Abstract:
A system for measuring a biological parameter, such as blood glucose, the system comprising the steps of directing laser pulses from a light guide into a body part consisting of soft tissue, such as the tip of a finger to produce a photoacoustic interaction. The resulting acoustic signal is detected by a transducer and analyzed to provide the desired parameter.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to apparatus for use in non-invasive in vivo monitoring of physiological substances such as blood and the like. 
     2. Discussion of the Art 
     One particular, but not exclusive, application of the present invention is in the monitoring of blood glucose, for example in the management of diabetes mellitus. It is accepted that the management of diabetes can be much improved by routine monitoring of blood glucose concentration and clinicians suggest that monitoring as often as four times per day is desirable. 
     The monitoring technique currently available for use by patients involves using a spring loaded lancet to stab the finger to obtain a blood sample which is transferred to a glucose test strip. The concentration is derived either by reading the test strip with a reflectance meter or by visual comparison of colour change against a colour scale. Many diabetics find the testing onerous as the technique is painful, inconvenient, messy, potentially embarrassing and offers a site for the transmittance and acceptance of infection. 
     Techniques have also been developed for non invasive measurement using transmittance or reflectance spectroscopy. However the required instruments are expensive and it is difficult to obtain accurate and repeatable measurements. 
     There are also known various types of in vivo chemical sensors. These rely on implanting minimally invasive sensors under the skin surface, but such sensors have poor long term reproducibility and bio-compatibility problems. 
     There is therefore a need for improved means for routine monitoring of blood glucose in a manner which is simple and straightforward to use. 
     The present invention makes use of photoacoustic techniques. The fundamentals of photoacoustic techniques are well known per se. A pulse of light, typically laser light, is applied to a substance containing an analyte of interest in solution or dispersion, the wavelength of the applied light being chosen to interact with the analyte. Absorption of the light energy by the analyte gives rise to microscopic localised heating which generates an acoustic wave which can be detected by an acoustic sensor. These techniques have been used to measure physiological parameters in vitro. 
     U.S. Pat. Nos. 5,348,002 and 5,348,003 (Caro) propose the use of photoacoustics in combination with photoabsorption for the measurement of blood components in vivo. However, the arrangement proposed by Caro has not been demonstrated as a workable system and may suffer from interference to a degree which would preclude useful acoustic signals, and since they would also suffer from interference and resonance effects from hard structures such as bone. 
     It has also been proposed by Poulet and Chambron in  Medical and Biological Engineering and Computing , Nov. 1985, Page 585 to use a photoacoustic spectrometer in a cell arrangement to measure characteristics of cutaneous tissue, but the apparatus described would not be suitable for measuring blood analytes. 
     Published European Patent Application 0282234A1 (Dowling) proposes the use of photoacoustic spectroscopy for the measurement of blood analytes such as blood glucose. This disclosure however does not show or suggest any means which would permit the required degree of coupling to body tissues for use in vivo. 
     SUMMARY OF THE INVENTION 
     Accordingly, the present invention provides a sensor head for use in photoacoustic in vivo measurement, comprising a housing shaped to engage a selected body part, light transmission means terminating in said housing so as to transmit light energy form a light source to enter the body part along a beam axis, and acoustic transducer means mounted in the housing to receive acoustic waves generated by photoacoustic interaction within the body part, the acoustic transducer means being disposed in the housing to receive said acoustic wave in a direction of high acoustic energy. 
     The expression “direction of high acoustic energy” is used herein to denote a direction other than the forward direction of the light beam. Preferably, the transducer means is disposed so as to intercept acoustic energy propagating at right angles to the optical beam axis, or at an angle to the optical beam axis which may be down to about 20°, typically about 45°. 
     An exact measure of the angle of high acoustic energy can be worked out but is dependent upon the specific geometry of the light source, the properties of the tissue and the absorption coefficient of the tissue. One model for understanding the propagation of the acoustic energy in any homogenous media was developed by Huyghens and is called the principle of superposition. In this model each volume element that is illuminated by the light generates an acoustic pressure wave that radiates outward in a spherical manor. The magnitude of the pressure wave at each volume element depends on the intensity of the optical beam at that location, the absorption coefficient of the material at that location, the wavelength of light and on several other physical properties of the material such as the speed of sound and the specific heat. The signal measured at the detector is just the superposition of all pressure waves from all points that are illuminated by the source light. An analytical solution for the pressure wave has been worked out for a few cases in aqueous material. The analytical case that best matches the in-vivo measurements is that of a cylindrical optical beam propagating in a weekly absorbing material. In this case the direction of highest acoustic energy is perpendicular to the optical axis. The base detector location is with the plane of the detector perpendicular to the acoustic energy, or parallel to the optical axis. This is because the acoustic detector has the highest sensitivity when the acoustic energy strikes the detector perpendicular to the plane of the detector. This analytical model is not completely accurate for the in-vivo measurement case because of scattering of the tissue and because the tissue absorbs more than the model predicts. These differences indicate that a different position for the detector will be optimal. A detailed numeric model is required to determine the best detector location and is dependent upon the beam properties (focused to a point, colligated, etc.), body site (finger, earlobe, arm etc.) and wavelength. One skilled in the art can readily develop an appropriate mode. However, suitable locations for a detector will generally be at an angle to the optical axis. Angles between 40 and 90 degrees should be suitable. 
     In one preferred arrangement, the acoustic transducer means is arranged parallel to the optical beam axis. This arrangement is particularly suitable for use where the selected body part is the distal portion of a finger, in which case the housing may include a generally half-cylindrical depression in which the finger may be placed with the light transmission means aimed at the end of the finger. 
     Preferably, the acoustic transducer means comprises a piezoelectric transducer which most preferably is of a semi-cylindrical shape. This transducer may be provided with a backing of lead or other dense material, and the backing may have a rear surface shaped to minimise internal acoustic reflection. 
     Alternative transducer means include a capacitor-type detector, which is preferably small and disk-shaped; an integrated semiconductor pressure sensor; and an optical pressure sensor, for example based on an optical fibre. 
     In an alternative arrangement, the plane of the transducer may be arranged to be perpendicular to the optical axis to detect the acoustic wave which is propagating in a direction opposite to the direction of the light beam. For example, the acoustic transducer means may be part-spherical with an aperture to allow access for the light beam. This may be particularly suitable for engagement with a body part other than the finger, for example the back of the arm. 
     The generation of a surface acoustic wave is an inherent aspect of the in vivo pulsed photoacoustic generation in tissue and may be used to characterize tissue properties such as density. A surface wave detector may be provided in the sensing head assembly. 
     Preferably means are provided for ensuring a consistent contact pressure between the selected body part and the acoustic transducer means. In the case where the selected part is the distal portion of the finger, said means may be provided by mounting the portion of the housing engaged by the finger in a resiliently biased fashion against the remainder of the housing, and providing means to ensure that measurement is effected when the predetermined force or pressure is applied by the subject against the resilient bias. In the case where the selected part is the earlobe, said means may be provided by placing the ear between two plates and applying pressure to the ear with springs or weights or other force method. The two plates holding the ear may contain a removable insert. The two plates may be flat or may be of another shape to optimally position the detector with respect to the beam axis. 
     In addition, the present invention provides a sensor head for use in photoacoustic in-vivo measurements, comprising a housing shaped to receive a removable insert, a removable insert that engages a selected body part, the insert being fitted to an individual, allowing for a range of sizes of body parts to be used, and further comprising light transmission means terminating in or near said removable insert so as,to transmit light energy from a light source or sources to enter the body part along a beam axis, and an acoustic transducer means mounted in the housing or in the removable insert to receive acoustic waves generated by photoacoustic interaction within the body part to receive said acoustic waves in a direction of high acoustic energy. 
     From another aspect the present invention provides an in vivo measuring system comprising a sensor head as hereinbefore defined in combination with a light source coupled with the light transmission means, and signal processing means connected to receive the output of the acoustic transducer means and to derive therefrom a measurement of a selected physiological parameter. 
     Preferably, the light transmission means is a fiber distribution system where each light source is connected to an individual fiber and when multiple light sources are used the multiple fibres are joined by some standard fiber combining method, such as a wavelength division multiplexer or a fiber coupler. The fiber that comes from the light source, or contains the combined light for a multiple source system, is then terminated in proximity to the body part being measured. The fiber could be in contact with the body part or alternatively standard optics, such as lenses, beamsplitters and such, could be employed to convey the light from the end of the fiber to the body part. A reference detector or several reference detectors and beamsplitters can be added to the optical distribution system to determine the energy of the light entering the body part. 
     Alternatively, the optical distribution system may contain mechanical holders, lenses and such to convey the light from the source, or sources, to a location in proximity to the body part being measured. A reference detector or several reference detectors and beamsplitters can be added to the optical distribution system to determine the energy of the light entering the body part. 
     The acoustic signal from the detector contains information in both time and frequency, and there may be information from several sources. The processing means is preferably a multi-dimensional processing method, such as Classical Least Squares (CLS) or Partial Least Squares (PLS). Alternatively the processing method may be more flexible, such as a Neural Network. In addition to these methods the signals may be analysed for their frequency content using such techniques as Fourier Analysis or Frequency Filtering In addition techniques may be employed that use time information such as the time delay from source trigger. Techniques that combine both frequency and time information may be employed, such as Wavelet analysis. 
     The light source is preferably a laser light source and is most suitably a pulsed diode laser, but may utilise a set of such lasers or utilise a tunable laser source. In a particularly preferred form, suitable for use in measuring blood glucose concentration, a laser diode is used with a wave length in the range of approximately 600 nm to 10,000 nm and a pulse duration of the order of 5 to 500 ns. 
     The delivery to the measurement site may be either directly or by optical fibre with a suitable optical element to focus the beam into the tissue. 
     Preferably means are provided for time multiplexing multiple sources when multiple sources are used. Each source is switched on, and it generates an optical pulse, or a set of optical pulses. This pulse, or set of pulses, generates an acoustic signal that is detected by the detector. Each source is pulsed in sequence until all sources have been used to generate their own signal. 
     The measuring system may conveniently be in the form of a self contained system including a power supply and a readout, which may be carried on the person and used at any convenient time. 
     It is also possible for such a self contained system to incorporate, or to be provided with facilities for connection to, a cellular telephone, two-way pager or other communication device for routine transmission of measurements taken to a central data collection point. 
     In addition the measuring system may have provision for manipulating the body part under measurement and for performing additional measurement of the tissue to get other information about the state of the physiology of the issue. It is well-known in the art that squeezing a section of tissue to increase the pressure and then releasing the pressure will cause changes in the total blood volume in the measurement site. The present invention may allow for this type of manipulation including the squeezing of a body part, such as an earlobe, and making photo acoustic measurements at several different pressures. The present invention may also allow for the measurement of the temperature of the body site and to apply a correction to the measurements based upon the temperature of the body site. 
     Another type of physiological manipulation is body temperature. It is known in the art that several parameters involved in the detection of the photo acoustic signal, such as the speed of sound, are dependent upon the temperature of the medium the signal is propagating through (the tissue). Also the profusion of the blood in the small capillaries is dependent upon the temperature of the tissue. Additional information about the tissue can be obtained if the photo acoustic measurement is made at several temperatures, both higher and lower than ambient temperature. This additional information is used to better eliminate interferences to the determination of the analyte under investigation. These are only two examples of manipulating the body site and are not intended to be an exhaustive list, and they can be used in combination with other manipulation techniques. 
     The in-vivo measuring system may comprise a means for storing calibration coefficients or operation parameters or both calibration coefficients and operational parameters, in order to calibrate the instrument and to set critical operational parameters. 
     Another aspect of the present invention provides a means for adjusting the calibration coefficients and operational parameters to be specific to a particular person and may be used to adjust for such things as body part size, skin color, skin condition, amount of body fat, efficiency of the detector and efficiency of the source(s). 
     In addition the present invention may provide for having the specific calibration coefficients and operational parameters be contained in a storage site located in the removable insert. This allows for the system to be both mechanically and operationally configured to a particular individual. Additionally the invention may allow for the calibration coefficients and operational parameters to be stored in two locations, one in the non-removable housing and one in the removable insert with some of the coefficients and parameters stored in each location. This allows for reader system coefficients to be stored in the reader and coefficients specific to an individual to be stored in the removable insert for that person, enabling many people to use the same reader. 
     Another aspect of the present invention provides means for connecting the non-invasive measuring system to an invasive measuring system for the purpose of calibrating or adjusting the operational parameters of the non-invasive measuring system. Such connection may be accomplished, but is not limited to, communication by a wire, IR link or radio waves. 
     Another aspect of the present invention provides a method for removing instrument drift from the measurement comprising the steps of: 
     1. Placing a standard in the reader in place of the body part. 
     2. Measuring the signal from the standard for each wavelength and storing the values in the calibration storage location. 
     3. Before making a measurement of a body part, placing the calibration standard in the reader. 
     4. Measuring the signal from the standard for each source. 
     5. Comparing the just measured standard values to the stored calibration values. 
     6. Calculating correction factors for each source wavelength. 
     7. Removing the standard and placing the body part in the reader. 
     8. Measuring the signal from the body part for each source. 
     9. Adjusting the measured values using the calculated correction factors. 
     In addition to the signal correction factors a correction factor can be calculated for the instrument temperature. This can be applied to each signal with a different correction coefficient. 
     The invention further provides a method of measuring a biological parameter in a subject, the method comprising the steps of: 
     directing one or more pulses of optical energy from the exterior into the tissue of a subject along a beam axis, the optical energy having a wavelength selected to be absorbed by tissue 
     components of interest, thereby to produce a photoacoustic interaction; 
     detecting acoustic energy resulting from said photoacoustic reaction by means of a transducer positioned to intercept acoustic energy propagating in a direction other than the forward direction of said beam axis; and 
     deriving from said detected acoustic energy a measure of the parameter of interest; and a corresponding apparatus. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     Embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings in which: 
     FIGS. 1A,  1 B and  1 C are side views illustrating the principle of operation of one embodiment of the present invention; 
     FIG. 2 is a schematic perspective view showing a sensor head for use in carrying out the measurement illustrated in FIG. 1; 
     FIG.  3 . is a cross section view of the sensor head of FIG. 2; 
     FIG. 4 is a side view of the sensor head of FIG. 2; 
     FIG. 5 is a schematic perspective view of an apparatus incorporating the sensor head of FIGS. 2 to  4 ; 
     FIG. 6 is a perspective view illustrating an alternative form of sensor head; 
     FIG. 7 is a schematic end view showing another form of sensor head; 
     FIGS. 8 a  and  8   b  are a cross-sectional side view and a plan view, respectively, of a further sensor head; 
     FIG. 9 is a cross-sectional side view of one more embodiment of sensor head; 
     FIG. 10 is a perspective view of one type of ear interface apparatus; 
     FIG. 11 is a schematic of a multiple laser optical distribution system using lenses, mechanical mounts and a reference detector; 
     FIG. 12 is a schematic of a multiple laser optical distribution system using fiber optic cables and a fiber Wavelength Division Multiplexer (WDM), a beam splitter and a reference detector; 
     FIG. 13 is a perspective view of a finger interface apparatus with removable inserts that are moulded to fit one individual; 
     FIG. 13A shows part of the apparatus of FIG. 13 in greater detail; 
     FIG. 14 is a schematic of a semi-spherical detector that contains a hole for the light beam, with a vacuum system and a fiber distribution system; 
     FIG. 15 is a perspective view showing one form of the instrument utilizing the vacuum body interface, a semi-spherical detector and the multiple laser source with lenses and mechanical housing; 
     FIG. 16 is a perspective view showing one form of the instrument using an ear lobe body interface, with the added feature of being able to manipulate the pressure on the ear lobe; and 
     FIGS. 17,  18  and  19  are graphs illustrating an example. 
    
    
     DETAILED DESCRIPTION 
     Referring to FIG. 1, an important feature of the present invention lies in introducing light energy along an axis into an area of soft tissue and detecting the resulting acoustic response transverse to that axis. Accordingly, in the arrangement of FIG. 1A light energy from a diode laser (not shown) is transmitted via a fibre-optic guide  10  to the tip of a finger  12 . The photoacoustic interaction occurs in an approximately cylindrical region indicated at  14  from which acoustic energy is radiated in a generally cylindrical manner and is detected by a transversely arranged acoustic transducer  16 . 
     In FIGS. 1B and 1C, the principle is similar. The finger  12  is pressed against a support with force F. In FIG. 1B, the incident light beam indicated at L is directed as in FIG. 1A, and the transducer  16  is at an angle of 45 degrees thereto. In FIG. 1B, the angle is 90 degrees as in FIG. 1A, but the incident beam is directed differently into the fingertip. 
     In the present embodiment, the laser wavelength is chosen to achieve high degree of absorption by glucose present in the blood. A suitable wavelength is in the range approximately 1000 to 3000 nm. The laser pulse duration is chosen to be short, typically of the order of 5 to 500 ns, in order to minimise thermal diffusion and thus to optimise the acoustic waveform. For the same reasons, it is desirable to use a spot size which is sufficiently small to minimise thermal diffusion, typically a spot size of the order of 0.05 mm to 0.50 mm. 
     The efficiency of the photoacoustic detection is also influenced by the positioning and dimensions of the acoustic transducer in relation to the characteristic extinction length of the tissue at the principal wavelengths chosen for measurement. In the fingertip arrangement of FIG. 1, the system efficiency will be improved by optimising the length of the transducer crystal parallel to the axis of the finger, but the length should not be so great as to give rise to undesired signals which would occur at the point of entry of the optical energy into the finger and by reason of interaction of the acoustic energy with bone or other hard tissue. 
     A second limit on the size of the acoustic detector derives from the wavelength of the acoustic wave in the tissue. Again making use of Huyghens principal of superposition we view each point of tissue, that is illuminated by the incoming light, as a point source that generates a spherical pressure wave. The signal measured at the detector is just the superposition of all pressure waves from all points that are illuminated by the source light. Normally if the size of the detector is increased then the signal should also increase because more energy is received by the detector. However if the acoustic detector is too large then a pressure wave generated from a tissue element will create a pressure wave that will strike the both ends of the detector. If the paths length from the tissue element to the first end of the detector is different than the path length to the second end of the detector and if this difference in path length is about one half of the acoustic signal wavelength then the signal will destructively interfere with itself and will reduce the magnitude of the measured signal. 
     Referring to FIG. 2, one manner of carrying out the arrangement shown in FIG. 1 makes use of a sensor head having a finger rest  18  which is slidably moveable within housing  20  closed by a front plate  22 . The user inserts his finger in a semi-cylindrical depression  24  in the finger rest  18  with the finger tip engaged against an end surface  28  which includes an exit face  26  of the optical fibre  10 . The finger is then pressed downwardly against a resilient bias to enable a standardised contact to be obtained between the skin and the acoustic transducer. The finger tip may first be dipped in water or coated with an aqueous gel to improve the acoustic coupling. 
     Referring to FIGS. 3 and 4, in this preferred arrangement the acoustic transducer comprises a semi-cylindrical piezoelectric transducer  30 . The transducer  30  is provided with a backing member  32  of lead or another dense substance, the rear face  34  of which is shaped in irregular curves. The use of the semi-cylindrical transducer  30  maximises the area for reception of acoustic energy from the finger, while the use of a dense backing material minimises ringing effects within the transducer. Additionally, the rear face  34  is shaped as shown to reduce reflection of acoustic energy back towards the piezo crystal. 
     FIG. 3 also shows the finger rest biased upwardly by the use of constant tension springs  38 . 
     FIG. 5 illustrates schematically the apparatus of FIGS. 2 and 3 embodied in a self-contained, portable blood monitoring apparatus including a user readout  40 . An apparatus of this nature allows a diabetic to monitor blood glucose concentration in a convenient manner, as frequently as may be desired, and in a painless and discreet manner. 
     Other forms of photoacoustic sensor head are possible within the scope of the present invention. For example, FIG. 6 shows an arrangement in which a light guide  50  and an acoustic transducer  52  are applied to a finger  54  by means of a hinged clamp member  56 . FIG. 7 shows a finger  60  engaged by a light guide  62  and an acoustic transducer  64  which are carried on a moveable assembly  66  with the finger  60  being trapped between the moveable assembly  66  and a fixed anvil  68 . 
     It is also possible to arrange the sensor head to cooperate with a soft tissue surface of the body, for example a soft part of the abdomen. FIGS. 8 a  and  8   b  show an arrangement in which a cup shaped member  70 , suitably of rubber, causes a light guide  72  and an acoustic transducer  74  to be contacted with a bulge of soft tissue  76  which may for example be drawn into contact by means of a partial vacuum within the member  70  caused by suction through a conduit  78 , or by other mechanical or adhesive means. 
     A somewhat similar arrangement is shown in FIG. 9 in which a planar mount  80  carrying a light guide  82  and acoustic transducer  84  is secured to a soft area of body by means of surgical adhesive  86 . 
     Referring to FIG. 10, one method of performing measurement on an ear lobe involves placing the ear lobe between a fixed plate  87  and a movable plate  88 . The acoustic detector  89  is mounted partially perpendicular that is at an acute angle, to the beam axis defined as line going from the center of a lens  90  to the center of a window  91 . It has been found that the system works satisfactorily with the detector  89  at an angle or 45° to the beam axis. The window  91  and the detector  89  are placed in direct contact with the ear and the opposite plate  88  places pressure on the ear using a suitable mechanism (not shown). This particular embodiment of the ear interface apparatus incorporates an alignment ring  92  which is temporarily attached to the ear and fits over the window housing  91  to aid in aligning ear into the same location every time. 
     Referring to FIG. 11, one method of combining light sources into the instrument is to use a mechanical housing  93  with several holes used to align lenses  95  and laser diodes  94 . The housing shown uses a hexagonal array of seven holes. The sources and lenses are arranged in such a way that they all focus to the same location  96  which could be on the surface of the body part. This design does not show the inclusion of beamsplitters and reference detectors but they can be added in an alternative arrangement. 
     An alternative method of combining several sources into one beam is shown in FIG.  12 . Several laser diodes  97  are shown coupled to individual fiber optic cables  131 . These cables  132  are combined using a fiber Wavelength Division Multiplexer (WDM)  98 . Alternative combination methods exist including couplers and multi-fiber bundles. The combined light exits the WDM  98  in a single fiber  104  and terminates at the focal point of a lens  131 . This end of the fiber is imaged to the end of the finger  103  to a spot  102  using another lens  130 . Some of the light is split off the main beam using a beam splitter  100  and focused onto a reference detector  101  using another lens  99 . Additional reference detectors and/or beamsplitters can be added to the distribution system without changing its function. Alternatively a reference detector could look directly at the body part to measure the light reflecting off the surface, as a measure of the overall light energy entering the body part. 
     Referring to FIG. 13, another method of using a finger as the body part and including removable inserts is shown. A finger  105  is inserted into an insert  106  that is used to customize the finger holder to a particular finger. The moulded insert  106  is placed into a housing  107 . The finger  105  is placed against a semi-cylindrical acoustic detector in a module  108  which is also attached to the housing  107 . A cover  109  for the housing  107  contains a mechanism  111  to apply constant force to the finger  105 . The light beam  110  is introduced into the finger  105  using a suitable optical distribution system (not shown). FIG. 13A shows the module  108  in greater detail. A base  200  carries a part-cylindrical piezo transducer  202  on a support  204 .  206  indicates a coaxial connector to communicate the transducer signal. 
     FIG. 14 shows a schematic of an alternative to the vacuum arrangement shown in FIGS. 8 and 9. In this system a photoacoustic reader  121  is placed against the skin  113  with a semi-spherical detector  112  in contact with the skin  113 . A vacuum pump  115  and vacuum seal  116  create a negative pressure and pull the skin  113  against the detector  112 . Processing electronics  119  energizes light sources  118  and an optical distribution system  117  routes the light to the body part through a hole in the top of the semi-spherical detector  112 . The optical distribution system  117  directs a small portion of the light to a reference detector  114 . The processing electronics  119  measures the signal from the acoustic detector  112  and the reference detector  114  for each optical source  119  and calculates the glucose value. The value is displayed on a display  120 . 
     FIG. 15 shows a similar system  125 , only using another type of optical distribution system  127 . Again a vacuum pump  123  creates a negative pressure which draws the skin up to an acoustic detector  122 . Processing electronics  124  signals light sources in optical distribution system  127  to illuminate and a signal is generated at acoustic detector  122 . The processing electronics  124  calculates the proper value and displays it on a display  126 . 
     FIG. 16 shows an alternative arrangement of a photo-acoustic reader. In this system  128 , the vacuum system is replaced with an ear squeeze mechanism  129  which applies pressure to the ear. An acoustic detector  130  detects the signals from the ear lobe. 
     In the most straightforward forms of the invention, a single analyte such as glucose in blood can be measured by using light of selected wavelengths and by measuring the area or the amplitude of the received acoustic pulse. It is preferable to make each measurement by using a train of pulses, for example about 100 pulses, and averaging the results in order to minimise the effects of noise and pulse effects in the blood flow. 
     The accuracy of the detection system is governed, in part, by the Signal to Noise Ratio (SNR) of the system. Variations in the intensity and duration of the light source can cause the acoustic signal to contain variations. A normalization technique, such as taking the ratio of the acoustic signal to the optical signal, can significantly reduce the effect of the source variations, thereby improving the signal to noise ratio of the system. The optical signal can be measured with a reference detector, or several reference detectors, one for each source or one for a wavelength range. An equation describing this type of normalization follows:          Normalized                 Signal     =       Acoustic                 Signal       Optical                 Signal                              
     In some cases the relationship between the optical signal land the acoustic signal changes with wavelength and light intensity. When this is the case the accuracy of the measurement can be further enhanced by determining the energy dependence of the photoacoustic signal. This may be determined by establishing the specific relationship between the photoacoustic signal land the incident energy from a set of measurements and using this relationship to compensate for the non linear response. An equation describing this type of normalization is as follows:          Normalized                 Signal     =       Acoustic                 Signal         Scaling                 Factor   *   Optical                 Signal     +   Offset                              
     Other normalization methods can also apply. The time interval between the optical pulse and the detection of the acoustic signal may be used to characterise physical properties such as the velocity of sound in the tissue. In addition, in another embodiment of the device the damping of the acoustic oscillations may be used to monitor the elastic properties of the tissue and, in particular, the compressibility. Both of these aspects may be used in the person to person calibration of the photoacoustic response. 
     More complex analysis of the received acoustic energy is possible. For example, a time-gating technique may be used to derive measurement at varying depths within the tissue being examined. Alternatively, an array of detectors can be employed to determine the profile of the absorption of the acoustic signal at different depths and locations. This depth profile will change with the absorption coefficient and could be used as additional information to determine the analyte concentration. It is also possible to derive information relating to a number of analytes of interest by more sophisticated analysis of the received acoustic energy wave forms, for example by analysis of the frequency spectrum by Fourier transform or wavelet analysis techniques. 
     Alternatively, or in combination with the frequency techniques and multiple detectors, multiple light sources can aid in the determination of the concentration of a number of analytes. 
     There are a number of tissue features which may vary from person to person or with in the same person over time which impact the photoacoustic signal observed. To obtain an accurate measurement of a given analyte, such as glucose, it may be helpful to also determine the concentration of other analytes such as haemoglobin which may act as interferants. One approach is to generate several distinct photoacoustic signals using excitation light of several different wavelengths. For example, excitation light of a wavelength of which haemoglobin absorbs strongly but glucose has little if any absorption could be sued to obtain a measure of the haemoglobin concentration with which to normalize the effect of haemoglobin on measurements made on different persons or on the same person at different times. These measurements which are to be normalized might be based on the photoacoustic signal generated by light of a wavelength at which glucose absorbs. 
     It is also possible to measure the concentration of such interferants by other means, such as infrared light absorption, and thus normalize or correct the photoacoustic signal representative of the desired analyte for variations in these interferants. Thus, for example, the photoacoustic signal representative of glucose could be corrected for variations in haemoglobin concentration determined by optical absorption techniques such as those taught in U.S. Pat. No. 5,702,284. 
     For the reliable and reproducible determination of glucose a signal to noise ratio of at least 10,000 is recommended. In this regard water is typically present in human tissue of a concentration of about 50 molar while glucose is present at a concentration of about 5 millimolar in a normal individual. 
     Apparatus and method embodying the present invention have been found to yield accurate and repeatable results. In the case of blood glucose measurement, the clinical range of glucose concentration is approximately 5-10 m mol/l in healthy subjects, and up to 40 m mol/l in diabetics. An analysis based on simple absorption models suggests that the change in photoacoustic signal over this range might be as little as 0.2%. The present invention has been found to provide a change in photoacoustic signal of up to 140% for a change in glucose concentration of 15m mol/l. 
     The precise mechanisms involved are not at present fully understood. It is believed, however, that absorption occurs primarily in body plasma and is modified by the presence of glucose, and that this affects beam geometry. 
     EXAMPLE 
     The blood glucose levels of three individuals, one normal individual, one type  1  diabetic and one type  2  diabetic, were followed over a two hour period following each individual taking about 75 grams of glucose orally in an aqueous solution by both photoacoustics and direct blood measurement. The results are reported in FIGS. 17,  18  and  19 . Photoacoustic measurements were made every five minutes and blood measurements were made very ten minutes. The blood samples were venous blood samples analysed by the standard glucose oxidase method using a Yellow Springs instrument. The error bands for the blood measurements were derived from the literature accompanying the testing instrument while those for the photoacoustic results were based on the averages taken over 1000 pulses. The results were obtained from a configuration similar to that illustrated in FIG. 1 in which  10  was an end of a 1 km multimode fibre optic cable which was placed against the finger  12 . The other end received 600 nanosecond pulses of 1040 nanometer light from a Q switched Nd:YAG laser delivering 2,7 micro joules per pulse for each measurement. Raman interactions in the fibre caused the production of light an additional wavelengths as set forth in the following table: 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
               
               
                   
                 Average pulse 
                   
                   
               
               
                   
                 energy in 
                 Pulse width 
                 Approximate 
               
               
                 Wavelength in nm 
                 microJoules 
                 in ns 
                 bandwidth in nm 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1064 
                 2.7 
                 600 
                  4 
               
               
                 1120 
                 2.25 
                 500 
                  6 
               
               
                 1176 
                 2.0 
                 450 
                  8 
               
               
                 1240 
                 1.5 
                 425 
                 12 
               
               
                 1308 
                 0.85 
                 400 
                 15 
               
               
                 1390 
                 0.3 
                 350 
                 20 
               
               
                 1450 
                 0.1 
                 350 
                 20 
               
               
                 1500 
                 0.2 
                 350 
                 20 
               
               
                 1550 
                 0.18 
                 360 
                 20 
               
               
                   
               
             
          
         
       
     
     The resulting photoacoustic signal was detected by a 5 mm disc transducer with a lead backing and fed to an amplifier and an oscilloscope. The transducer was generally placed as  16  in FIG. 1 but was not precisely parallel to the beam axis; its detection plane was at an angle of about 20 degrees to the beam axis. The photoacoustic signal was evaluated in terms of the difference in voltage signal from the positive peak of the compression to the negative peak of the relaxation of the acoustic pulse. 
     The change in photoacoustic response correlated well with the change in blood glucose concentration over the two hour measurement period. A correlation of 0.89 was achieved on samples ranging from 4 to 35 m mol/l. 
     Other modifications and improvements may be made to the foregoing embodiments within the scope of the present invention as defined in the claims.