid-state spectrophotometer that the Noninvasive blood analyte detects that is used for for No. 6816241, it adopts a plurality of light emitting diodes (LED) and linear detector arrays, these light emitting diodes are with different but have overlapping wavelength luminous, so that generate continuous broad ray spectrum.Therefore it and difference of the present invention are that it has used array and the array of detectors of LED.
Thus, exist the demand that non-invasively detects the system of the glucose in the human subject to a kind of like this: this system utilize wavelength can pulse (pulsable) and can select, the selectable one-wavelength laser radiographic source of intensity, involve do not need mechanical moving element spectroscope with reference to scheme, and by utilizing the two object of reference spectrophotometers of twin-beam that improved instrument baseline stability is provided.
Summary of the invention
The present invention is devoted to a kind of equipment that non-invasively detects the biological analyte in the sample.This equipment comprises: optical system has at least one radiographic source and at least one ray detector; Measuring system is operationally joined with optical system; Control/disposal system is operationally joined with measuring system and is had embedded software system; User interface/peripheral system is operationally joined with control/disposal system, is used to the user to provide and control/disposal system mutual; And power-supply system, operationally join with measuring system, control/disposal system, user interface/peripheral system or their any combination, be used for providing electric power for each system.The embedded software system of control/disposal system is handled the signal that obtains from measuring system, to determine the concentration of biological analyte in the sample.
Can use the come together concentration of biological analyte definite sample of the absorption spectrum that obtains from optical system and the calibration vector of storage in the past by control/disposal system.Sample can be a kind of in living tissue interstitial fluid (ISF), living tissue capillary bed and/or the blood sample.Optical parametric oscillator (TPCOPO) device that described radiographic source can be that emission wavelength can be selected and emissive porwer is selectable, horizontal pump, subtend is propagated or emission wavelength can be selected and the selectable diode laser matrix of emissive porwer in a kind of.Ray detector can be made by InGaAs or Ge.
Described biological analyte can be glucose, blood fat or alcohol.If biological analyte is glucose or blood fat, then radiogenic emission spectrum can cover the scope from about 1200nm to about 1900nm, and the response of ray detector can cover the scope from about 1200nm to about 1900nm.If biological analyte is an alcohol, then radiogenic emission spectrum can cover the scope from about 800nm to about 1300nm, and the responding ability of ray detector can cover the scope from about 800nm to about 1300nm.
User interface/peripheral system can constitute and be used for reminding the user by the demonstration of audible tone and/or text message under the situation of doubtful hypoglycemia or hyperglycaemia; Under doubtful hypoglycemic situation, use bluetooth module to remind other people who is equipped with the bluetooth alarm bell; Use GPS module to determine user's position, and under hypoglycemic situation, send the emergency text message or the biological analyte concentration data is transferred to centralized server to a telephone number; And when obtaining encoded readings of glucose concentration, they are transferred to by sequencing and control the insulin pump of discerning described coding and being connected to the user, so that uelralante automatically via bluetooth module.
Described at least one radiographic source can be made by optical crystal, semiconductor material single layer structure or their combination in any.Semiconductor pump source can integrate with Beam Control structure and TPCOPO layer, to realize that emission wavelength is selected and intensity is selected.In one embodiment, described at least one radiographic source comprises GaAs Bragg reverberator, GaAs narrowband coherent source pump and the GaAs oct beam deflecting layer of a pair of GaAs of having TPCOPO active layer.Pumping source and Beam Control structure can or be parallel to the TPCOPO layer or be in the end in Bragg chamber along the whole length in Bragg chamber, before in pumping source being put into the Bragg chamber that comprises the TPCOPO layer, realize Beam Control.Can be electrically connected separately pump layer and GaAs oct beam deflecting layer.The electric current that imposes on the pump layer can be determined the intensity of institute's divergent-ray, and the voltage that imposes on GaAs oct beam deflecting layer can be determined the wavelength of institute's divergent-ray.
The present invention also is devoted to a kind ofly non-invasively to detect the method for the biological analyte in the sample by utilizing approximating light beam on two spaces to carry out spectrophotometric with reference to (hereinafter being called " TECS "), and described method is applicable to the diffuse reflection of measuring interstitial fluid.The method comprising the steps of: utilize first radiographic source, second radiographic source, first ray detector and second ray detector that optical system is provided, thereby set up approximating four beam paths on the space by this system; Utilize the different functions of time to modulate these sources; So that all optical element transmissions of this optical system and/or the mode that reflects these light beams dispose this optical system; A point place in this system opens first pair of light beam and second pair of beam separation, first pair of light beam is focused on user's the skin and with second pair of light beam to focus in the sample for reference; The signal that demodulation is produced by first detecting device and second detecting device and will opening because of the Signal Separation that light beam causes; Calculate spectrophotometric transmittance with ratio according to first ratio and second ratio.
First ratio can be because of the first radiogenic ray be incident on second ray detector the skin diffuse reflectance signal be incident on the ratio of the reference diffuse reflectance signal on second ray detector because of the second radiogenic ray, second ratio can be to be incident on the instrument signal on first ray detector and to be incident on the ratio of the instrument signal on first ray detector because of the second radiogenic ray because of the first radiogenic ray.Spectrophotometric transmittance can be used for determining the concentration of biological analyte in the sample.Described optical system can have separate areas between sample beam and reference beams, this zone is confined to the inside of optical glass device.Separated region between sample beam and the reference beams can be protected by shell.
Under the introduction below the reference accompanying drawing is considered and the situation of claims, the method of operating of the related elements of these and other feature of the present invention and structure and function will become more apparent, all these accompanying drawings constitute the part of this instructions, and wherein similar Reference numeral refers to the appropriate section in each different accompanying drawings.As employed in this instructions and the appending claims, singulative " ", " one " and " being somebody's turn to do " comprise a plurality of related objects, unless offer some clarification in addition in the literary composition.
Description of drawings
Fig. 1 is the synoptic diagram of equipment that is used for detecting the biological analyte of sample according to the present invention.
Fig. 2 is the synoptic diagram of optical system of the equipment of Fig. 1;
Fig. 3 is the synoptic diagram of another kind of embodiment of optical system of the equipment of Fig. 1;
Fig. 4 is the detailed maps of the equipment of Fig. 1.
Fig. 5 is the synoptic diagram according to radiation source module of the present invention;
Fig. 6 is the synoptic diagram according to radiation detection module of the present invention;
The a-c of Fig. 7 is respectively the curve map of signal of output of curve map, its enlarged drawing and switch integrator of one-period of discrete time kapillary diffuse signal of the output of graphic extension detecting device; And
The a-c of Fig. 8 is the block diagram according to horizontal pump subtend propagates light parametric oscillator of the present invention.
Embodiment
For introduction hereinafter, term " on ", D score, " left side ", " right side ", " vertically ", " level ", " top ", " bottom ", " laterally ", " vertically " and their derivative should according to the present invention in the accompanying drawings the institute orientation of getting towards related to the present invention like that.But, should be appreciated that the present invention can take various optional variation, unless expressly stated otherwise.Should also be understood that drawing in the accompanying drawing and the following describes the concrete device of introducing in the book only is exemplary embodiment of the present invention.Therefore, it is determinate the concrete size relevant with embodiment disclosed herein and other physical features should not being interpreted as.
With reference to Fig. 1, be used for determining that the equipment 1 of biological analyte comprises optical system 11, measuring system 12, controller/processor system 13, user interface/peripheral system 14, power-supply system 15 and embedded software system (not shown).Each system comprises several subsystems.
With reference to Fig. 2 and continue with reference to Fig. 1, optical system 11 comprise radiation source module 17, radiation detection module 23 and operationally join with detector module 23 with source module 17 and by special-purpose hapteron 47 by the fibre-optical probe 44 that contact and user's skin operationally joins.Fibre-optical probe 44 comprises that being used for of banding together is delivered to several optical fiber 45 of skin 63 and several in addition being used for picking up from the diffuse reflection of skin 63 and with it and being delivered to the optical fiber 46 of detector module 23 of banding together with ray from source module 17.Source module 17 can be, but be not limited to one or more TPCOPO or diode laser matrix.The source emission spectrum has covered the 1200nm that is used for glucose and lipids detection to 1900nm's be used for the wavelength coverage of the 800nm of alcohol detection to 1300nm, launches with 64 to 256 different wavelength.Detecting device can be made response on a 50-50 basis in identical scope.Detector module 23 can be, but be not limited to Ge detecting device, InGaAs detecting device or expansion InGaAs detecting device.
With reference to Fig. 3 and the continuity with reference to Fig. 1, the embodiment that the another kind of optical system 11 can Gong be selected for use comprises at least two radiographic sources (" 1 " 49, source and source " 2 " 50) and at least two ray detectors (detecting device " 1 " 51 and detecting device " 2 " 52).
" 1 " 49, source and source " 2 " 50 can be, but be not limited to one or more TPCOPO or diode laser matrix.Ideally, " 1 " 49, source and source " 2 " the 50th, wavelength can be pulsed and can be selected and the selectable one-wavelength laser radiographic source of intensity.The result who uses the selectable solid-state radiographic source of emission wavelength can obtain using single photoelectric detector and do not need spectrograph, therefore have size less, can be battery-powered, wear-resisting, stability improves and the improved advantage of drifting about.In addition, use opening/closing and the source that can at every turn launch with a kind of wavelength very apace makes that radiation power can be higher, the diffuse signal and the signal to noise ratio (S/N ratio) that cause causing because of ISF are enhanced, especially diffuse signal and the signal to noise ratio (S/N ratio) that causes because of detectable capillary blood is improved, therefore except ISF glucose, can also realize the detection of capillary blood glucose.As previously discussed, such radiographic source can be TPCOPO, diode laser matrix or other source.Diode laser matrix provides the ray of several wavelength that cover desired wide spectrum.Though TPCOPO only uses a laser diode as pump, diode laser matrix uses a laser diode for each wavelength.Not only there is application in the source of wide spectral coverage in field of spectroscopy, in any field of using monochromatic source application is arranged all, such as communication, demonstration, room illumination or the like.Small-sized, high efficiency, quick and wide region adjustable solid monochromatic source is applicable to all these fields; But, individually, prior aries such as laser diode of regulating such as monochromator, optical parametric oscillator (OPO), light emitting diode (LED), by heat/piezoelectricity or eq effect and dye laser have the above-mentioned feature of part, but do not have whole above-mentioned features.
Detecting device " 1 " 51 and detecting device " 2 " 52 can be, but be not limited to Ge detecting device, InGaAs detecting device or expansion InGaAs detecting device.Two radiographic sources and two ray detectors have the identical spectra coverage, for glucose and lipids detection be 1200nm to 1900nm, be that 800nm is to 1300nm for alcohol detection.Source emission individual different wavelength of M (64-256) and detecting device can be made response to same scope on a 50-50 basis.
Detecting device " 2 " 52 be used for detection of skin and contrast signal the two, it is right that these two forms biological light beam, and detecting device " 1 " 51 is used for detecting instrument stability light beam, right such as the instrument light beam.The signal definition that will obtain from two right light paths of light beam that are incident on the detecting device is: be incident on instrument signal S on the detecting device " 1 " 51 because of what the ray of source " 1 " 49 caused
11, be incident on instrument signal S on the detecting device " 1 " 51 because of what the ray of source " 2 " 50 caused
12, be incident on skin diffuse reflectance signal S on the detecting device " 2 " 52 because of what the ray of source " 1 " 49 caused
21Be incident on reference diffuse reflectance signal S on the detecting device " 2 " 52 with ray because of source " 2 " 50 causes
22Transmitted spectrum is that the ratio according to two ratios calculates:
T=(S
21/ S
22)/(S
11/ S
12) (equation 1)
Any preset time during measuring, only enable a source.If two light beams are spatially very approaching, then they can have identical transmission, reflection and interference and optics/electrooptic block drift and the influence disturbed will obtain offsetting.Therefore, be cost to use two radiographic sources, needn't mobile mirror, just can provide the irreflexive sampling of reference standard, simultaneously, use two detecting devices that stability of instrument additionally is provided.Thus, this spectroscope is with reference to scheme, and TECS does not need mechanical moving element, and twin-beam is two to provide improved instrument baseline stability with reference to spectrophotometer by utilizing.As mentioned above, this scheme has adopted two sources and two detecting devices, these two sources and two detecting devices formed two right in the space near the light beams of place's sampling, these two light beams are to standing same interference.
With reference to Fig. 4, and continue to show the more detailed synoptic diagram of a kind of preferred implementation of equipment 1 of the present invention with reference to Fig. 1.The centralized control parts of equipment 1 are controller/processor systems 13.Controller/processor system 13 is by resident FLASH storer (non-volatile) guiding of in store program and program and the control survey system 12 among the executive resident SRAM (static RAM).Controller/processor system 13 is carried out various functions synergistically with user interface/peripheral system 14, include but not limited to, temporarily be stored in all diffuse reflections and dark signal among the SRAM, handle these signals to derive absorption spectrum, and determine concentration of glucose subsequently, these data are kept in the FLASH storer, drive hummer 31, via lcd controller 29 with this data presentation on the monochrome or color graphics LCD 30 of small size (1.5 " * 1.0 "), via the input of function button switch 32 acceptance from the user, via USB interface 33 and USB joint 34 or bluetooth module 28 with this data upload in computing machine, closely remote control prompting is provided and provides remote prompting via bluetooth module 28 via GPS module 27 definite users' position and via GSM/GPRS module 26.Another pushbutton switch, electric power starting/X button switch 36 is used to open equipment 1.Press same switch 36 and will close this equipment, but must be in controller/processor system 13 request of sending via display 30 and confirm via function button switch 32 by the user subsequently after just can close this equipment.Controller/processor system 13 also comprises real-time clock (RTC) (not shown), even it also can keep track of time when equipment 1 power down and provide the date and time mark for each time measurement.
Thereby, collaborative by with user interface/peripheral system 14, controller/processor system 13 has possessed the ability of carrying out various functions.For example, controller/processor system 13 can show glucose readings and obtain time and calculating and the demonstration trend and the ratio of this reading last time on LCD 30.Controller/processor system 13 can calculate and the various statistics of demonstration on LCD 30, such as the moving average (trend) in the seclected time section with move minimum-maximum deviation every day, and when requirement is arranged, their functions as the time are plotted on the LCD 30.This system can provide the chance of the mg/dL of unit that selects concentration of glucose or mmol/L and can obtain the time mark of the time of glucose readings with reflection in nonvolatile memory and store the glucose readings collection that reaches a year for the user, shows when needed or uploads in the computing machine via USB interface 33 or bluetooth module 28 according to doing selection.
Under the situation of doubtful hypoglycemia or hyperglycaemia, can remind the user and videotex information on LCD 30 by the tone of hearing that produces by hummer 31.In addition, under doubtful hypoglycemic situation, equipment 1 can use embedded with bluetooth module 28 to remind and be equipped with the bluetooth alarm bell and be positioned at other people who far reaches 10 meters distances far away.Equipment 1 can also be determined user's position by using GPS module 27, and under hypoglycemic situation, can send the text message of requiring assistance to the phone such as rescue service " 911 " and/or other telephone number of working out in advance (comprising the centralized server that is embedded in GPRS (GPRS) or the global system for mobile communications (GSM)), perhaps simply the concentration of glucose data be transferred to the centralized server that is used for the telemedicine purpose.Equipment 1 can also transfer to the insulin pump that is connected with the user with these readings via bluetooth module 28 when obtaining readings of glucose concentration, and with insulin pump, forms artificial pancreas.If use equipment 1 by this way, then controller/processor system 13 must be encoded to data by the pseudo-random sequence of being shared by equipment 1 and insulin pump, disturbs with nigh other user by chance so that avoid.
Refer again to Fig. 4 in addition, electric power system 15 comprises chargeable small size battery 37.Battery 37 can be, but be not limited to Li ion-type battery.Overdischarge and short-circuit condition can not take place and low and notification controller/processor system 13 must recharge the time at cell voltage in power management/battery protection subsystem 35 protection batteries 37.It also comprises DC/DC transducer voltage regulator subsystem 39,40,41 and 42, and this subsystem produces all circuits needed voltages of biasing and distributes for the various subsystem with ON/OFF ability produces voltage under the control of controller/processor system 13.
With reference to Fig. 5 and continue, show the circuit of radiation source module 17 with the circuit of EOBS driver 20 and VCSEL driver 18 with reference to Fig. 1 and 4." 1 " 49, source or source " 2 " 50 (LD1-LDM) have and can be chosen as transmitted intensity up to 500mW via VCSEL driver 18 by the voltage level of intensity D/A converter 19, and can be under the order of controller/processor system 13 by selecting control 68 and demoder 69 to continue short time On/Off (1-100 μ s) by switching transistor SLD1-SLDM 70.The source emission wavelength can also be selected in scope of being mentioned and the different wave length mentioned via EOBS driver 20 by the voltage level of intensity D/A converter 21.The thermistor 72 that radiation source module 17 also comprises thermoelectric (al) cooler 71 (TEC) and is associated is controlled at 25 ℃ with cause source module temperature controller 16 with temperature.
With reference to Fig. 6 and continue, show the circuit of radiation detector module 23 with the circuit of detecting device amplifier 24 with reference to Fig. 1 and 4.Radiation detector module 23 comprises that one or two converts the light diffuse signal detecting device 51,52 of electric signal to, and with cause detector module temperature controller 22 temperature is controlled at 10 ℃ TEC 76 and relevant thermistor 77.Detecting device amplifier 24 is synchronously handled electrical diffuse reflectance signal by switch integrator circuit 74 and correlated double sampling circuit 75 with the switch control of ray under the switch control of controller/processor system 13.24 signal A/D converters 25 are with the reflected signal digitizing and output it to controller/processor system 13.Obtain whole group data, comprise skin, reference and dark signal in all wavelengths passage, can spend the time of 1-20ms.In near 10 seconds Measuring Time, repeat (500-10000 time) acquisition process N time.Under continuous mode, can change under the situation of one-shot battery per 5 minutes in per 12 hours and repeating one-shot measurement, perhaps repeat one-shot measurement changing under the situation of one-shot battery per 10 minutes in per 24 hours.
The software of controller/processor system 13 is handled these signals, at first to make the noise minimum, calculates transmissivity and absorption spectrum then, last computational analysis substrate concentration.In theory, transmissivity is defined as ratio:
T=I/I
0=e
-kd(Beer-Lambert law) (equation 2)
The I representative is in response to incident transmitted intensity I
0Diffuse reflection intensity, k represents extinction coefficient (tissue or reference standard), d represents penetration range.Under the situation of ISF, measure skin diffuse reflectance, reference diffuse reflectance and photodetector dark current.In the introduction below, the boldface type representative vector.Transmitted spectrum is according to I
Skin/ I
0Divided by I
Ref/ I
0Double ratio calculate.Therefore, T=I
Skin/ I
RefThereby, avoided measurement incident ray I
0Necessity.The ray R that is detected
Skin, R
RefComprise the strong component D that causes because of detector dark current
2, this strong component D
2Introduced irrelevant noise, it must have been cut.Therefore, after all signals have been carried out on average centering, according to T=(R
Skin-D2)/(R
Ref-D
2) calculate transmitted spectrum and define absorption spectrum by following formula:
X=-logT (equation 3)
Software sub-elect the skin of 3 * N * M array, reference and interlunation sequence sampled signal.With 0.5Hz each signal sequence skin, reference and dark are carried out low-pass filtering by sharp Digital Filtering with Zero Phase Error, to reduce excessive noise.In order to derive the ISF absorption spectrum, at first the data computation transmitted spectrum that each group is obtained asks average then, and uses average transmitted spectrum to calculate absorption spectrum.But, the derivation of capillary absorption spectrum needs more the processing.The skin diffuse reflectance signal comprises very big DC component under each wavelength path, this DC component mainly causes because of the ISF diffuse reflection, the sub-fraction of wherein said DC component because of the capillary diffuse reflection cause (～1%), sub-fraction be cause because of the detector dark signal and most cause because of uncorrelated white noise.This signal is by the modulation of heart pump action, and the heart pump action higher stroke occurs in the systole phase of heart, and lower stroke occurs in the diastole of heart.Thus, equipment 1 provides possibility with reference to scheme for the glucose of measuring in the capillary by utilizing the spectroscope that does not need reference standard and/or mechanical motion part.Thereby equipment 1 provides improved instrument baseline stability, and comprises the processing that the optimal synchronisation time signal of diffuse signal under each wavelength that the cardiac pulses of minimum and slow variation is modulated detected and formed according to the ratio of maximal value and minimum value transmittance.Thisly one paths is sampled with reference to scheme, this path along with each time heartbeat during the change of minimum value and maximum photon and approaching in time change constantly.
With reference to Fig. 7 a-7c, show output the one-period under a wavelength channel of this signal at detecting device.This signal disperses in time, because between wavelength channel, radiographic source is opened 1-100 μ s and closed 1-20ms.The frequency spectrum of this signal comprises aforementioned one group of DC component and has the component of heart rate and these signals of more groups of fundamental frequencies with switching signal and harmonic frequency.For apply pulse differential spectroscopy (PDS), must determine stroke.Operate near DC, this realizes in the following manner.Skin and dark signal sequence are all carried out low-pass filtering by sharp Digital Filtering with Zero Phase Error with 2Hz, to reduce excessive noise.With 0.5Hz they are carried out high-pass filtering by sharp Digital Filtering with Zero Phase Error then, to eliminate strong DC component.Can separate via FFT or by the synchronization counterpart of utilizing the cardiac pulses signal then and transfer to determine stroke.
Can derive the copy of cardiac pulses signal by the estimation that the time series that use has a skin diffuse reflectance signal under the passage of about 1275nm wavelength is carried out pulse rate.Ray under this wavelength penetrates epidermis and arrives capillary bed, and any other wavelength of the depth ratio of arrival is all firmly got many.Because 6-12 cycle arranged in the Measuring Time section, so by to arriving/leave R
SkinThe positive stroke of peak value ask average and to arriving/leave R
RefThe negative stroke of peak value ask on average, calculate transmissivity as mentioned above like that.Alternatively, can determine stroke similarly by under the fundamental frequency of switching frequency, operating.But, in addition this method also requires by these signal times are down-converted to DC with the synchronization counterpart of switching signal.
At last, the calibration vector b with storage before uses absorption spectrum to predict concentration of glucose:
y
p=Xb (equation 4)
This calibration vector obtains by partial least square method:
B=(X
TX)
-1X
Ty
R(equation 5)
y
RBe by accurate intrusion apparatus obtain with reference to reading.By in determining the process of calibration vector, adding the existing knowledge relevant (such as being to discuss in the article of " On Wiener filtering and the physics behind statisticalmodeling "), can significantly reduce for the spectrum of calibrating required acquisition and invasive quantity with reference to reading at the title that Marbach showed with spectrum.Thus, the needed single alignment time can be reduced to several hrs from a lot of skies.
With reference to Fig. 8 a-8c, TPCOPO provides and has obtained the means of optical parametric oscillation, and is similar to traditional OPO, and TPCOPO needs pump.Adjusting is to realize by the incident angle that changes pump light beam.TPCOPO can be by the nonlinear optical crystal manufacturing of routine, such as, but be not limited to LiNbO3, KTP and other material.But, the transverse design attribute of TPCOPO also allows to use semiconductor material manufacturing, such as GaAs and ZnSe single layer structure.By VCSEL semiconductor pump source oct beam control structure (EOBS) is integrated with TPCOPO, all characteristics of above-mentioned tunable light source have been realized.For example, this device can be by the GaAs Bragg reverberator of a pair of GaAs of having TPCOPO active layer, constitute as the solid-state narrowband coherent source of the GaAs such as VCSEL of pump with between the GaAs oct beam deflecting layer between them.
TPCOPO layer and Bragg reverberator design at the wavelength of pump.In this embodiment, pump and beam-control element can be parallel to the TPCOPO layer along the whole length in Bragg chamber, perhaps they can be in an end in Bragg chamber, before in pump being put into the Bragg chamber that comprises the TPCOPO layer, realize sufficient Beam Control ability.The member that applies driving voltage is electrically connected separately with pump and EOBS layer.Offer the electric power decision optical output power of pump, and impose on the voltage decision light output energy (that is frequency) of EOBS layer.Can be an independent element with the structure fabrication of being introduced or be made as an array.The synthem of TPCOPO shown in Fig. 8 is Bragg reverberator 80, EOBS Beam Control layer 81, pump 82, TPCOPO active layer 83, component substrate 84.In Fig. 8 a, pump is positioned at outside, Bragg chamber.If desired pump and EOBS or TPCOPO material are not suitable for, the EOBS layer needs excessive path realize sufficient Beam Control, if perhaps pump and/or EOBS layer taken in excess pump or TPCOPO output frequency then can be of great use.In this structure, the EOBS layer can be replaced by acousto-optic or piezo-beam key-course, and needs not to be " growth " to the Bragg chamber.In Fig. 8 b, pump and EOBS layer are placed on inside, Bragg chamber, to realize the more high conversion efficiency of pump energy, realize to allow freely designing of EOBS path under the situation of sufficient angular deflection but need before the pump ripple enters the TPCOPO layer, repeatedly pass the pump ripple at the EOBS layer to the output energy.In Fig. 8 c, pump, EOBS and TPCOPO layer stack gradually on the former top.This is the simplest design, if the EOBS layer effectively deflection pump output and pump and EOBS layer all do not have taken in excess pump or output frequency.
Though regard embodiment the most practical and preferred embodiment as and the present invention be described in detail for the purpose of graphic extension based on current, but be appreciated that, these details only provide for such purpose, the present invention is not limited to disclosed embodiment, but opposite, the intent of the present invention is to cover thought and change within the scope and the equivalence that is in claims.For example, should be appreciated that the present invention expects, on degree as much as possible, one or more features of any embodiment can be combined with one or more features of any other embodiment.
Claims (25)
1. a Noninvasive detects the equipment of the biological analyte in the sample, comprising:
A) optical system comprises at least one radiographic source and at least one ray detector;
B) measuring system is operationally joined with optical system;
C) control/disposal system is operationally joined with measuring system and is had embedded software system;
D) user interface/peripheral system is operationally joined with control/disposal system, is used to the user to provide and control/disposal system mutual; With
E) power-supply system is operationally joined with measuring system, control/disposal system, user interface/peripheral system or their combination in any, is used for to they provide electric power,
Wherein, the embedded software system of control/disposal system is handled the signal that obtains from measuring system, to determine the concentration of biological analyte in the sample.
2. according to the described equipment of claim 1, wherein, use the come together concentration of biological analyte definite sample of the absorption spectrum that obtains from optical system and the calibration vector of storage in the past by the embedded software system of control/disposal system.
3. according to the described equipment of claim 1, wherein, described sample is living tissue interstitial fluid, living tissue capillary bed, blood sample or their any combination.
4. according to the described equipment of claim 1, wherein, described radiographic source be emission wavelength can select and the selectable TPCOPO device of emissive porwer or emission wavelength can be selected and the selectable diode laser matrix of emissive porwer in a kind of.
5. according to the described equipment of claim 1, wherein, described ray detector is to be made by InGaAs, Ge or their any combination.
6. according to the described equipment of claim 1, wherein, described biological analyte is glucose, blood fat, alcohol or their any combination.
7. according to the described equipment of claim 6, wherein, radiogenic emission spectrum has covered the scope from about 1200nm to about 1900nm.
8. according to the described equipment of claim 6, wherein, the responding ability of ray detector has covered the scope from about 1200nm to about 1900nm.
9. according to the described equipment of claim 1, wherein, biological analyte is an alcohol, and radiogenic emission spectrum has covered the scope from about 800nm to about 1300nm.
10. according to the described equipment of claim 9, wherein, biological analyte is an alcohol, and the responding ability of ray detector has covered the scope from about 800nm to about 1300nm.
11. according to the described equipment of claim 1, wherein, user interface/peripheral system constitutes and is used for:
A) under the situation of doubtful hypoglycemia or hyperglycaemia, remind the user by the demonstration of audible tone and/or text message;
B) under doubtful hypoglycemic situation, use the alarm bell module to remind other people who is equipped with alarm bell;
C) use GPS module to determine user's position, and under hypoglycemic situation, send the emergency text message or the biological analyte concentration data is transferred to centralized server to a telephone number;
D) when obtaining encoded readings of glucose concentration, they are transferred to by sequencing and control the insulin pump of discerning described coding and being connected to the user, so that uelralante, perhaps their any combination automatically via the alarm bell module.
12. according to the described equipment of claim 1, wherein, described at least one radiographic source is to be made by optical crystal, semiconductor material single layer structure or their combination in any.
13. according to the described equipment of claim 12, wherein, semiconductor pump source and Beam Control structure and TPCOPO layer integrate, to realize that emission wavelength is selected and intensity is selected.
14. according to the described equipment of claim 13, wherein, described at least one radiographic source is by GaAs Bragg reverberator, the GaAs narrowband coherent source pump of a pair of GaAs of having TPCOPO active layer and place the GaAs oct beam deflecting layer between them to constitute.
15. according to the described equipment of claim 14, wherein, pumping source and Beam Control structure or be parallel to the TPCOPO layer or be in the end in Bragg chamber along the whole length in Bragg chamber before in pumping source being put into the Bragg chamber that comprises the TPCOPO layer, realize Beam Control.
16., wherein, pump layer and GaAs oct beam deflecting layer are electrically connected separately according to the described equipment of claim 14.
17. according to the described equipment of claim 14, wherein, the electric current that imposes on the pump layer is determined the intensity of institute's divergent-ray.
18. according to the described equipment of claim 14, wherein, the voltage that imposes on GaAs oct beam deflecting layer is determined the wavelength of institute's divergent-ray.
19. a Noninvasive detects the method for the biological analyte in the sample, approximating light beam carries out the spectrophotometric reference to this method on two spaces by utilizing, and wherein said method is applicable to the diffuse reflection of measuring interstitial fluid and comprises step:
A) utilize first radiographic source, second radiographic source, first ray detector and second ray detector that optical system is provided, thereby set up approximating four beam paths on the space by this system;
B) utilize the different functions of time to modulate these sources;
C) so that all optical element transmissions of this optical system and/or the mode that reflects these light beams dispose this optical system;
D) at a some place of this system first pair of light beam and second pair of beam separation are opened, first pair of light beam focused on user's the skin and and focus in the sample for reference second pair of light beam;
E) signal that produces by first detecting device and second detecting device of demodulation and will opening by signal and beam separation that detecting device produces; With
F) ratio according to first ratio and second ratio calculates spectrophotometric transmittance.
20. in accordance with the method for claim 19, wherein, first ratio be owing to the first radiogenic ray be incident on second ray detector the skin diffuse reflectance signal with because the second radiogenic ray is incident on the ratio of the reference diffuse reflectance signal on second ray detector, second ratio is to be incident on the instrument signal on first ray detector and to be incident on the ratio of the instrument signal on first ray detector because of the second radiogenic ray because of the first radiogenic ray.
21. in accordance with the method for claim 19, wherein, spectrophotometric transmittance is used for determining the concentration of sample biological analyte.
22. in accordance with the method for claim 19, wherein, described optical system has separate areas between sample beam and reference beams, and this zone is confined to the inside of optical glass device.
23. in accordance with the method for claim 22, wherein, the separated region between sample beam and the reference beams is protected by shell.
24. a spectrophotometric reference method of utilizing the pulse differential spectroscopy, described method is fit to be applied to the capillary blood diffuse reflection through the following steps, and described step comprises:
A) provide optical system with at least one light path;
B) to an approaching in time changing paths is sampled along with minimum and maximum photon path changing during the heartbeat;
C) detect time signal under each wavelength simultaneously;
D) calculate spectrophotometric transmittance according to the maximal value of diffuse signal and the ratio of minimum value; With
E) use spectrophotometric transmittance to determine the concentration of biological analyte in the sample.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69041805P | 2005-06-14 | 2005-06-14 | |
| US60/690,418 | 2005-06-14 | ||
| US11/451,864 | 2006-06-13 |
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| CN101263388A true CN101263388A (en) | 2008-09-10 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200680029664 Pending CN101263388A (en) | 2005-06-14 | 2006-06-14 | Method and apparatus for the non-invasive sensing of glucose in a human subject |
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| Country | Link |
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| CN (1) | CN101263388A (en) |
| ZA (1) | ZA200710800B (en) |
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| CN102641126A (en) * | 2011-02-15 | 2012-08-22 | 通用电气公司 | Sensor, apparatus and method for non-invasively monitoring blood characteristics of subject |
| CN102933138A (en) * | 2010-06-18 | 2013-02-13 | 霍夫曼-拉罗奇有限公司 | Methods and apparatus for decentralized diabetes monitoring |
| CN105873512A (en) * | 2013-12-27 | 2016-08-17 | 三美电机株式会社 | Biological-information measurement device |
| CN106166072A (en) * | 2015-05-19 | 2016-11-30 | 萨姆特得有限责任两合公司 | The method and apparatus that in Bio-ontology, the non-intruding of the measurand of analyte determines |
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| CN105873512A (en) * | 2013-12-27 | 2016-08-17 | 三美电机株式会社 | Biological-information measurement device |
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| US11412963B2 (en) | 2015-01-21 | 2022-08-16 | National Institutes for Quantum Science and Technology | Method for measuring concentration of substance in blood |
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| CN106166072B (en) * | 2015-05-19 | 2021-02-09 | 萨姆特得有限责任两合公司 | Method and device for non-invasive determination of a measured variable of an analyte in a biological body |
| CN106166072A (en) * | 2015-05-19 | 2016-11-30 | 萨姆特得有限责任两合公司 | The method and apparatus that in Bio-ontology, the non-intruding of the measurand of analyte determines |
| US10876965B2 (en) | 2015-12-09 | 2020-12-29 | Diamontech Ag | Apparatus and method for analyzing a material |
| US11280728B2 (en) | 2015-12-09 | 2022-03-22 | Diamontech Ag | Device and method for analyzing a material |
| CN108369182A (en) * | 2015-12-09 | 2018-08-03 | 迪亚蒙泰克有限公司 | Device and method for analysis of material |
| CN110178006A (en) * | 2016-11-22 | 2019-08-27 | 艾尔威尔有限公司 | NDIR glucose detection in liquid |
| US10983046B2 (en) | 2016-11-22 | 2021-04-20 | Airware, Inc. | Enhanced optical data capture using NDIR for liquids |
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