Abstract:
This specification discloses a method and apparatus for noninvasive measurement of human body component, such as glucose, in vivo. The apparatus includes near infrared spectroscopy based laser sources driven at carrier frequency lying within the absorption line of the component. The apparatus also drive the laser diodes with a modulation frequency to generate frequency difference between the measuring light and reference beam, and the interference of the two beam results in a beat signal, which frequency is proportional to optical path difference between the measuring light and reference beam. We can detect the spectrum of the scattering light, which propagate at specifically single optical path, by select the frequency using a phase sensitive detector (PSD) circuit. The apparatus include several laser sources and its controllers which modulate the laser&#39;s radiation, and includes an optical fiber coupler and splitter to split the laser into measuring and reference beam, and includes PSD circuit to detect the signal by the frequency. The apparatus further includes a signal processor that applies a derivative spectroscopy technique, such as wavelength modulation spectroscopy, to determine the concentration of the component in the body.

Description:
FIELD OF THE INVENTION 
       [0001]    This invention relates to the method and apparatus to detect human component noninvasive. Particularly, this invention relates to the use of modulated tunable diode lasers (TDLs) in order to improve the measuring accuracy of noninvasive determining the concentration of the human component, such as glucose, in vivo. 
       BACKGROUND 
       [0002]    The component in human body is the significant information for evaluating human health condition and is also the crucial standard for medical diagnose. The component is very low contents in the human body. The current testing method is to obtain the blood sample from finger tip, earlobe or vein, then use one-off reagent to handle chemical testing. This kind of invasive measurement is very complicate, painful and has the risk of infection. It restricts the on time and frequent measurement, and hampers the proper healthy treatment and management. In this respect, noninvasive human blood composition testing is of significant meaning in the treatment of disease and also in the research of disease. 
         [0003]    Among every component of the human blood, glucose concentration is the most focused subject. Glucose concentration is the most effective index for diabetic diagnose and treatment. Diabetic is a kind of metabolic disturbance which is caused by the abnormal component of glucose, and also can result in some kind of severe complicating disease such as diabetic ketoacidosis, cardiovascular disease, renal failure, ablepsia, acrogenic gangrene and infection. Diabetic is now becoming one of the biggest threat to human health. 
         [0004]    Kaiser [U.S. Pat. No. 4,169,676, Oct. 2, 1979] is the first one who uses optical method to test human component. Dähne [U.S. Pat. No. 4,655,225, Apr. 7, 1987] proposed to use dispersive near-infrared Spectrophotometers in the human component test. Today, the methods of human component measurement are mainly concerned of the following ways: polarization method, Raman spectrology, light scattering coefficient method, opto-acoustic spectral method, mid-infrared spectrology, near-infrared spectrology, optical Coherence Tomography (OCT), and so on. Polarization method&#39;s testing position is the eyeball which is difficult for the patient to accept; and the oculogyration may change the optical path and enlarge the testing mistake; and several components within the eyeball will disturb the polarization and the double refraction will interfere and reduce the transition light intensity; and the deflection angle of glucose solution too small to detect. The difficulty of Raman spectrum method is that the absorption and scattering signal in biological tissue are very weak and the background fluorescence interference comes from protein molecule is very powerful. Opto-acoustic spectrum method is too sensitive to the change of tissue structure and mid-infrared spectrum method is not very good at penetrating the tissue deeply enough. 
         [0005]    The near infrared absorption, which wavelength range is 780 nm-2500 nm, is mainly caused by frequency doubling of the molecular vibration or combination frequency of several compounds which have the chemical bond X—H, such as C—H, and O—H, and N-H. Based on the characteristic absorption spectrum, the ingredient contents can be tested, and glucose can be done also. Recently, the progress of computer and chemometrics technology enhance the sensitivity, precision, accuracy and reliability of quantitative analysis dramatically, near infrared spectroscopy widely used in some crucial area such as pharmacy, agriculture and petroleum. Compared with middle infrared wavelength area, the detector has much higher sensitivity and response speed, the radiant efficiency of the light source is higher, its optical elements are more reliable, costless, and have less effect from the outside working environment. Little or no need for sample preparation so that it is suit for rapid field test and real-time analysis. Near infrared spectrum method has the merits of high-speed, nondestructive, high efficiency and also has high penetrating ability of human sap and parenchyma, therefore it is the proper test wavelength area for the measurement. A successful example is the success of noninvasive measuring of human blood oxygen saturation degree using near infrared light. 
         [0006]    The key obstacles which reduce the accuracy of noninvasive near-infrared human components test lie in the following:
       (1) The signal is always very weak because of the huge amount of water in tissue which absorbs light in near infrared region very effective. And the glucose concentration in the blood is low, which less than 0.1%, and its absorption in near infrared region is very weak. To detect the components in vivo requires the instrument with very high Signal-to-Noise ratio (SNR).   (2) Variety of measuring condition: The variety of testing condition such as testing position, and borne pressure, and the area of incident light, will greatly change the optical path of light transport in the tissue. And the signal caused by this change is much more significant than that caused by the variety of glucose concentration. It is difficult to immobilize this change condition or eliminate them, to obtain the useful signal.   (3) Variety of human physiological statue: The variety of human physiological statue changes the signal greatly, which is much bigger than that caused by concentration variety of the components. So, it results in the overwhelming of the useful signal for determining the concentration of the human component.       
 
         [0010]    The signal is the multi-result of blood component and optical character of the skin. Many components of human body have absorption in near infrared spectrum, at the mean time, these spectrum are often over overlapping. The light transportation process is very complicate and has lots of optical path between the emission and reception. As shown in  FIG. 2 , there is big randomness of optical length. In direct receiving light scheme, all of this optical path which has experienced lots of the absorption and scattering of the human tissue coming into the photoelectric detector and cause the high complexity of the signal. 
       SUMMARY OF THE INVENTION 
       [0011]    In order to overcome all these difficulties and get a solution of the overlapping spectrum, high complexity and low particularity of the signal, the object of this invention is to provide a method and apparatus for noninvasive human components measurement using near infrared spectroscopy with optional optical length. By measuring the absorption spectrum from certain position on human body and certain testing of particular optical length, this noninvasive, real-time, high speed human body composition measurement can be achieved. 
         [0012]    The technical scheme of the invention is in: a method for noninvasive human component measurement with an optional optical length, which performs the human component measurement by detecting a laser transportation in human tissue and is characterized in that: said laser is modulated, based on an interference between measuring beam and reference beam, the interference&#39;s beating frequency is proportional to an optical length difference between the measurement light and the reference light, and by selecting a certain reference optical length and using a phase sensitive detector circuit to process the beating signal, a single optical length is selected from those human tissue scattering light so as to apply the measurement to a certain depth and part of the tissue. 
         [0013]    Preferably, said step of selecting a signal optical length from those human tissue scattering light consists of either adopting a single detector or a single light source, or adopting a plurality of detectors or a plurality of light sources; and irradiating the light to a large area or receiving the scattering from a large area. 
         [0014]    Preferably, the scattering light from human tissue with different optical lengths are simultaneously detected, and selecting at least one of the measuring optical lengths fitting the floating reference principle, which is the zero or rear zero sensitivity, used as the reference value; and selecting another one that fitting the floating reference principle, which is the maximum sensitivity, used as the measuring value for calculation the concentration of the component in the body. 
         [0015]    Preferably, the beating signals are selectively received according to their frequency; so as to select the different optical lengths propagating in the tissue, filter out the interferences from other light beams with different optical lengths. 
         [0016]    Preferably, the optical length of the selected scattering light is changed by using the optional frequency method, so as to be adaptable to the difference among floating point, i.e., the reference point and measurement point, due to different human body characteristics. 
         [0017]    The technical scheme of the invention is also in: an apparatus for noninvasive human component measurement with an optional optical length, which include a light driving controller, a light source, an interference light path, a signal conditioning circuit, a probe, a modulation signal generator and a micro computer, and is characterized in that: said light source is formed by a plurality of laser diodes; the signal conditioning circuit is formed by a preamplifier, a phase locking amplifier and an A/D converter; and a signal outputted from the A/D converter is inputted into the micro computer. 
         [0018]    Preferably, the laser used in the measurement has a near infrared wavelength of 800 nm to 2500 nm which includes the frequency doubling vibration and combination frequency vibration of glucose molecule. 
       OBJECTS OR ADVANTAGES OF THE PRESENT INVENTION 
       [0019]    The invention is based on the interference between measuring beam and reference beam, where the beating frequency is proportional to the optical length difference between measuring beam and reference beam. By selecting certain reference optical length and using phase sensitive detector circuit to process beating signal, the single optical length is selected from human tissue scattering light. In the respect of single optical length reception, the enhancement of detector area or multiple detectors can result in the increase of light intensity so as to enhance the SNR. 
         [0020]    In addition, this invention measure plural number optical length of the scattering light simultaneously. One of these is fit for the floating wavelength principle so as to build a realization of floating wavelength measurement method. Use modulation, filtering, pre-processing of the spectrum to realize the noninvasive, real-time and quickly human body component measurement. Therefore, this invention is convenient and has very high reliability of the testing result. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0021]      FIG. 1  shows the principle of floating reference measurement method. 
           [0022]      FIG. 2  shows the distribution of optical length between emission light and reception light. 
           [0023]      FIG. 3  shows the characteristic of the laser modulation and beating signal. 
           [0024]      FIG. 4  is a diagram showing the system structure of Embodiment 1 and is also used for publication. 
           [0025]      FIG. 5  is the drawing of the probe. 
           [0026]      FIG. 6  is the structure drawing of Embodiment 2. 
           [0000]    
         
           
                 
               
                 
                 
                 
               
             
                 
                     
                 
                 
                   Reference Signs 
                 
                 
                     
                 
               
               
                 
                     
                 
               
            
             
                 
                     
                   1, 2, 3 
                   diode laser control drivers 
                 
                 
                     
                   4, 5, 6 
                   laser diodes 
                 
                 
                     
                   7, 8, 9, 11, 
                   optical fibers 
                 
                 
                     
                   13, 13-1, 13-2, 13-3, 
                   optical fibers 
                 
                 
                     
                   14, 15, 15-1, 15-2, 15-3, 
                   optical fibers 
                 
                 
                     
                   19, 19-1, 19-2, 19-3, 
                   optical fibers 
                 
                 
                     
                   20, 37 
                   optical fibers 
                 
                 
                     
                   10, 12, 
                   optical fiber couplers 
                 
                 
                     
                   18, 18-1, 18-2, 18-3, 36 
                   optical fiber coupler 
                 
                 
                     
                   16, 16-1, 16-2 
                   probes 
                 
                 
                     
                   17 
                   part of tissue to be tested 
                 
                 
                     
                   21, 21-1, 21-2, 21-3 
                   balanced photoelectric receivers 
                 
                 
                     
                   22, 22-1, 22-2, 22-3 
                   preamplifiers 
                 
                 
                     
                   23, 24, 25, 26 
                   phase locking amplifiers 
                 
                 
                     
                   27 
                   A/D converter 
                 
                 
                     
                   28 
                   micro computer 
                 
                 
                     
                   29 
                   modulation signal generator 
                 
                 
                     
                   30 
                   display 
                 
                 
                     
                   31 
                   keyboard 
                 
                 
                     
                   32 
                   configuration of incidence laser path 
                 
                 
                     
                   33 
                   configuration of reference light path 
                 
                 
                     
                   34 
                   configuration of measuring light path 
                 
                 
                     
                   35 
                   housing of the probe 
                 
                 
                     
                     
                 
               
            
           
         
       
       
    
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS 
       [0027]    This invention is benefit of laser&#39;s coherence, directivity and high intensity, uses several laser diodes with various wavelength operated in frequency or time division mode, and wavelength modulated; and tests certain area of human body based on interference laser spectrum; and amplifies all the frequency components simultaneously, and extracts at least one of the frequency components fitting the floating reference principle, which is the zero or rear zero sensitivity, used as the reference value; and extracts at least one of the frequency components that fitting the floating reference principle, which is the maximum sensitivity, used as the measuring value; and calculates the concentration of human components using the reference value and measuring value with the micro computer. 
         [0028]    The object of this invention is to provide a noninvasive, real-time and in-vivo method and apparatus for testing human components. In order to overcome these difficulties, such as spectrum overlapping, high complexity and low particularity of the signal, the invention is achieved through modulated diode laser realizing certain optical length spectroscopy fitting floating reference methods, and testing certain human body area. 
       The Principle of Floating Reference Method 
       [0029]    When light transmit in the tissue, there exist a point M, called measurement point, where scattering light is the most sensitive to glucose concentration and a zero sensitive point C, called reference point, as shown in  FIG. 1 . The spectrum signal of reference point C contains the entire physiology changing which is irrelevant to glucose concentration. Measurement point M contains the largest amount signal of blood glucose concentration so that it is the best point for the testing. Measurement at these two point simultaneously and process difference afterward could reduce the interference of physiology changing significantly and enhance the precision and sensitivity of glucose concentration measurement. 
       Interference Modulating Laser Spectroscopy 
       [0030]    Single optical length selection is based on the technology of interference modulating laser spectroscopy: The laser radiation, which is wavelength modulated so the wavelength changes with time (as shown in FIG.  3 - a ), is split into two beams, one is used as reference, called reference beam; and the other is for measuring, and called measuring beam. Measuring beam transmitted in optical fiber and collimated at the position that has plentiful arterial blood. Then the backward scattered light is collected and coupled into the fiber. It meets and interferers with the reference beam in fiber fused coupler. Because of the optical path difference between the two beams, the frequency of interference beating is given as: 
         [0000]    
       
         
           
             
               
                 
                   
                     f 
                     d 
                   
                   = 
                   
                     
                       β 
                        
                       
                           
                       
                        
                       nL 
                     
                     
                       λ 
                       2 
                     
                   
                 
               
               
                 
                   
                     ( 
                     1 
                     ) 
                   
                    
                   
                       
                   
                 
               
             
           
         
       
       
         
           
             Where:
           λ is the central wavelength of the laser;   β is modulation factor of the laser diode; and   nL is the optical length of the measurement light (the testing fiber and reference fiber have the same length).   
         
           
         
       
     
         [0035]    The frequency of the interference beating is fixed for a single optical length, as shown in FIG.  3 - b . As for the light scattered when transmitted in the body tissue, there are innumerable counts of optical length, so it is corresponding to innumerable counts of beating frequency, which obey the same distribution, as shown in  FIG. 2 . Thus, the scattering lights with different light paths in the tissue are converted into the beating signals with different frequencies. 
         [0036]    In addition, the detected beating signal is amplitude modulated, converted from the wavelength modulated laser, and has the same frequency with the modulation frequency. The low frequency beating signal is mainly about 1/f noise and fundamental wave equals to modulating frequency, 2f, 3f are the harmonics of modulating frequency. The application of wavelength modulation spectroscopy is to transfer the DC signal to high frequency signal and can reduce various noise so as to improve the measuring SNR greatly. 
       Extracting Information of Certain Optical Length 
       [0037]    Based on the technology of interference modulating laser spectroscopy mentioned above, the information of certain optical length can be extracted from selecting the interference beating frequency by using phase sensitive detector (PSD), as shown in  FIG. 2 . It can also filter the disturbing signal comes from other optical length, noise, and so on. 
         [0038]    The information of different optical length of scattering light is obtained by adjusting the center frequency of PSD circuit; and the regulation of optical length range is obtained by setting the bandwidth of PSD circuit; and the information of multiple optical length is obtained by setting several signal channels, that is several PSD circuit with different central frequency, where each channel corresponds to different scattering optical length. 
         [0039]    The technology of interference modulating laser spectroscopy profit from laser&#39;s coherence, directivity and high intensity, the laser radiation is focused onto the small point with plenty arterial blood of the body, so as to realize high spatial resolution. the indiscipline distribution of the light transportation, which scatters from protein, fat and muscle, is reduced benefit from single optical measurement of The technology of interference modulating laser spectroscopy, so as to reduce the signal randomicity and the spectrum&#39;s complexity which caused by the discrepancy of the tissue. the ration of certain optical characteristic and the concentration prediction of human component is realized. 
         [0040]    The preferred embodiments of the invention will be illustrated with reference to the drawings below. 
       EMBODIMENT 1 
       [0041]    Embodiment 1 of the invention is shown in  FIG. 4 , the system includes a laser driver controller  1 , a laser driver controller  2 , a laser driver controller  3 , a laser source  5 , a laser source  6 , an interference laser spectrum light path  7 , an interference laser spectrum light path  8 , an interference laser spectrum light path  9 , an interference laser spectrum light path  10 , an interference laser spectrum light path  11 , an interference laser spectrum light path  12 , an interference laser spectrum light path  13 , an interference laser spectrum light path  14 , an interference laser spectrum light path  15 , an interference laser spectrum light path  18 , an interference laser spectrum light path  21 , a signal processing circuit  22 , a signal processing circuit  23 , a signal processing circuit  24 , a signal processing circuit  25 , a signal processing circuit  26 , a signal processing circuit  27 , a micro computer  28 , an optical probe  16 , a modulation signal generator  29 , a display  30  and a keyboard  31 . This system is used to realize the interference laser spectrum technology and the multi-optical length separation technology. 
         [0042]    The light source is near-infrared coherent source, which can use laser diode, gas laser, or dye laser. Several laser sources with different wavelength are used to cover the necessary wavelengths which needed for the components in human body. In the respect of glucose concentration measurement, we adopt several wavelength in the area of second order frequency doubling of glucose molecule (wavelength band from 1100 to 1300 nm), and first order frequency doubling area of glucose molecule (wavelength band from 1500 to 1800 nm), combination frequency area (wavelength band from 2100 to 2500 nm). In the embodiment, we adopt multiple laser diodes (three laser diodes are shown in the principle figure) 
         [0043]    The laser driver controller ( 1 ,  2 ,  3 ) are used to control the output power of the diode laser, and to modulate the wavelength and to measure and control the temperature of diode laser. 
         [0044]    Interference laser spectrum light path is comprised of a fiber  7 , a fiber  8 , a fiber  9 , a fiber  11 , a fiber  13 , a fiber  14 , a fiber  15 , a fiber  19 , a fiber  20 , an optical fiber coupler  10 , an optical fiber coupler  12 , an optical fiber coupler  18 , and a balanced photoelectric receiver  21 . N numbers of lasers (three are shown in the figure) output the emitted laser into the fiber  7 , the fiber  8 , the fiber  9  and through the N×1 optical fiber coupler  10  (3×1 optical fiber coupler in the figure) into the fiber  11 . The 1×2 optical fiber coupler  12  is used to separate the light into the measurement fiber  14  and the reference fiber  13 ; the laser that transmits in the measurement fiber  14  arrives at the optical probe, and through the incidence laser light path  32 , irradiates onto the skin tissue. The scattering light from deep skin tissue is collected by the measurement light path  34  into the fiber  15 , and is interfered with the reference light from fiber  13  in the optical fiber coupler  18 . The interfered beam reaches the balanced photoelectric receiver  21  through the fiber  19 . The reflection light from the surface of skin is collected by the reference light path  33  and is then transmitted to the fiber  20  and then to the balanced photoelectric receiver  21  for reducing the laser source noise and other common-mode noise. 
         [0045]    We set up several signal channel of demodulation circuit including a preamplifier  22 , a phase locking amplifier  23 , a phase locking amplifier  24 , a phase locking amplifier  25 , a phase locking amplifier  26 , an A/D converter  27 . The preamplifier  22  amplified the output signal from the balanced photoelectric receiver  21  and the signals from the preamplifier  22  contain absorption information of human component and transmit into several phase locking amplifiers (four are shown in the figure), the output of the modulation signal generator  29  will also be sent into these phase locking amplifiers whose central frequencies are set differently to create several signal channels. Different signal channels correspond to different scattering light lengths. At least one reference value that satisfies the floating reference principle, which is the zero or rear zero sensitivity, is selected as the reference value for calculation and another one that satisfies the floating reference measurement principle, which is the maximum sensitivity, is selected as the measurement value for calculation. The entire output signal from phase locking amplifiers will be sent to the multi-channel AD converters  27  and thus be converted into a digital signal. 
         [0046]    The micro computer  28 , which can be embedded controller, PC, or signal chip processor, administrates the testing system through the peripheral circuits, which include the keyboard  31 , the display  30 , the laser driver controller  1 , the laser driver controller  2 , the laser driver controller  3 , the modulation signal generator  29 , and the multi-channel AD converter  27 . The commands and necessary information is input through the keyboard. A display is used to show the operation information, which can be a digitron, a liquid crystal display (LCD), or a cathode ray tube (CRT). The micro computer  28  controls the temperature and current of the laser source  4 , and the laser source  5 , and the laser source  6  through the laser driver controller  1 , the laser driver controller  2 , the laser driver controller  3  respectively, and performs the modulation and output of the laser signal. The modulation signal generator  29  gives the characteristic parameters of the diode laser, which include modulation mode, and modulation factors, and modulation frequency. The multi-channel AD converter  27  outputs the signal into the micro computer  28  which performs digital signal processing including digital filtering, fault elimination, temperature compensation and background deduction and calculating the prediction value of human component according to the rating curve, and then the results are displayed on the display  30 . 
       Explanation of the Probe 
       [0047]    The proposal of the probe is shown in  FIG. 5 , including an incidence laser light path  32 , a reference light path  33 , a measurement light path  34  and a housing  35 . A fiber  14 , a fiber  15  and a fiber  20  are used to connect the probe with the interference laser spectrum light path. The light from the fiber  14  will be collimated with the incidence laser light path  32  and is pointed at the testing object. An optical stop is set up between the laser light path  32  and the measurement light path  34 . The scattering light will be tested by the measurement light path  34  only if the light passes the deep tissue of the skin. After coupling into the testing fiber  20 , the reflection light from the skin will be collected by the reference light path  33  into the fiber  15 . 
       EMBODIMENT 2 
     The Application of a Plurality of Detectors 
       [0048]    Embodiment 2 concerns a human component measurement system with a plurality of detectors as shown in  FIG. 6 . The 1×2 optical fiber coupler  12  is used to split the light beam into two beams. One of them passes a fiber  37  and then arrives at an optical fiber coupler  36  where the light is separated into three light paths as the reference lights to be transmitted through the fibers  13 - 1 ,  13 - 2 ,  13 - 3  to the optical fiber couplers  18 - 1 ,  18 - 2 ,  18 - 3 . The other one passes a fiber  14  and arrives at a probe  16 - 1  to be transmitted through an incident laser light path  32  to irradiate the skin tissue. The measurement light collected by the probes  16 - 1  and  16 - 2  are transmitted to the optical fiber couplers  18 - 1 ,  18 - 2 ,  18 - 3  through fibers  15 - 1 ,  15 - 2 ,  15 - 3  so as to be interfered with the reference lights. The beating signal will be received by photoelectric receivers  21 - 1 ,  21 - 2 ,  21 - 3  and amplified by preamplifiers  22 - 1 ,  22 - 2 ,  22 - 3 . A phase locking amplifier  24 , a phase locking amplifier  25 , a phase locking amplifier  26  are used to select different optical lengths. An A-D converter  27  is used to perform the analog-digital conversion. A micro computer  28  is used to perform digital signal processing including digital filtering, fault elimination, temperature compensation and background deduction and calculating the prediction value of human component according to the rating curve, and then the results are displayed on the display  30 . 
         [0049]    The phase locking amplifier  24 , the phase locking amplifier  25 , and the phase locking amplifier  26  will be configured to obtain different frequencies so as to acquire several optical lengths to build several signal channels. At least one reference value that satisfies the floating reference measurement principle is selected as the reference value for calculation and another one that satisfies the floating reference measurement principle is selected as the measurement value for calculation.