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&#39;s tissue of known thickness within a certain time period can be correlated to an individual&#39;s blood glucose level.

Description:
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&#39;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&#39;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&#39;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&#39;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&#39;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 )= n   0 (λ)+ k (λ)* C;   (2)
 
where n 0 (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:
 
     
       
         
           
             
               
                 
                   
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     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 n 0 (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&#39;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 10 8  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 n 0 (λ)=1.325 is used to monitor tissue with a thickness L of 0.05 m, and c=3*10 8  m/s, the theoretical limit of the device sensitivity contains S th (C)=4.5*10 3  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 N 0  pulses is proportional to the glucose concentration in the tissue and by gauging the changes in the time interval, fluctuations in the individual&#39;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, n 0 (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 N 0  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 N 0  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: 
     
       
         
           
             
               
                 
                   
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     As is apparent, the device sensitivity in the time measurement mode is directly proportional to the number of pulse circulation N 0 , 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 n 0 (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 L 1 . 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 L 2 , where L 2 =(L 1   2 +S 2 ) 0.5 . In operation, multiplexer  139  commutates the two detectors&#39; 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 L 1  and L 2 , 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&#39;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&#39;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&#39;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&#39;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&#39;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.