# Patent

## Title
Optical non-invasive blood monitoring system and method

## Abstract

A simple noninvasive technique that is capable of very accurate and fast blood analyte, e.g., glucose, level monitoring is provided. Fluctuation in the levels of glucose and other analytes affect the refractive index of blood and extra cellular fluid in biological tissue. Given that the propagation speed of light through a medium depends on its refractive index, continuous monitoring of analyte levels in tissue is achieved by measuring characteristics of the tissue that can be correlated to the refractive index of the tissue. For instance, the frequency or number of optical pulse circulations that are transmitted through an individual's tissue of known thickness within a certain time period can be correlated to an individual's blood glucose level.

## Background
REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part application of application Ser. No. 11/492,451 which was filed on Jul. 25, 2006 now U.S. Pat. No. 7,486,976.


FIELD OF THE INVENTION
The present invention is directed to instruments and methods for performing non-invasive measurements of analyte concentrations and for monitoring, analyzing and regulating tissue status, such as tissue glucose levels.
BACKGROUND OF THE INVENTION
Diabetes is a chronic life threatening disease for which there is presently no cure. It is the fourth leading cause of death by disease in the United States and over a hundred million people worldwide is estimated to be diabetic. Diabetes is a disease in which the body does not properly produce or respond to insulin. The high glucose concentrations that can result from this affliction can cause severe damage to vital organs, such as the heart, eyes and kidneys.
Type I diabetes (juvenile diabetes or insulin-dependent diabetes mellitus) is the most severe form of the disease, comprising approximately 10% of the diabetes cases in the United States. Type I diabetics must receive daily injections of insulin in order to sustain life. Type II diabetes, (adult onset diabetes or non-insulin dependent diabetes mellitus) comprises the other 90% of the diabetes cases. Type II diabetes is often manageable with dietary modifications and physical exercise, but may still require treatment with insulin or other medications. Because the management of glucose to near-normal levels can prevent the onset and the progression of complications of diabetes, persons afflicted with either form of the disease are instructed to monitor their blood glucose concentration in order to assure that the appropriate level is achieved and maintained.
Traditional methods of monitoring the blood glucose concentration of an individual require that a blood sample be taken daily. This invasive method can be painful, inconvenient, and expensive, pose the risk of infection and does not afford continuous monitoring. So-called semi-invasive (or less-invasive) methods require an individual to take samples through the skin but the techniques do not puncture blood vessels. Most semi-invasive glucose monitoring devices measure the concentration of glucose that is present in the interstellar fluid that is between the skin's surface and underlying blood vessels. The devices could be implanted to provide continuous (real time) glucose level monitoring but individuals would have to undergo implantation surgery. Moreover, once implanted the devices are often inaccessible for maintenance.
Another glucose measuring method involves urine analysis, which, aside from being inconvenient, may not reflect the current status of the patient's blood glucose because glucose appears in the urine only after a significant period of elevated levels of blood glucose. An additional inconvenience of these traditional methods is that they require testing supplies such as collection receptacles, syringes, glucose measuring devices and test kits. Although disposable supplies have been developed, they are costly and can require special methods for disposal.
Many attempts have been made to develop a painless, non-invasive external device to monitor glucose concentrations. The various approaches have included electrochemical and spectroscopic technologies, such as near-infrared spectroscopy and Raman spectroscopy. These systems measure blood glucose concentration based on IR blood absorption and emission at selected wavelengths. A major problem with these non-invasive optical techniques is that blood glucose absorption in the near, mid or far IR regions is very weak. Compounding this problem is the fact that water, proteins, fat, and other tissue components tend to blur the glucose fingerprint and thereby attenuate the detectable signals and as a result these blood glucose monitoring devices are not very accurate. Techniques used to compensate for the poor signals and the related signal-to-noise problems including complicated spectral analysis and processing instrumentation have not been successful. Thus, despite extensive efforts, none of these methods has, so far, yielded a non-invasive device or method for the in vivo measurement of glucose that is sufficiently accurate, reliable, convenient and cost-effective for routine use.
SUMMARY OF THE INVENTION
The present invention is based in part on the recognition that glucose levels affect the refractive index of blood and extra cellular fluid. Biological tissue is a very complex composition and, as used herein, the phrase “refractive index of tissue” refers to a composite or collective refractive index that is derived from the different refractive indices of the various materials that are present in the tissue being monitored. Given that the propagation speed of light through a medium v depends on its refractive index n, as v=c/n, where c is the speed of light in vacuum, it is possible to continuously monitor glucose levels in tissue by measuring characteristics of the tissue that can be correlated to the refractive index of the tissue and to the speed at which electromagnetic radiation travels through the tissue.
For instance, with the present invention, the frequency or number of optical pulse circulations that are transmitted through tissue of known thickness within a certain time period can be correlated to the individual's blood glucose level. Thus, the invention provides a simple design that is capable of very accurate and fast blood glucose level monitoring.
In one aspect, the invention is directed to a device for noninvasive measurement of the levels of at least one analyte in a subject that includes:
means for irradiating the subject through tissue with electromagnetic radiation;
means for detecting the radiation that passes through the tissue;
means for calculating the speed at which the electromagnetic radiation passes through the tissue;
means for monitoring at least one of back or forward scattering of electromagnetic radiation within the tissue; and
means for correlating the calculated speed of the electromagnetic radiation to the concentration of the at least one analyte in the subject.
In another aspect, the invention is directed to a device for noninvasive measurement of the levels of at least one analyte in a subject that includes:
means for irradiating the subject through tissue with electromagnetic radiation;
means for detecting the radiation that passes through the tissue;
means for calculating the speed at which the electromagnetic radiation passes through the tissue; and
means for correlating the calculated speed of the electromagnetic radiation to the concentration of the at least one analyte in the subject, wherein the device defines a plurality of measuring channels and wherein the plurality of measuring channels are operated by a single electronic processing unit.
The means for irradiating the subject through tissue with electromagnetic radiation does not need to generate pulses at regular intervals.
In a further aspect, the invention is directed to a device for noninvasive measurement of the levels of glucose in a subject that includes:
means for irradiating the subject through tissue with electromagnetic radiation having a wavelength such that the speed of the electromagnetic radiation propagating through the tissue is sensitive to the glucose concentration in the tissue;
means for detecting the radiation that passes through the tissue;
means for calculating the speed at which the electromagnetic radiation passes through the tissue;
means for monitoring at least one of back or forward scattering of electromagnetic radiation within the tissue; and
means for correlating the calculated speed of the electromagnetic radiation to the concentration of glucose in the subject.
In a yet another aspect, the invention is directed to a noninvasive method of monitoring the levels of at least one analyte in a subject that includes the steps of:
(a) irradiating the subject through tissue of known thickness with electromagnetic radiation;
(b) detecting the radiation that passes through the tissue;
(c) calculating the speed at which the electromagnetic radiation passed through the tissue; and
(d) correlating the calculated speed of the electromagnetic radiation to the concentration of the at least one analyte (e.g., glucose) in the subject.
While the invention will be illustrated with glucose, it is understood that the invention provides the ability to achieve continuous monitoring and control of other blood constituents or analytes such as, for example, cholesterol, triglycerides, urea, amino acids, and proteins, e.g., albumin and enzymes.



BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1, 4, and 5 are schematics of alternative configurations of non-invasive glucose level monitoring instruments;
FIG. 2 is a graph showing the change in pulse circulation frequency vs. glucose concentration measured with a glucose monitoring device using radiation source with a wavelength of 850 nm;
FIG. 3 is a graph showing the sensitivity of a glucose monitoring device vs. electronic processing unit (EPU) time delay;
FIGS. 6-13 are schematics of alternative configurations of non-invasive glucose level monitoring instruments that employ a single electronic processing unit;
FIG. 14 is a cross-sectional view of a glucose monitoring device when worn on the wrist of an individual;
FIG. 15 depicts the glucose monitoring device with the display panel;
FIG. 16 depicts the glucose monitoring device as worn on the wrist.
FIG. 17 illustrates the operation of the glucose monitoring device transmitting data and regulating an insulin pump; and
FIGS. 18A and 18B depict an ear-worn glucose monitoring device.



DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As shown in FIG. 1, the glucose monitoring device includes an optical or light source of electromagnetic radiation 1 and detector 2 which, are connected to an electronic processing unit (EPU) 3. EPU 3, which includes a pulse generator 5, amplifier 6, counter 7 and timer 8, is capable of generating, amplifying and counting electronic pulses and monitoring time precisely. Source 1 and detector 2 are preferably disposed on opposite sides of glucose-containing tissue 4, which is to be monitored.
Optical source 1 can comprise any suitable conventional source such as, for sample, a laser, a laser diode, a light emitting diode (LED), or some other type of light emitting device that is capable of generating light in a relatively narrow wavelength band in a high frequency pulse regime. The intensity should be sufficient to transmit through tissue being monitored but the intensity and energy levels of the radiation must not be hazardous to the tissue. The radiation is preferably within the ultra-violet (UV), visible, infrared radiation (IR), and radio frequency (RF) ranges. The light source 1 could also comprise a broadband light source such as a white light LED. Such a broadband light source can also be paired with one or more optical filters that are designed to pass only specific wavelength bands of light. Light source 1 can also include appropriate optics that collimates and directs a beam of radiation into tissue 4.
Detector 2 can comprise a photodetector or any other type of device capable of high speed sensing the light that is transmitted through tissue 4. The detector 2 could be configured to sense the intensity of one or more particular wavelength bands. Suitable optics can be employed to collect and focus the transmitted radiation into the detector. The EPU can be built using separate components or it can design as an integrated microchip that supports several measurement channels.
For testing purposes, the glucose monitoring device can be calibrated by using an aqueous solution that contains the appropriate amounts of glucose, salts, proteins and other ingredients that are sufficient to simulate the tissue that would be monitored.
In operation, tissue 4 is positioned between source 1 and detector 2 of the glucose monitoring device such that the thickness of the tissue through which radiation passes remains relatively constant during the monitoring process. Once tissue 4 is secured, the device is activated so that pulse generator 5 produces an initial single electrical pulse to optical source 1, in addition, pulse generator 5 simultaneously signals timer 8 to begin its timing mechanism. Upon receiving the single electrical pulse, optical source 1 generates an optical pulse, which propagates through the monitored tissue 4. When the optical pulse reaches detector 2, the detector generates an electrical pulse to amplifier 6 which in turn commands counter 7 to register a pulse circulation and signals pulse generator 5 to generate another single electrical pulse. Thereupon, pulse generator 5 immediately generates a second single pulse to optical source 1 and the process of registering the circulating pulses is repeated. At the lapsed of a pre-selected and installed time duration, timer 8 sends a signal to counter 7 to record the number of pulse circulations that were registered during the preceding time interval. In the meantime, pulse generator 5 continues to generate a second set of pulses for a new measurement sequence. As further described herein, for this glucose monitoring device which operates in the pulse circulation frequency measurement mode (also referred to as pulse measurement mode), the number of pulses registered within a prescribed time frame is proportional to the glucose concentration in the tissue and by gauging the changes in this pulse circulation frequency, fluctuations in the individual's glucose concentration can be measured. With the inventive technique, it is possible to circulate and detect a large number of pulse propagations through the tissue even in a relatively short period of time, with each monitored pulse contributing to the final glucose concentration measurement. The precision and high sensitivity exhibited by the invention are attributable, in part, to the fact that the large number of readings minimize the adverse effects that are contributed by aberrations and fluctuations caused by noise and other extraneous factors.
The relationship between the number N of pulse circulations measured within a time period t is expressed as follows:




  
    
      
        
          N
          =
          
            
              t
              
                
                  
                    L
                    ⁢
                    
                      
                    
                    ⁢
                    n
                  
                  c
                
                +
                
                  Δ
                  ⁢
                  
                    
                  
                  ⁢
                  τ
                
              
            
            =
            
              t
              
                
                  L
                  v
                
                +
                
                  Δ
                  ⁢
                  
                    
                  
                  ⁢
                  τ
                
              
            
          
        
        ;
      
    
    
      
        (
        1
        )
      
    
  




where L is the thickness of the monitored tissue, n is the tissue's refractive index, c is the speed of light in vacuum, v=c/n is the propagation speed of the pulse in the tissue, and Δτ is the time delay in the EPU. (See, A. V. Loginov et al., “Fiber optic devices of data collecting and processing,” Novosibirsk, “Nauka,” Siberian Branch, 1991.) Similarly, the dependence of the tissue refractive index n=n (λ, C) on the wavelength λ and glucose concentration C in the tissue can be presented as:

n(λ,C)=n0(λ)+k(λ)*C;  (2)

where n0(λ) is the refractive index of the tissue without glucose, k(λ) is the refractive index sensitivity to glucose concentration, and C is the blood glucose concentration. Applying the relationship of equation (2), for a given radiation of wavelength λ, the correlation between the number (or frequency) N(C) of registered pulse circulations and the glucose concentration C can be expressed as:





  
    
      
        
          
            N
            ⁡
            
              (
              C
              )
            
          
          =
          
            t
            
              
                
                  L
                  ·
                  
                    (
                    
                      
                        
                          n
                          0
                        
                        ⁡
                        
                          (
                          λ
                          )
                        
                      
                      +
                      
                        
                          k
                          ⁡
                          
                            (
                            λ
                            )
                          
                        
                        *
                        C
                      
                    
                    )
                  
                
                c
              
              +
              
                Δ
                ⁢
                
                  
                
                ⁢
                τ
              
            
          
        
        ;
      
    
    
      
        (
        3
        )
      
    
  




and as a corollary, the relationship between the changes in the frequency of registered pulse circulations to glucose concentration becomes:





  
    
      
        
          
            Δ
            ⁢
            
              
            
            ⁢
            
              N
              ⁡
              
                (
                C
                )
              
            
          
          =
          
          ⁢
          
            
              
                N
                ⁡
                
                  (
                  0
                  )
                
              
              -
              
                N
                ⁡
                
                  (
                  C
                  )
                
              
            
            =
            
              
                
                  L
                  ·
                  
                    k
                    ⁡
                    
                      (
                      λ
                      )
                    
                  
                  ·
                  C
                  ·
                  t
                  ·
                  c
                
                
                  
                    
                      
                        
                          [
                          
                            
                              L
                              ·
                              
                                (
                                
                                  
                                    
                                      n
                                      0
                                    
                                    ⁡
                                    
                                      (
                                      λ
                                      )
                                    
                                  
                                  +
                                  
                                    
                                      k
                                      ⁡
                                      
                                        (
                                        λ
                                        )
                                      
                                    
                                    ·
                                    C
                                  
                                
                                )
                              
                            
                            +
                            
                              Δ
                              ⁢
                              
                                
                              
                              ⁢
                              
                                τ
                                ·
                                c
                              
                            
                          
                          ]
                        
                        ·
                      
                    
                  
                  
                    
                      
                        [
                        
                          
                            L
                            ·
                            
                              
                                n
                                0
                              
                              ⁡
                              
                                (
                                λ
                                )
                              
                            
                          
                          +
                          
                            Δ
                            ⁢
                            
                              
                            
                            ⁢
                            
                              τ
                              ·
                              c
                            
                          
                        
                        ]
                      
                    
                  
                
              
              ≈
              
                
                  L
                  ·
                  
                    k
                    ⁡
                    
                      (
                      λ
                      )
                    
                  
                  ·
                  C
                  ·
                  t
                  ·
                  c
                
                
                  
                    [
                    
                      
                        L
                        ·
                        
                          
                            n
                            0
                          
                          ⁡
                          
                            (
                            λ
                            )
                          
                        
                      
                      +
                      
                        Δ
                        ⁢
                        
                          
                        
                        ⁢
                        
                          τ
                          ·
                          c
                        
                      
                    
                    ]
                  
                  2
                
              
            
          
        
        ;
      
    
    
      
        (
        4
        )
      
    
  




where N(0) is the frequency of the pulse circulation when the glucose concentration C=0. As is apparent, by monitoring the changes in the pulse circulation frequency (PCF), the invention enables detection of extremely small fluctuations in the glucose concentration within the tissue. The sensitivity S(C) of the device to the glucose concentration can be expressed as:





  
    
      
        
          S
          ⁡
          
            (
            C
            )
          
        
        =
        
          
            
              d
              
                (
                
                  Δ
                  ⁢
                  
                    
                  
                  ⁢
                  
                    N
                    ⁡
                    
                      (
                      C
                      )
                    
                  
                
                )
              
            
            
              d
              C
            
          
          ≅
          
            
              
                L
                ·
                
                  k
                  ⁡
                  
                    (
                    λ
                    )
                  
                
                ·
                t
                ·
                c
              
              
                
                  [
                  
                    
                      L
                      ·
                      
                        
                          n
                          0
                        
                        ⁡
                        
                          (
                          λ
                          )
                        
                      
                    
                    +
                    
                      Δ
                      ⁢
                      
                        
                      
                      ⁢
                      
                        τ
                        ·
                        c
                      
                    
                  
                  ]
                
                2
              
            
            .
          
        
      
    
    
      
        (
        5
        )
      
    
  




Analysis of equation (5) shows that the glucose monitoring device sensitivity is directly proportional to the measurement time interval t and inversely proportional to the EPU time delay, Δτ. The sensitivity is independent of the glucose concentration level in the tissue, which is consistent with the linear nature of the relationship between glucose monitor output signal (pulse circulation frequency) and the glucose concentration level. In order not to saturate the measurement process, the optical pulse duration should be smaller (shorter) than EPU time delay, Δτ.
A simulation of a glucose monitoring device employing radiation with a wavelength of 850 nm in measuring glucose levels in a tissue with thickness L of 0.05 m was conducted to illustrate the relationship between the output signal and glucose concentration and the effects of the EPU time delay. Measurement time interval t contained t=1 sec. At a wavelength λ of 850 nm, for equation (2), the refractive index sensitivity to the glucose concentration, k(λ)=1.515*10−6 (dL/mg) and n0(λ)=1.325. (See, J. S. Maier, et. al. “Possible Correlation between Blood Glucose Concentration and Reduced Scattering Coefficient of Tissues in the Near-Infrared,” Optics Letters, Vol. 19, No. 24. pp. 2062-2064, Dec. 15, 1994.) FIG. 2 is a graph depicting the change in pulse circulation frequency (that is, the output pulse circulation frequency ΔN(C)) as a function of glucose concentration in the tissue when measured at three different EPU delay times of 1, 2, and 5 nanoseconds. As is apparent, the pulse circulation frequency ΔN(C) has a linear relationship with the blood glucose level. The linear character of the output signal (pulse circulation frequency) and the device's ability to exhibit constant sensitivity throughout the measurement range are important design criteria. Moreover, given that the glucose concentration is reflected in the changes of the pulse circulation frequency, it is not necessary to calibrate the device against the glucose measurement range for an individual.
A simulation of a glucose monitoring device employing radiation with a wavelength of 850 nm for measuring glucose levels in a tissue with a thickness L of 0.05 m was conducted to illustrate the effects of the measurement time interval. FIG. 3 is a graph of the glucose monitoring sensitivity as a function of EPU delay time as measured at three different measurement time intervals of 1, 3, and 10 seconds. The data shows that using longer measurement time intervals increases the sensitivity and resolution. As is apparent from the graph, the inventive glucose monitoring technique exhibits extremely high sensitivity and thus is capable of very accurate real time blood glucose level measurements. The sensitivity data also demonstrate that the inventive glucose monitoring device is capable of extremely high resolution. For example, when a device is operated at a 1 second measurement duration time, a pulse circulation frequency of 108 Hz (which corresponds to an EPU delay time of about 10−8 s), and an assumed counter frequency error of about 10−1 Hz, the glucose monitoring device is expected to exhibit a resolution of about 0.05 mg/dL.
With regard to sensitivity, a device reaches its theoretical limit when Δτ=0:




  
    
      
        
          S
          ⁡
          
            (
            C
            )
          
        
        ≅
        
          
            
              
                k
                ⁡
                
                  (
                  λ
                  )
                
              
              ·
              t
              ·
              c
            
            
              L
              ·
              
                
                  n
                  0
                  2
                
                ⁡
                
                  (
                  λ
                  )
                
              
            
          
          .
        
      
    
    
      
        (
        6
        )
      
    
  




Thus, for example, when a glucose monitoring device that is operating at a wavelength λ of 850 nm so that the refractive index sensitivity to the glucose concentration k(λ)=1.515*10−6 (dL/mg) and n0(λ)=1.325 is used to monitor tissue with a thickness L of 0.05 m, and c=3*108 m/s, the theoretical limit of the device sensitivity contains Sth(C)=4.5*103 Hz/(mg/dL) when the measurement time interval t is 1 second. Pulse duration is the limiting factor in this case.

FIG. 4 illustrates another embodiment of the glucose monitoring device in which blood glucose levels are monitored in the time interval measurement mode (also referred to as time measurement mode), which means that the time interval necessary for the circulation of a defined number of pulses is the measure of the glucose level. As shown, this glucose monitoring device includes an optical or light source of electromagnetic radiation 11 and detector 12 which are connected to electronic processing unit (EPU) 13. EPU 13, which includes an electrical pulse generator 15, amplifier 16, counter 17 and timer 18, is capable of generating, amplifying and counting electronic pulses and monitoring time precisely. Source 11 and detector 12 are preferably disposed on opposite sides of glucose-containing tissue 14, which is to be monitored.
In operation, tissue 14 is positioned between source 11 and detector 12 such that the thickness of the tissue through which radiation passes remains relatively constant during the monitoring process. Once tissue 14 is secured, the device is activated so that pulse generator 15 produces an initial single electrical pulse to optical source 11, in addition, pulse generator 15 signals timer 18 to begin its timing mechanism. Upon receiving the single electrical pulse, optical source 11 generates an optical pulse, which propagates through the monitored tissue 14. When the optical pulse reaches detector 12, the detector generates an electrical pulse to amplifier 16 which in turn commands counter 17 to register a pulse circulation and signals pulse generator 15 to generate another single electrical pulse. Thereupon, pulse generator 15 immediately generates a second single pulse to optical source 11 and the process of registering the circulating pulses is repeated. When the number of registered pulse circulations reaches a pre-selected and installed number, counter 17 sends a command to timer 18 to record this time. In the meantime, pulse generator 5 continues to generate pulses for a new measurement sequence. As further described herein, for this technique, the time interval for the circulation of N0 pulses is proportional to the glucose concentration in the tissue and by gauging the changes in the time interval, fluctuations in the individual's glucose concentration can be measured.
The dependence of the time interval t on the glucose concentration in the tissue can be presented as:




  
    
      
        
          t
          ⁡
          
            (
            C
            )
          
        
        =
        
          
            N
            0
          
          ·
          
            [
            
              
                
                  L
                  ·
                  
                    (
                    
                      
                        
                          n
                          0
                        
                        ⁡
                        
                          (
                          λ
                          )
                        
                      
                      +
                      
                        
                          k
                          ⁡
                          
                            (
                            λ
                            )
                          
                        
                        ·
                        C
                      
                    
                    )
                  
                
                c
              
              +
              
                Δ
                ⁢
                
                  
                
                ⁢
                τ
              
            
            ]
          
        
      
    
    
      
        (
        7
        )
      
    
  




where, as before, L is the thickness of the monitored tissue, n0(λ) is the refractive index of the tissue without glucose, k(λ) is the refractive index sensitivity to glucose concentration, C is the blood glucose concentration, c is the speed of light in vacuum, and Δτ is the time delay in the EPU.

The relationship between the changes in the time of circulation of N0 pulses to blood glucose concentration can be expressed as:




  
    
      
        
          Δ
          ⁢
          
            
          
          ⁢
          
            t
            ⁡
            
              (
              C
              )
            
          
        
        =
        
        ⁢
        
          
            
              t
              ⁡
              
                (
                C
                )
              
            
            -
            
              t
              ⁡
              
                (
                0
                )
              
            
          
          =
          
            
              
                
                  N
                  0
                
                ·
                
                  [
                  
                    
                      
                        L
                        ·
                        
                          (
                          
                            
                              
                                n
                                0
                              
                              ⁡
                              
                                (
                                λ
                                )
                              
                            
                            +
                            
                              
                                k
                                ⁡
                                
                                  (
                                  λ
                                  )
                                
                              
                              ·
                              C
                            
                          
                          )
                        
                      
                      c
                    
                    +
                    
                      Δ
                      ⁢
                      
                        
                      
                      ⁢
                      τ
                    
                  
                  ]
                
              
              -
              
                
                  N
                  0
                
                ·
                
                  [
                  
                    
                      
                        L
                        ·
                        
                          
                            n
                            0
                          
                          ⁡
                          
                            (
                            λ
                            )
                          
                        
                      
                      c
                    
                    +
                    
                      Δ
                      ⁢
                      
                        
                      
                      ⁢
                      τ
                    
                  
                  ]
                
              
            
            =
            
              
                
                  
                    N
                    0
                  
                  ·
                  L
                  ·
                  
                    k
                    ⁡
                    
                      (
                      λ
                      )
                    
                  
                
                c
              
              ·
              
                C
                .
              
            
          
        
      
    
    
      
        (
        8
        )
      
    
  




where t(0) is the time interval required to achieve N0 pulses of circulation when glucose concentration C=0.

Finally, the sensitivity S(C) of the device operating in the time measurement mode to the glucose concentration can be expressed as:




  
    
      
        
          S
          ⁡
          
            (
            C
            )
          
        
        =
        
          
            
              d
              
                (
                
                  Δ
                  ⁢
                  
                    
                  
                  ⁢
                  
                    t
                    ⁡
                    
                      (
                      C
                      )
                    
                  
                
                )
              
            
            
              d
              C
            
          
          =
          
            
              
                
                  N
                  0
                
                ·
                L
                ·
                
                  k
                  ⁡
                  
                    (
                    λ
                    )
                  
                
              
              c
            
            .
          
        
      
    
    
      
        (
        9
        )
      
    
  




As is apparent, the device sensitivity in the time measurement mode is directly proportional to the number of pulse circulation N0, tissue thickness L and the refractive index sensitivity to glucose concentration k(λ), and does not depend on the EPU time delay Δτ and tissue refractive index n0(λ) without presence of glucose. It is expected that the glucose monitoring device operating in the time measurement mode will have comparable accuracy and sensitivity as that of the glucose monitoring device configured to operate in the pulse measurement mode as shown in FIG. 1.
The glucose monitoring devices of the present invention can employ a combination of measurements at different wavelengths to compensate for variations in tissue thickness and its temperature, and presence of other blood components during glucose monitoring, and other factors. In this case, the system can employ a single broadband source with appropriate band pass filters and a detector that is capable of detecting radiation at different wavelengths. Alternatively, the system can employ a plurality measurement channels with each channel preferably having a light source and receiver or detector. In either case, the system can use one or several EPUs. The data that is gather either in the pulse measurement mode or the time measurement mode.
Because both channels are subject to the same major sources of error, e.g., background changes, the combination of data will provide a highly accurate indication of the amount of glucose present.
In addition to measuring glucose, the device can also be designed to monitor other analytes by selected the appropriate wavelength for the measurement source and detector. These analytes include, for example, cholesterol, triglycerides, urea, amino acids, and proteins, e.g., albumin and enzymes. Moreover, the device can be designed to measure a plurality of analytes simultaneously by employing radiation with a plurality of different wavelength regions that are responsive to the analytes being monitor.
FIG. 5 illustrates another embodiment of the glucose monitoring device that includes two separate EPUs and associated optical sources and detectors to monitor tissue 50. EPU 52 operates optical source 56 that generates a reference radiation and detector 54 and EPU 58 operates optical source 60 that generates a measurement radiation and detector 62. Both EPUs preferably operate in the same measurement mode, i.e., time measurement mode or pulse measurement mode. Alternatively, one can operate in the time measurement mode and the other in the pulse measurement mode. Analysis of the combined readings provides an accurate measurement of the glucose concentration of tissue 50 as described above.
Implementing the two EPU design illustrated in FIG. 5 is complicated in that constructing two identical electronic processing units is often difficult to achieve. Each EPU may have different technical parameters and sensitivities to environmental factors such as temperature or humidity that affect the accuracy and repeatability of the measurement.
FIG. 6 illustrates a glucose level monitoring unit that obviates this problem by employing a single EPU 103 that controls measurements along all the measurement channels which will improve accuracy and repeatability of the monitoring. EPU 103 includes multiplexer 109 along with processor 110, counter 107, pulse generator 105, timer 108, and amplifier 106. The device is configured to have two measurement channels through tissue 124: (i) the first is defined by the arrangement of optical source 126 and detector 121 and (ii) the second by the arrangement of optical source 126 and detector 122. Optical source 126 can be a single broadband source or one that contains several individual sources emitting at different wavelengths. To avoid interference with other measurement channels, each detector 121 and 122 can be equipped with an optical filter to monitor radiation at the desired wavelength. The device can be designed to operate in the pulse measurement mode and/or time measurement mode.
FIG. 7 illustrates an arrangement of the optical sources and detectors that includes a plurality individual optical sources and detectors. In this embodiment, optical source 80, which consists of three individual optical sources, emits radiation at three distinct wavelengths that are detected by three corresponding detectors each equipped with an individual optical filter that selectively transmits radiation within a particular wavelength range. So that radiation propagates through essentially the same monitored area of tissue or has the same physical path for different measurement channels, the individual optical sources should be positioned close to each other and similarly the individual detectors should be arranged in close proximity as well.
A technique for ensuring that radiation of different wavelengths propagates through the monitored tissue along the same physical path uses optical combining and optical splitting which are illustrated in FIGS. 8A and 8B. An optical combiner 84 combines signals from a plurality of optical sources; in this case, three optical sources 85, 86 and 87, which emit radiation having wavelengths of λ1, λ2, and λ3, respectively. In the configuration shown in FIG. 8A, detector 88, with three corresponding detectors, is positioned on the opposite side of the tissue to receive the signals. In the configuration shown in FIG. 8B, an optical splitter 90 delivers input radiation to the detectors 91, 92, and 93, which detect radiation at wavelengths of λ1, λ2, and λ3, respectively.
In operation of the glucose monitoring device of FIG. 6, on command from processor 110, multiplexer 109 connects detector 121 to the input of amplifier 106. The blood glucose concentration is measured by operation of the first measurement channel that includes source 126 and detector 121 at wavelength λ1. In the same fashion, on command from processor 110, multiplexer 109 connects detector 122 to the input of amplifier 106. The blood glucose concentration is then measured via the second measurement channel that includes source 126 and detector 122 at wavelength λ2. Processor 110 calculates glucose concentration level based on both measurements. With this device, employing the same electronic components in the single EPU 103 during all phases of measurements decreases electronics instability error. At the same time, obtaining 2-wavelength measurements provide temperature sensitivity compensation that improves the accuracy of the glucose monitoring. As is apparent, the total number of measurement channels and corresponding wavelengths can be more than 2 if desired.
FIG. 9 illustrates another embodiment of the glucose monitoring device with multiple measurement channels that employs a single EPU 163 that includes demultiplexer 153, processor 160, counter 157, pulse generator 155, timer 158, and amplifier 156. The device is equipped with dual optical sources 161, 162 that emit radiation at two distinct wavelengths λ1 and λ2, respectively, and a single detector 165 which is capable of detecting radiation at both wavelengths. The device is configured to form two measurement channels: (i) the first is defined by the arrangement of optical source 161 and detector 165 and (ii) the second by the arrangement of optical source 162 and detector 165.
On command from processor 160, demultiplexer 153 connects pulse generator 155 with source 161. In this configuration, the blood glucose concentration calculated through measurements from the first measurement channel at wavelength λ1. Similarly, on command from processor 150, demultiplexer 153 connects pulse generator 155 to source 162 whereby the blood glucose concentration is calculated based on measurements from the second measurement channel at wavelength λ2.
As is apparent, the number of optical sources and corresponding measurement channels (and wavelengths) employed with this device can be greater than two, if desired. The device can operate in both modes: pulse measurement mode and time measurement mode. In order for the radiation to propagate through the same monitored area of tissue 164 or to have the same physical path for different measurement channels, the optical sources should positioned close to each other. Optical combining and splitting can be also used to ensure the same physical pass of the propagating through the monitored tissue radiation of the different wavelengths.
Attenuation of the propagating radiation is a very good indicator of environmental conditions within tissue, thus besides measuring the refractive index of tissue, the glucose monitoring device measures the attenuation of radiation that is propagated through tissue. By monitoring the coefficient of attenuation it is possible, for example, to compensate for temperature variations. In general, monitoring the coefficient of attenuation improves the glucose concentration measurements by compensating for background variations.
FIG. 10 illustrates a glucose level monitoring device configured to measure both refractive index and attenuation that employs a single EPU 133 that includes multiplexer 139 along with processor 150, counter 137, pulse generator 135, timer 138, and amplifier 136. This device is equipped with a first detector 141 and a second detector 142 arranged to define two measurement channels: (i) the first is defined by the arrangement of optical source 146 and detector 141 and (ii) the second by the arrangement of optical source 146 and detector 142. The first detector 141 is positioned directly opposite optical source 146 at a distance L1. The second detector 142 is positioned laterally from first detector 141 at a distance S so that the distance between optical source 146 and detector 142 is L2, where L2=(L12+S2)0.5. In operation, multiplexer 139 commutates the two detectors' output signals to processor 150 and to amplifier 136 at the same time. The attenuation coefficient can be calculated from the signals from detector 141 and 142 which are derived from radiation traveling from optical source 146 through tissue 144 along paths L1 and L2, respectively.
FIG. 11 illustrates another embodiment of a multiple measurement channel glucose monitoring device that employs a single EPU 183 that includes electronic multiplexer 179, electronic demultiplexer 173, processor 170, counter 177, pulse generator 175, timer 178, and amplifier 176. The device is equipped with optical sources 181 and 182 that emit radiation at two distinct wavelengths λ1 and λ2, respectively, that are detected by corresponding detectors 185 and 186, respectively. To prevent the influence of scattered radiation from the adjacent measurement path, each detector is equipped with the appropriate optical filter that transmits radiation in the selected wavelength range. The device is configured to form two measurement channels: (i) the first is defined by the arrangement of optical source 181 and detector 185 and (ii) the second by the arrangement of optical source 182 and detector 186. The output from detectors 185 and 186 are connected to the input of multiplexer 179 and the output from multiplexer 179 is an input to amplifier 176. Pulse generator 175 is connected to the input of demultiplexer 173, while demultiplexer outputs are connected to sources 181 and 182. As is apparent, the number of measurement channels and wavelengths employed can be more than two if desired.
In operation, on command from processor 170, demultiplexer 173 connects pulse generator 175 with source 181 and multiplexer 179 connects detector 185 to the input of amplifier 176. In this configuration, the blood glucose concentration in tissue 180 is calculated based on a data from the first measurement channel. Similarly, on command from processor 170, demultiplexer 173 connects pulse generator 175 to optical source 182 and multiplexer 179 connects detector 186 to the input of amplifier 176. In this configuration the blood glucose concentration is calculated based on a data from the second measurement channel. The device can operate in the pulse measurement mode and/or time measurement mode.
Another technique for improving the accuracy of glucose measurements is to account for tissue background conditions. This can be accomplished with the glucose monitoring device shown in FIG. 12, which measures forward and back scattering radiation along with the intensity of the transmitted optical pulses through tissue 254. The device employs a single EPU 233 that includes processor 240, counter 247, pulse generator 245, timer 248, amplifiers 206, 246 and 249. An optical source 251 and primary detector 255 are arranged to define a primary measurement channel. In operation, processor 240 monitors the amplitude of the optical pulses by monitoring the output of amplifier 246, whereas first and second secondary detectors 253 and 252 are positioned to monitor the intensities of the forward and back scattering radiation, respectively, that are generated as the optical pulses propagate from optical source 251 to primary detector 255.
The blood glucose concentration is calculated on the basis of the measured optical pulse frequency circulation and its intensity and the intensities of the forward and/or back scattering radiation. The same functionality is applicable to the time measurement mode.
The same scattering radiation technique can be applied to each measurement channel in a glucose concentration monitoring device that has multiple measurement channels. For example, as shown in FIG. 13, this 2-channel 2-wavelength design includes means for measuring forward and back scattering associated with each of the primary two primary measurement channels.
As shown, the glucose monitoring device employs a single EPU 263 that includes electronic multiplexer 289, electronic demultiplexer 281, processor 270, counter 277, pulse generator 275, timer 285, and amplifier 286. The device is equipped with optical sources 292 and 293 that emit radiation at two distinct wavelengths λ1 and λ2, respectively, that are detected by corresponding detectors 297 and 298, respectively. To prevent the influence of scattered radiation from the adjacent measurement path, each detector with the appropriate an optical filter that transmits radiation the selected wavelength range. The output from detectors 297 and 298 are connected to the input of multiplexer 289 and the outputs from multiplexer 289 are inputs to amplifier 286. Pulse generator 275 is connected to the input of demultiplexer 281, while demultiplexer outputs are connected to sources 292 and 293.
The device is further equipped with first and second secondary detectors 296 and 291 which are positioned to detect the intensities of the forward and back scattering, respectively, that is generated as radiation with a wavelength of λ1 from optical source 292 propagates through tissue 294. Similarly, third and fourth secondary detectors 299 and 295 are positioned to detect the intensities of the forward and back scattering, respectively, generated by radiation with a wavelength of λ2 from optical source 293. Preferably, secondary detectors 291 and 296 have transmission filters at λ1, and detectors 295 and 299 have transmission filters at λ2. Signals from detectors 291, 295, 296 and 299, prior to being amplified, are delivered to process 270 in the same manner as presented in FIG. 12.
In operation, on command from processor 270, demultiplexer 281 connects pulse generator 275 with source 292 and multiplexer 289 connects detector 297 to the input of amplifier 286. In this configuration, the blood glucose concentration is calculated from measurements derived from this first measurement channel. Similarly, on command from processor 270, demultiplexer 281 connects pulse generator 275 to optical source 293 and multiplexer 298 connects detector 298 to the input of amplifier 286. In this configuration the blood glucose concentration is calculated from measurements derived from the measurement channel. The device can operate in the pulse measurement mode and/or time measurement mode at both wavelengths.
The blood glucose concentration is calculated on the basis of the measured optical pulse frequency circulation and its intensity and the intensities of the forward and/or back scattering radiation. The same functionality is applicable to the time measurement mode.
The glucose monitoring device can be employed to monitor tissue from any part of an individual, which allows the propagation of the optical pulse. A preferred device as shown in FIG. 14 is designed to be worn around the wrist. The device includes an EPU 34 and associated optical source 36 and detector 32. The EPU 34 and detector 32 are enshrouded in a protective case or housing 30 while optical source 36 is attached to an adjustable wristband 40. Wrist band 40 is worn so that detector 32 and optical source 36 are preferably on direct opposite sides of the wrist so that radiation emitted from optical source 36 is received by detector 32 after passing through the tissue. Optical source 36 is connected to EPU 34 via cable 38 that is embedded in wristband 40. As shown in FIGS. 15 and 16, the glucose monitor device can also include a liquid crystal display unit 42 with a glucose indicator on the face of case surface 36. The display unit can also comprise a printer, a display screen, or a magnetic or optical recording device.
For individuals who have serious diabetic conditions, the display unit can include a control apparatus that regulates an insulin pump or similar infusion device that is worn or implanted on the individual's body. When configured to be surgically implanted into a user, for example, at a particular location in the venous system, along the spinal column, in the peritoneal cavity, or other suitable site to deliver an infusion formulation to the user. External infusion pumps, which connect to patients through suitable catheters or similar devices, can also be employed. Implantable devices that supply insulin are described, for example, in U.S. Pat. No. 6,122,536 to Sun et al. and US Patent Publication No. 2004/0204673 to Flaherty, U.S. Pat. No. 7,024,245 to Lebel et al, U.S. Pat. No. 6,827,702 to Lebel et al., U.S. Pat. No. 6,427,088 to Bowman et al., and U.S. Pat. No. 5,741,211 to Renirie et al., which are incorporated herein by reference.
As shown in FIG. 17, an insulin pump 20 responds to signals transmitted from a glucose monitoring device 22 to control the administration of insulin. For example, the glucose monitoring device can be equipped with a control circuit that generates a control signal, such as a radio frequency (RF) signal, for remotely controlling the insulin pump 20 which is equipped with an antenna to receive the control signals. The control signals are converted to actuator signals that regulate an actuator driver within the insulin pump 20. Should the measured glucose level of the individual fall below a prescribed threshold, the glucose monitoring device can signal the insulin pump to deliver an appropriate amount of a medical formulation such as an insulin formulation into the individual. The insulin pump 20 can be equipped with an actuator driver that is responsive to the actuator signals and thereby inject an amount of insulin formulation from a reservoir within the insulin pump and into the individual. In addition, glucose monitoring device 22 can transmit signals to a database 24 and doctor's office 26 with a record of the glucose levels.
For convenience of use, as shown in FIGS. 18A and 18B, the glucose monitoring device 95 is housed in an earpiece that is worn on a patient's ear. The device includes optical sources 96 and detectors 97 that are positioned opposite sides of an earlobe, which is heavily saturated with blood vessels. Measurements can be transmitted to the blood glucose level display, which can be worn on the patient's wrist. As depicted in FIG. 17, the glucose monitoring device can generates a control signal for remotely controlling the insulin pump 20 or transmit signals to a database 24 and doctor's office 26 with a record of the glucose levels.
The foregoing has described the principles, preferred embodiments and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of present invention as defined by the following claims.

## Claims

1. A device for noninvasive measurement of the levels of at least one analyte in a subject that comprises:
means for irradiating the subject through tissue with electromagnetic radiation;
means for detecting the radiation that passes through the tissue;
means for calculating the speed at which the electromagnetic radiation passes through the tissue;
means for monitoring at least one of back and forward scattering of electromagnetic radiation within the tissue; and
means for correlating the calculated speed of the electromagnetic radiation and the intensity of the at least one of back and forward scattering of the electromagnetic radiation to the concentration of the at least one analyte in the subject.

2. The device of claim 1 comprising means for monitoring attenuation of electromagnetic radiation within the tissue.

3. The device of claim 1 wherein the means for monitoring at least one of back and forward scattering of the electromagnetic radiation monitors both back and forward scatting of electromagnetic radiation within the tissue.

4. The device of claim 1 wherein the means for irradiating the subject emits pulses of radiation and the means for detecting the radiation measures the number of pulses of radiation that passes through the tissue during a defined time period which is referred as the pulse circulation frequency measurement.

5. The device of claim 4 wherein the means for correlating the calculated speed of the electromagnetic radiation and the intensity of the at least one of back and forward scattering of the electromagnetic radiation to the concentration of the at least one analyte in the subject calculates the changes, if any, of the pulse circulation frequency being measured.

6. The device of claim 1 wherein the means for irradiating the subject emits pulses of radiation and the means for detecting the radiation measures the time period required for a defined number of pulses of radiation to pass through the tissue which is referred to as the time interval measurement.

7. The device of claim 6 wherein means for correlating the calculated speed of the electromagnetic radiation and the intensity of the at least one back and forward scattering of the electromagnetic radiation to the concentration of the at least one analyte in the subject calculates the changes, if any, of the time interval being measured.

8. The device of claim 1 further comprising means for dispensing a medical formulation in response to a determination of the concentration of the at least one analyte in the subject.

9. The device of claim 1 wherein the at least one analyte is selected from the group consisting of glucose, cholesterol, triglycerides, urea, protein, and mixtures thereof.

10. The device of claim 1 wherein said at least one analyte is glucose.

11. The device of claim 1 wherein the concentration of two or more analytes are measured and the means for irradiating the subject emits electromagnetic radiation at two or more different wavelengths.

12. The device of claim 1 wherein the means for irradiating the subject through the tissue with electromagnetic radiation functions at different wavelengths.

13. The device of claim 1 wherein the means for irradiating the subject comprises means for supporting the device such that the electromagnetic radiation passes through a defined thickness of the tissue.

14. A device for noninvasive measurement of the levels of at least one analyte in a subject that comprises:
means for irradiating the subject through tissue with electromagnetic radiation at a plurality of different wavelengths;
means for detecting the radiation that passes through the tissue;
means for calculating the speed at which the electromagnetic radiation passes through the tissue; and
means for correlating the calculated speed of the electromagnetic radiation to the concentration of the at least one analyte in the subject, wherein the device employs a single electronic processing unit and wherein the means for calculating and the means for correlating are part of the electronic processing unit.

15. The device of claim 14 wherein the means for irradiating comprises a plurality of optical sources of electromagnetic radiation that irradiates the tissue.

16. The device of claim 14 wherein the means for detecting comprises a plurality of detectors that detect radiation that is transmitted through the tissue.

17. The device of claim 14 wherein the electronic processing unit comprises a multiplexer and a demultiplexer.

18. The device of claim 14 wherein the means for irradiating comprises an optical combiner that combines signals from a plurality of optical sources and wherein the means for detecting comprises an optical splitter that delivers input radiation to a plurality of detectors.

19. The device of claim 14 wherein the means for irradiating directs electromagnetic radiation with different wavelengths through the subject along different physical paths of different lengths.

20. The device of claim 14 further comprises means for monitoring at least one of back and forward scattering radiation.

21. The device of claim 20 wherein the means for monitoring at least one of back and forward scattering radiation monitors both back and forward scattering radiation.

22. A device for noninvasive measurement of the levels of glucose in a subject that comprises:
means for irradiating the subject through tissue with electromagnetic radiation having a wavelength such that the speed of the electromagnetic radiation propagating through the tissue is sensitive to the glucose concentration in the tissue;
means for detecting the radiation that passes through the tissue;
means for calculating the speed at which the electromagnetic radiation passes through the tissue;
means for monitoring at least one of back and forward scattering of electromagnetic radiation within the tissue; and
means for correlating the calculated speed of the electromagnetic radiation and the intensity of the at least one of back and forward scattering of electromagnetic radiation to the concentration of glucose in the subject.

23. The device of claim 22 comprising means for monitoring attenuation of electromagnetic radiation within the tissue.

24. The device of claim 22 wherein the means for irradiating the subject emits pulses of radiation and the means for detecting the radiation measures the number of pulses of radiation that passes through the tissue during a defined time period, which is referred as the pulse circulation frequency measurement.

25. The device of claim 24 wherein the means for correlating the calculated speed of the electromagnetic radiation to the concentration of the glucose in the subject calculates the changes, if any, of the pulse circulation frequency being measured.

26. The device of claim 22 wherein the means for irradiating the subject emits pulses of radiation and the means for detecting the radiation measures the time period required for a defined number of pulses of radiation to pass through the tissue which is referred to as the time interval measurement.

27. The device of claim 26 wherein the means for correlating the calculated speed of the electromagnetic radiation and the intensity of the at least one of back and forward scattering of electromagnetic radiation to the concentration of the at least one analyte in the subject calculates the changes, if any, of the time interval being measured.

28. The device of claim 22 further comprising means for dispensing an insulin formulation in response to a determination of the concentration of the glucose in the subject.

29. A device for noninvasive measurement of the levels of glucose in a subject that comprises:
means for irradiating the subject through tissue with electromagnetic radiation at a plurality of different wavelengths wherein electromagnetic radiation of at least one wavelength is such that the speed of the electromagnetic radiation propagating through the tissue is sensitive to the glucose concentration in the tissue;
means for detecting the radiation that passes through the tissue;
means for calculating the speed at which the electromagnetic radiation passes through the tissue; and
means for correlating the calculated speed of the electromagnetic radiation to the concentration of glucose in the subject, wherein the device employs a single electronic processing unit and wherein the means for calculating and the means for correlating are part of the electronic processing unit.

30. The device of claim 29 wherein the means for irradiating comprises a plurality of optical sources of electromagnetic radiation that irradiates the tissue.

31. The device of claim 29 wherein the means for detecting comprises a plurality of detectors that detect radiation that is transmitted through the tissue.

32. The device of claim 29 wherein the electronic processing unit comprises a multiplexer and a demultiplexer.

33. The device of claim 29 wherein the means for irradiating comprises an optical combiner that combines signals from a plurality of optical sources and wherein the means for detecting comprises an optical splitter that delivers input radiation into a plurality of detectors.

34. The device of claim 29 wherein the means for irradiating directs electromagnetic radiation with different wavelengths through the subject along different physical paths of different lengths.

35. The device of claim 29 comprises means for monitoring at least one of forward and back scattering radiation.

36. The device of claim 35 wherein the means for monitoring at least one of back and forward scattering radiation monitors both back and forward scattering radiation.

37. A noninvasive method of monitoring the levels of at least one analyte in a subject that comprises:
(a) irradiating the subject through tissue of known thickness with electromagnetic radiation;
(b) detecting the radiation that passes through the tissue;
(c) calculating the speed at which the electromagnetic radiation passed through the tissue;
(d) (i) monitoring attenuation of the radiation that passes through the tissue and/or (ii) monitoring at least one of back and forward scattering of electromagnetic radiation within the tissue; and
(e) correlating the calculated speed of the electromagnetic radiation and either the attenuation of the radiation or the intensity of the at least one of back and forward scattering or both the attenuation of the radiation and the intensity of the at least one back and forward scattering to the concentration of the at least one analyte in the subject.

38. The method of claim 37 wherein step (d) comprises monitoring attenuation of the radiation that passes through the tissue.

39. The method of claim 37 wherein step (d) comprises monitoring at least one of back and forward scattering of electromagnetic radiation within the tissue.

40. The method of claim 37 wherein step (d) comprises monitoring both back and forward scattering of electromagnetic radiation within the tissue.

41. The method of claim 37 wherein step (a) comprises directing pulses of radiation through the tissue and step (b) comprises detecting the number of pulses that passes through the tissue during a defined time period, which is referred as the pulse circulation frequency measurement.

42. The method of claim 41 wherein step (d) comprises calculating the changes, if any, of the pulse circulation frequency being measured.

43. The method of claim 37 wherein step (a) comprises directing pulses of radiation and step (b) comprises measuring the time period required for a defined number of pulses of radiation to pass through the tissue which is referred to as the time interval measurement.

44. The method of claim 43 wherein step (d) comprise calculating the changes, if any, of the time interval being measured.

45. The method of claim 37 further comprising the step of dispensing a medical formulation in response to a determination of the concentration of the at least one analyte in the subject.

46. The method of claim 37 wherein the at least one analyte is selected from the group consisting of glucose, cholesterol, triglycerides, urea, protein, and mixtures thereof.

47. The method of claim 37 wherein said at least one analyte is glucose.

48. The method of claim 37 wherein the concentration of two or more analytes are measured and step (a) comprises irradiating the subject with electromagnetic radiation at two or more different wavelengths.

49. The method of claim 37 wherein step (a) comprises irradiating the subject through tissue with electromagnetic radiation at different wavelengths.