GB2357845A

GB2357845A - Correction of photoacoustic signal in a biological measurement system

Info

Publication number: GB2357845A
Application number: GB0108163A
Authority: GB
Inventors: Hugh Alexander Mackenzie; John Matthew Lindberg
Original assignee: OPTEL INSTR Ltd
Current assignee: OPTEL INSTR Ltd
Priority date: 1997-03-07
Filing date: 1998-03-09
Publication date: 2001-07-04
Anticipated expiration: 2018-03-09
Also published as: GB2357845B; GB2357846A; GB2357846B; GB0108163D0; GB2322941B; GB0108164D0; GB9804828D0; GB2357844A; GB2322941A; GB0108162D0

Abstract

A biological parameter such as blood glucose is measured by directing laser pulses from a light guide (10) into a body part consisting of soft tissue, such as the tip of a finger (12) to produce a photoacoustic interaction (14). The resulting acoustic signal is detected by a transducer (16). A method of correcting the measurement of the biological parameter is provided comprising determining the concentration of other constituents in the body part, such as haemoglobin, which have a significant effect on the photoacoustic signal and tend to vary from individual to individual or overtime, and adjusting the measurement to remove the effect of variations in the concentrations of the other constituents.

Description

2357845 1 1 Biological Measurement System 2 3 This invention relates to

apparatus for use in non4 invasive in vivo, monitoring of physiological 5 substances such as blood and the like. 6 7 One particular, but not exclusive, application of 8 the present invention is in the monitoring of blood 9 glucose, for example in the management of diabetes 10 mellitus. It is accepted that the management of 11 diabetes can be much improved by routine monitoring 12 of blood glucose concentration and clinicians 13 suggest that monitoring as often as four times per 14 day is desirable.

16 The monitoring technique currently available for use 17 by patients involves using a spring loaded lancet to 18 stab the finger to obtain a blood sample which is 19 transferred to a glucose test strip. The concentration is derived either by reading the test 21 strip with a reflectance meter or by visual 22 comparison of colour change against a colour scale.

23 Many diabetics find the testing onerous as the 24 technique is painful, inconvenient, messy, 2 1 potentially embarrassing and offers a site for the 2 transmittance and acceptance of infection. 3 4 Techniques have also been developed for non invasive 5 measurement using transmittance or reflectance 6 spectroscopy. However the required instruments are 7 expensive and it is difficult to obtain accurate and 8 repeatable measurements. 9 10 There are also known various types of in vivo 11 chemical se.-.is-jrs. These rely on implanting 12 minimally invasive sensors under the skin surface, 13 but such sensors have poor long term reproducibility 14 and bio-compatibility problems. is 16 There is therefore a need for improved means for 17 routine monitoring of blood glucose in a manner 18 which is simple and straightforward to use. 19 20 The present invention makes use of photoacoustic 21 techniques. The fundamentals of photoacoustic 22 techniques are well known per se. A pulse of light, 23 typically laser light, is applied to a substance 24 containing an analyte of interest in solution or 25 dispersion, the wavelength of the applied light 26 being chosen to interact with the analyte. 27 Absorption of the light energy by the analyte gives 28 rise to microscopic localised heating which 29 generates an acoustic wave which can be detected by 30 an acoustic sensor. These techniques have been used 31 to measure physiological parameters in vitro. 32 3 1 US Patents 5348002 and 5348003 (Caro) propose the 2 use of photoacoustics in combination with 3 photoabsorption for the measurement of blood 4 components in vivo. However, the arrangement 5 proposed by Caro has not been demonstrated as a 6 workable system and may suffer from interference to 7 a degree which would preclude useful acoustic 8 signals, and since they would also suffer from 9 interference and resonance effects from hard 10 structures such as bone. 11 12 It has also been proposed by Poulet and Chambron in 13 Medical and Biological Engineering and Computing, 14 November 1985, Page 585 to use a photoacoustic is spectrometer in a cell arrangement to measure 16 characteristics of cutaneous tissue, but the 17 apparatus described would not be suitable for 18 measuring blood analytes. 19 20 Published European Patent Application 0282234A1 21 (Dowling) proposes the use of photoacoustic 22 spectroscopy for the measurement of blood analytes 23 such as blood glucose. This disclosure however does 24 not show or suggest any means which would permit the 25 required degree of coupling to body tissues for use 26 in vivo. 27 28 Accordingly, the present invention provides a sensor 29 head for use in photoacoustic in vivo measurement, 30 comprising a housing shaped to engage a selected 31 body part, light transmission means terminating in 32 said housing so as to transmit light energy from a

4 1 light source to enter the body part along a beam 2 axis, and acoustic transducer means mounted in the 3 housing to receive acoustic waves generated by 4 photoacoustic interaction within the body part, the 5 acoustic transducer means being disposed in the 6 housing to receive said acoustic wave in a direction 7 of high acoustic energy. 8 9 The expression "direction of high acoustic energy" 10 is used herein to denote a direction other than the 11 forward direction of the light beaRi. Preferably, 12 the transducer means is disposed so as to intercept 13 acoustic energy propagating at right angles to the 14 optical beam axis, or at an angle to the optical beam axis which may be down to about 20', typically 16 about 450.

17 18 An exact measure of the angle of high acoustic 19 energy can be worked out but is dependent upon the specific geometry of the light source, the 21 properties of the tissue and the absorption 22 coefficient of the tissue. one model for 23 understanding the propagation of the acoustic energy 24 in any homogenous media was developed by Huyghens and is called the principle of superposition. In 26 this model each volume element that is illuminated 27 by the light generates an acoustic pressure wave 28 that radiates outward in a spherical manor. The 29 magnitude of the pressure wave at each volume element depends on the intensity of the optical beam 31 at that location, the absorption coefficient of the 32 material at that location, the wavelength of light 1 and on several other physical properties of the 2 material such as the speed of sound and the specific 3 heat. The signal measured at the detector is just 4 the superposition of all pressure waves from all points that are illuminated by the source light. An 6 analytical solution for the pressure wave has been 7 worked out for a few cases in aqueous material. The 8 analytical case that best matches the in-vivo 9 measurements is that of a cylindrical optical beam propagating in a weekly absorbing material. In this 11 case the direction of highest acoustic energy is 12 perpendicular to the optical axis. The base 13 detector location is with the plane of the detector 14 perpendicular to the acoustic energy, or parallel to is the optical axis. This is because the acoustic 16 detector has the highest sensitivity when the 17 acoustic energy strikes the detectorperpendicular 18 to the plane of the detector. This analytical model 19 is not completely accurate for the in-vivo measurement case because of scattering of the tissue 21 and because the tissue absorbs more than the model 22 predicts. These differences indicate that a 23 different position for the detector will be optimal.

24 A detailed numeric model is required to determine the best detector location and is dependent upon the 26 beam properties (focused to a point, colligated, 27 etc.), body site (finger, earlobe, arm etc.) and 28 wavelength. one skilled in the art can readily 29 develop an appropriate mode. However, suitable locations for a detector will generally be at an 31 angle to the optical axis. Angles between 40 and 90 32 degrees should be suitable.

6 1 In one preferred arrangement, the acoustic 2 transducer means is arranged parallel to the optical 3 beam axis. This arrangement is particularly 4 suitable for use where the selected body part is the 5 distal portion of a finger, in which case the 6 housing may include a generally half-cylindrical 7 depression in which the finger may be placed with 8 the light transmission means aimed at the end of the 9 finger. 10 11 Preferably, ---'-e acoustic transducer means comprises 12 a piezoelectric transducer which most preferably is 13 of a semicylindrical shape. This transducer may be 14 provided with a backing of lead or other dense is material, and the backing may have a rear surface 16 shaped to minimise internal acoustic reflection. 17 18 Alternative transducer means include a capacitor19 type detector, which is preferably small and disk20 shaped; an integrated semiconductor pressure sensor; 21 and an optical pressure sensor, for example based on 22 an optical fibre. 23 24 In an alternative arrangement, the plane of the 25 transducer may be arranged to be perpendicular to 26 the optical axis to detect the acoustic wave which 27 is propagating in a direction opposite to the 28 direction of the light beam. For example, the 29 acoustic transducer means may be partspherical with 30 an aperture to allow access for the light beam. 31 This may be particularly suitable for engagement 7 1 with a body part other than the finger, for example 2 the back of the arm. 3 4 The generation of a surface acoustic wave is an 5 inherent aspect of the in vivo pulsed photoacoustic 6 generation in tissue and may be used to characterize 7 tissue properties such as density. A surface wave 8 detector may be provided in the sensing head 9 assembly. 10 11 P--. -ef-erably means are provided for ensuring a 12 consistent contact pressure between the selected 13 body part and the acoustic transducer means. In the 14 case where the selected part is the distal portion is of the finger, said means may be provided by 16 mounting the portion of the housing engaged by the 17 finger in a resiliently biased fashion against the 18 remainder of the housing, and providing means to 19 ensure that measurement is effected when the 20 predetermined force or pressure is applied by the 21 subject against the resilient bias. In the case 22 where the selected part is the earlobe, said means 23 may be provided by placing the ear between two 24 plates and applying pressure to the ear with springs 25 or weights or other force method. The two plates 26 holding the ear may contain a removable insert. The 27 two plates may be flat or may be of another shape to 28 optimally position the detector with respect to the 29 beam axis. 30 31 In addition, the present invention provides a sensor 32 head for use in photoacoustic in-vivo measurements, 8 1 comprising a housing shaped to receive a removable 2 insert, a removable insert that engages a selected 3 body part, the insert being fitted to an individual, 4 allowing for a range of sizes of body parts to be used, and further comprising light transmission 6 means terminating in or near said removable insert 7 so as to transmit light energy from a light source 8 or sources to enter the body part along a beam axis, 9 and an acoustic transducer means mounted in the housing or in the removable insert to receive 11 acoustic waves generated by photoa--,..,ustic 12 interaction within the body part to receive said 13 acoustic waves in a direction of high acoustic 14 energy.

is 16 From another aspect the present invention. provides 17 an in vivo measuring system comprising a sensor head 18 as hereinbefore defined in combination with a light 19 source coupled with the light transmission means, and signal processing means Connected to receive the 21 output of the acoustic transducer means and to 22 derive therefrom a measurement of a selected 23 physiological parameter.

24 Preferably, the light transmission means is a fiber 26 distribution system where each light source is 27 connected to an individual fiber and when multiple 28 light sources are used the multiple fibres are 29 joined by some standard fiber combining method, such as a wavelength division multiplexer or a fiber 31 coupler. The fiber that comes from the light 32 source, or contains the combined light for a 9 1 multiple source system, is then terminated in 2 proximity to the body part being measured. The 3 fiber could be in contact with the body part or 4 alternatively standard optics, such as lenses, beamsplitters and such. could be employed to convey 6 the light from the end of the fiber to the body 7 part. A reference detector or several reference 8 detectors and beamsplitters can be added to the -9 optical distribution system to determine the energy of the light entering the body part.

11 12 Alternatively, the optical distribution system may 13 contain mechanical holders, lenses and such to 14 convey the light from the source, or sources, to a is location in proximity to the body part being 16 measured. A reference detector or several reference 17 detectors and beamsplitters can be added to the 18 optical distribution system to determine the energy 19 of the light entering the body part.

21 The acoustic signal from the detector contains 22 information in both time and frequency, and there 23 may be information from several sources. The 24 processing means is preferably a multi-dimensional processing method, such as Classical Least Squares 26 (CLS) or Partial Least Squares (PLS). Alternatively 27 the processing method may be more flexible, such as 28 a Neural Network. In addition to these methods the 29 signals may be analysed for their frequency content using such techniques as Fourier Analysis or 31 Frequency Filtering In addition techniques may be 32 employed that use time information such as the time 1 delay from source trigger. Techniques that combine 2 both frequency and time information may be employed, 3 such as Wavelet analysis. 4 5 The light source is preferably a laser light source 6 and is most suitably a pulsed diode laser, but may 7 utilise a set of such lasers or utilise a tunable 8 laser source. In a particularly preferred form, 9 suitable for use in measuring blood glucose 10 concentration, a laser diode is used with a wave 11 length in the:-.ange of approximately 600 nm to 12 10,000 nm and a pulse duration of the order of 5 to 13 500 ns.

14 is The delivery to the measurement site may be either 16 directly or by optical fibre with a suitable optical 17 element to focus the beam into the tissue.

18 19 Preferably means are provided for time multiplexing multiple sources when multiple sources are used.

21 Each source is switched on, and it generates an 22 optical pulse, or a set of optical pulses. This 23 pulse, or set of pulses, generates an.acoustic 24 signal that is detected by the detector. Each source is pulsed in sequence until all sources have 26 been used to generate their own signal.

27 28 The measuring system may conveniently be in the form 29 of a self contained system including a power supply and a readout, which may be carried on the person 31 and used at any convenient time.

32 1 It is also possible for such a self contained system 2 to incorporate, or to be provided with facilities 3 for connection to, a cellular telephone, two-way 4 pager or other communication device for routine transmission of measurements taken to a central data 6 collection point.

7 8 In addition the measuring system may have provision 9 for manipulating the body part under measurement and for performing additional measurement of the tissue 11 to r,et other information about the state of ti'-Lf 12 physiology of the issue. It is well-known in the 13 art that squeezing a section of tissue to increase 14 the pressure and then releasing the pressure will is cause changes in the total blood volume in the 16 measurement site. The present invention may allow 17 for this type of manipulation including the 18 squeezing of a body part, such as an earlobe, and 19 making photo acoustic measurements at several different pressures. The present invention may also 21 allow for the measurement of the temperature of the 22 body site and to apply a correction to the 23 measurements based upon the temperature of the body 24 site.

26 Another type of physiological manipulation is body 27 temperature. It is known in the art that several 28 parameters involved in the detection of the photo 29 acoustic signal, such as the speed of sound, are dependent upon the temperature of the medium the 31 signal is propagating through (the tissue). Also 32 the profusion of the blood in the small capillaries (.7 12 1 is dependent upon the temperature of the tissue. 2 Additional information about the tissue can be 3 obtained if the photo acoustic measurement is made 4 at several temperatures, both higher and lower than 5 ambient temperature. This additional information is 6 used to better eliminate interferences to the 7 determination of the analyte under investigation. 8 These are only two examples of manipulating the body 9 site and are not intended to be an exhaustive list, 10 and they can be used in combination with other 11 manipulation techniques. 12 13 The invivo measuring system may comprise a means 14 for storing calibration coefficients or operation is parameters or both calibration coefficients and 16 operational parameters, in order to calibrate the 17 instrument and to set critical operational 18 parameters. 19 20 Another aspect of the present invention provides a 21 means for adjusting the calibration coefficients and 22 operational parameters to be specific to a 23 particular person and may be used to adjust for such 24 things as body part size, skin color, skin 25 condition, amount of body fat, efficiency of the 26 detector and efficiency of the source(s). 27 28 In addition the present invention may provide for 29 having the specific calibration coefficients and 30 operational parameters be contained in a storage 31 site located in the removable insert. This allows 32 for the system to be both mechanically and 13 1 operationally configured to a particular individual.

2 Additionally the invention may allow for the 3 calibration coefficients and operational parameters 4 to be stored in two locations, one in the non removable housing and one in the removable insert 6 with some of the coefficients and parameters stored 7 in each location. This allows for reader system 8 coefficients to be stored in the reader and 9 coefficients specific to an individual to be stored in the removable insert for that person, enabling 11 many people to use the same reader.

12 13 Another aspect of the present invention provides 14 means for connecting the non-invasive measuring is system to an invasive measuring system for the 16 purpose of calibrating or adjusting the operational 17 parameters of the non-invasive measuring system.

18 Such connection may be accomplished, but is not 19 limited to, communication by a wire, IR link or radio waves.

21 22 Another aspect of the present invention provides a 23 method for removing instrument drift from the 24 measurement comprising the steps of:

26 1. Placing a standard in the reader in place of 27 the body part.

28 29 2. Measuring the signal from the standard for each wavelength and storing the values in the 31 calibration storage location.

32 14 1 3. Before making a measurement of a body part, 2 placing the calibration standard in the reader.

3 4 4. Measuring the signal from the standard for each source.

6 7 5. Comparing the just measured standard values to 8 the stored calibration values.

9 6. Calculating correction factors for each source 11 wavelengt."-!.

12 13 7. Removing the standard and placing the body part 14 in the reader.

is 16 8. Measuring the signal from the body part for 17 each source.

18 19 9. Adjusting the measured values using the calculated correction factors.

21 22 In addition to the signal correction factors a 23 correction factor can be calculated for the 24 instrument temperature. This can be applied to each signal with a different correction coefficient.

26 27 The invention further provides a method of measuring 28 a biological parameter in a subject, the method 29 comprising the steps of:

31 directing one or more pulses of optical energy 32 from the exterior into the tissue of a subject 1 along a beam axis, the optical energy having a 2 wavelength selected to be absorbed by tissue 3 components of interest, thereby to produce a 4 photoacoustic interaction.

6 detecting acoustic energy resulting from said 7 photoacoustic reaction by means of a transducer 8 positioned to intercept acoustic energy 9 propagating in a direction other than the forward direction of said beam axis; and 11 12 deriving from said detected acoustic energy a 13 measure of the parameter of interest; and a 14 corresponding apparatus.

is 16 Embodiments of the invention will now be described, 17 by way of example only, with reference to the 18 accompanying drawings in which:

19 Figs. 1A,1B and 1C are.side views illustrating 21 the principle of operation of one embodiment of 22 the present invention; 23 24 Fig. 2 is a schematic perspective view showing a sensor head for use in carrying out the 26 measurement illustrated in Fig. 1; 27 Fig 3. is a cross section view of the sensor 28 head of Fig. 2; 29 Fig. 4 is a side view of the sensor head of 31 Fig. 2; 32 16 1 Fig. 5 is a schematic perspective view of an 2 apparatus incorporating the sensor head of 3 Figs. 2 to 4; 4 Fig. 6 is a perspective view illustrating an 6 alternative form of sensor head; 7 8 Fig. 7 is a schematic end view showing another 9 form of sensor head; 11 Figs. 8a and 8b are a crosssectional side view 12 and a plan view, respectively, of a further 13 sensor head; 14 is Fig. 9 is a cross-sectional side view of one 16 more embodiment of sensor head; 17 18 Fig. 10 is a perspective view of one type of 19 ear interface apparatus; 21 Fig. 11 is a schematic of a multiple laser 22 optical distribution system using lenses, 23 mechanical mounts and a reference detector; 24 Fig. 12 is a schematic of a multiple laser 26 optical distribution system using fiber optic 27 cables and a fiber Wavelength Division 28 Multiplexer (WDM), a beam splitter and a 29 reference detector; 17 1 Fig. 13 is a perspective view of a finger 2 interface apparatus with removable inserts that 3 are moulded to fit one individuall 4 Fig. 13A shows part of the apparatus of Fig. 13 6 in greater detail; 7 8 Fig. 14 is a schematic of a semi-spherical 9 detector that contains a hole for the light beam, with a vacuum system and a fiber 11 distribution system; 12 13 Fig. 15 is a perspective view showing one form 14 of the instrument utilizing the vacuum body is interface, a semi-spherical detector and the 16 multiple laser source with lenses and 17 mechanical housing; 18 19 Fig. 16 is a perspective view showing one form of the instrument using an ear lobe body 21 interface, with the added feature of being able 22 to manipulate the pressure on the ear lobe; and 23 24 Figs. 17, 18 and 19 are graphs illustrating an example.

26 27 Referring to Fig 1, an important feature of the 28 present invention lies in introducing light energy 29 along an axis into an area of soft tissue and detecting the resulting acoustic response transverse 31 to that axis. Accordingly, in the arrangement of 32 Fig 1A light energy from a diode laser (not shown) 18 1 is transmitted via a fibre-optic guide 10 to the tip 2 of a finger 12. The photoacoustic interaction 3 occurs in an approximately cylindrical region 4 indicated at 14 from which acoustic energy is radiated in a generally cylindrical manner and is 6 detected by a transversely arranged acoustic 7 transducer 16.

8 9 In Figs 1B and 1C, the principle is similar. The finger 12 is pressed against a support with force F.

11 In Fig 1B, the licident light beam indicated at L is 12 directed as in Fig 1A, and the transducer 16 is at 13 an angle of 45 degrees thereto. In Fig 1B, the 14 angle is 90 degrees as in Fig 1A, but the incident is beam is directed differently into the fingertip.

16 17 In the present embodiment, the laser wavelength is 18 chosen to achieve high degree of absorption by 19 glucose present in the blood. A suitable wavelength is in the range approximately 1000 to 3000 nm. The 21 laser pulse duration is chosen to be short, 22 typically of the order of 5 to 500 ns, in order to 23 minimise thermal diffusion and thus to optimise the 24 acoustic waveform. For the same reasons, it is desirable to use a spot size which is sufficiently 26 small to minimise thermal diffusion, typically a 27 spot size of the order of 0.05 mm to 0.50 mm.

28 29 The efficiency of the photoacoustic detection is also influenced by the positioning and dimensions of 31 the acoustic transducer in relation to the 32 characteristic extinction length of the tissue at 19 1 the principal wavelengths chosen for measurement. 2 In the fingertip. arrangement of Fig. 1, the system 3 efficiency will be improved by optimising the length 4 of the transducer crystal parallel to the axis of 5 the finger, but the length should not be so great as 6 to give rise to undesired signals which would occur 7 at the point of entry of the optical energy into the 8 finger and by reason of interaction of the acoustic 9 energy with bone or other hard tissue. 10 11 A sec,.-)nd limit on the size of the acoustic detcc-.or 12 derives from the wavelength of the acoustic wave in 13 the tissue. Again making use of Huyghens principal 14 of superposition we view each point of tissue, that 15 is illuminated by the incoming light, as a point 16 source that generates a spherical pressure wave. 17 The signal measured at the detector is just the 18 superposition of all pressure waves from all points 19 that are illuminated by the source light. Normally 20 if the size of the detector is increased then the 21 signal should also increase because more energy is 22 received by the detector. However if the acoustic 23 detector is too large then a pressure wave generated 24 from a tissue element will create a pressure wave 25 that will strike the both ends of the detector. if 26 the paths length from the tissue element to the 27 first end of the detector is different than the path 28 length to the second end of the detector and if this 29 difference in path length is about one half of the 30 acoustic signal wavelength then the signal will 31 destructively interfere with itself and will reduce 32 the magnitude of the measured signal.

1 Referring to Fig 2, one manner of carrying out the 2 arrangement shown in Fig 1 makes use of a sensor 3 head having a finger rest 18 which is slidably 4 moveable within housing 20 closed by a front plate 5 22. The user inserts his finger in a semi6 cylindrical depression 24 in the finger rest 18 with 7 the finger tip engaged against an end surface 28 8 which includes an exit face 26 of the optical fibre 9 10. The finger is then pressed downwardly against a 10 resilient bias to enable a standardised contact to ii be obtained between the skin and the acoustic 12 transducer. The finger tip may first be dipped in 1-3 water or coated with an aqueous gel to improve the _14 acoustic coupling. 15 16 Referring to Figs 3 and 4, in this preferred 17 arrangement the acoustic transducer comprises a 18 semi-cylindrical piezoelectric transducer 30. The 19 transducer 30 is provided with a backing member 32 20 of lead or another dense substance, the rear face 34 21 of which is shaped in irregular curves. The use of 22 the semi-cylindrical transducer 30 maximises the 23 area for reception of acoustic energy from the 24 finger, while the use of a dense backing material 25 minimises ringing effects within the transducer. 26 Additionally, the rear face 34 is shaped as shown to 27 reduce reflection of acoustic energy back towards 28 the piezo crystal. 29 30 Fig 3 also shows the finger rest biased upwardly by 31 the use of constant tension springs 38. 32 21 1 Fig 5 illustrates schematically the apparatus of 2 Figs. 2 and 3 embodied in a self-contained, portable 3 blood monitoring apparatus including a user readout 4 40. An apparatus of this nature allows a diabetic 5 to monitor blood glucose concentration in a 6 convenient manner, as frequently as may be desired, 7 and in a painless and discreet manner. 8 9 Other forms of photoacoustic sensor head are 10 possible within the scope of the present invention. 11 For example, Fig. 6 shows an arrangement in which a 12 light guide 50 and an acoustic transducer 52 are 13 applied to a finger 54 by means of a hinged clamp 14 member 56. Fig. 7 shows a finger 60 engaged by a is light guide 62 and an acoustic transducer 64 which 16 are carried on a moveable assembly 66 with the 17 finger 60 being trapped between the moveabl(. 18 assembly 66 and a fixed anvil 68. 19 20 It is also possible to arrange the sensor head to 21 co-operate with a soft tissue surface of the body, 22 for example a soft part of the abdomen. Figs. 8a 23 and 8b show an arrangement in which a cup shaped 24 member 70, suitably of rubber, causes a light guide 25 72 and an acoustic transducer 74 to be contacted 26 with a bulge of soft tissue 76 which may for example 27 be drawn into contact by means of a partial vacuum 28 within the member 70 caused by suction through a 29 conduit 78,or by other mechanical or adhesive 30 means. 31 22 1 A somewhat similar arrangement is shown in Fig. 9 in 2 which a planar mount 80 carrying a light guide 82 3 and acoustic transducer 84 is secured to a soft area 4 of body by means of surgical adhesive 86. 5 6 Referring to Fig. 10, one method of performing 7 measurement on an ear lobe involves placing the ear 8 lobe between a fixed plate 87 and a movable plate 9 88. The acoustic detector 89 is mounted partially 10 perpendicular that is at an acute angle, to the beam 11 axis defined a- line going from the center of a lens 12 90 to the center of a window 91. It has been found 13 that the system works satisfactorily with the 14 detector 89 at an angle or 45' to the beam axis. is The window 91 and the detector 89 are placed in 16 direct contact with the ear and the opposite plate 17 88 places pressure on the ear using a suitable 18 mechanism (not shown). This particular embodiment 19 of the ear interface apparatus incorporates an 20 alignment ring 92 which is temporarily attached to 21 the ear and fits over the window housing 91 to aid 22 in aligning ear into the same location every time. 23 24 Referring to Fig. 11, one method of combining light 25 sources into the instrument is to use a mechanical 26 housing 93 with several holes used to align lenses 27 95 and laser diodes 94. The housing shown uses a 28 hexagonal array of seven holes. The sources and 29 lenses are arranged in such a way that they all 30 focus to the same location 96 which could be on the 31 surface of the body part. This design does not show 32 the inclusion of beamsplitters and reference 23 1 detectors but they can be added in an alternative 2 arrangement. 3 4 An alternative method of combining several sources 5 into one beam is shown in Fig. 12. Several laser 6 diodes 97 are shown coupled to individual fiber 7 optic cables 131. These cables 132 are combined 8 using a fiber Wavelength Division Multiplexer (WDM) 9 98. Alternative combination methods exist including 10 couplers and multi-fiber bundles. The combined 11 lighL exits the WDM 98 in a single fiber 104 and 12 terminates at the focal point of a lens 131. This 13 end of the fiber is imaged to the end of the finger 14 103 to a spot 102 using another lens 130. Some of 15 the light is split off the main beam using a beam 16 splitter 100 and focused onto a reference detector 17 101 using another lens 99. Additional reference 18 detectors and/or beamsplitters can be added to the 19 distribution system without changing its function. 20 Alternatively a reference detector could look 21 directly at the body part to measure the light 22 reflecting off the surface, as a measure of the 23 overall light energy entering the body part. 24 25 Referring to Fig. 13, another method of using a 26 finger as the body part and including removable 27 inserts is shown. A finger 105 is inserted into an 28 insert 106 that is used to customize the finger 29 holder to a particular finger. The moulded insert 30 106 is placed into a housing 107. The finger 105 is 31 placed against a semi-cylindrical acoustic detector 32 in a module108 which is also attached to the housing 24 1 107. A cover 109 for the housing 107 contains a 2 mechanism 111 to apply constant force to the finger 3 105. The light beam 110 is introduced into the 4 finger 105 using a suitable optical distribution system (not shown). Fig. 13A shows the module 108 in 6 greater detail. A base 200 carries a part 7 cylindrical piezo transducer 202 on a support 204.

8 206 indicates a coaxial connector to communicate the 9 transducer signal.

11 Fig. 14 shows a schematic of an alternative to the 12 vacuum arrangement shown in Figs. 8 and 9. In this 13 system a photoacoustic reader 121 is placed against 14 the skin 113 with a semi-spherical detector 112 in is contact with the skin 113. A vacuum pump 115 and 16 vacuum seal 116 create a negative pressure and pull 17 the skin 113 against the detector 112. Processing 18 electronics 119 energizes light sources 118 and an 19 optical distribution system 117 routes the light to the body part through a hole in the top of the semi 21 spherical detector 112. The optical distribution 22 system 117 directs a small portion of the light to a 23 reference detector 114. The processing electronics 24 119 measures the signal from the acoustic detector 112 and the reference detector 114 for each optical 26 source 119 and calculates the glucose value. The 27 value is displayed on a display 120.

28 Fig. 15 shows a similar system 125, only using 29 another type of optical distribution system 127.

Again a vacuum pump 123 creates a negative pressure 31 which draws the skin up to an acoustic detector 122.

32 Processing electronics 124 signals light sources in 1 optical distribution system 127 to illuminate and a 2 signal is generated at acoustic detector 122. The 3 processing electronics 124 calculates the proper 4 value and displays it on a display 126.

6 Fig. 16 shows an alternative arrangement of a photo 7 acoustic reader. In this system 128, the vacuum 8 system is replaced with an ear squeeze mechanism 129 9 which applies pressure to the ear. An acoustic detector 130 detects the signals from the ear lobe.

11 12 In the most straightforward forms of the invention, 13 a single analyte such as glucose in blood can be 14 measured by using light of selected wavelengths and is by measuring the area or the amplitude of the 16 received acoustic pulse. It is preferable to make 17 each measurement by using a train of pulses, for 18 example about 100 pulses, and averaging the results 19 in order to minimise the effects of noise and pulse effects in the blood flow.

21 22 The accuracy of the detection system is governed, in 23 part, by the Signal to Noise Ratio (SNR) of the 24 system. Variations in the intensity and duration of the light source can cause the acoustic signal to 26 contain variations. A normalization technique, such 27 as taking the ratio of the acoustic signal to the 28 optical signal, can significantly reduce the effect 29 of the source variations, thereby improving the signal to noise ratio of the system. The optical 31 signal can be measured with a reference detector, or 32 several reference detectors, one for each source or 26 1 one for a wavelength range. An equation describing 2 this type of normalization follows:

3 4 Acoustic Signal Normalized Signal 6 Optical Signal 7 8 In some cases the relationship between the optical 9 signal land the acoustic signal changes with wavelength and light intensity. When this is the 11 case the accuracy of the measurement can be further 12 enhanced by determining the energy dependence of the 13 photoacoustic signal. This may be determined by 14 establishing the specific relationship between the is photoacoustic signal land the incident energy from a 16 set of measurements and using this relationship to 17 compensate for the non linear response. An equation 18 describing this type of normalization is as follows:

19 Acoustic Signal 21 Normalized Signal = 22 Scaling Factor Optical Signal + 23 Offset 24 Other normalization methods can also apply. The 26 time interval between the optical pulse and the 27 detection of the acoustic signal may be used to 28 characterise physical properties such as the 29 velocity of sound in the tissue. In addition, in another embodiment of the device the damping of the 31 acoustic oscillations may be used to monitor the 32 elastic properties of the tissue and, in particular, 27 1 the compressibility. Both of these aspects may be 2 used in the person to person calibration of the 3 photoacoustic response.

4 More complex analysis of the received acoustic 6 energy is possible. For example, a time-gating 7 technique may be used to derive measurement at 8 varying depths within the tissue being examined.

9 Alternatively, an array of detectors can be employed to determine the profile of the absorption of the 11 acoubtic signal at different depths and locations.

12 This depth profile will change with the absorption 13 coefficient and could be used as additional 14 information to determine the analyte concentration.

is It is also possible to derive information relating 16 to a number of analytes of interest by more 17 sophisticated analysis of the received acoustic 18 energy wave forms, for example by analysis of the 19 frequency spectrum by Fourier transform or wavelet analysis techniques.

21 22 Alternatively, or in combination with the frequency 23 techniques and multiple detectors, multiple light 24 sources can aid in the determination of the concentration of a number of analytes.

26 27 There are a number of tissue features which may vary 28 from person to person or with in the same person 29 over time which impact the photoacoustic signal observed. To obtain an accurate measurement of a 31 given analyte, such as glucose, it may be helpful to 32 also determine the concentration of other analytes 28 such as haemoglobin which may act as interferants.

One approach is to generate several distinct photoacoustic signals using excitation light of 4 several different wavelengths. For example, excitation light of a wavelength of which 6 haemoglobin absorbs strongly but glucose has little 7 if any absorption could be sued to obtain a measure 8 of the haemoglobin concentration with which to 9 normalize the effect of haemoglobin on measurements made on different persons or on the same person at -.i different times. These measurements which are to be 12 normalized might be based on the photoacoustic 13 signal generated by light of a wavelength at which 14 glucose absorbs.

is 16 It is also possible to measure the concentration of 17 such interferants by other means, such as infrared 18 light absorption, and thus normalize or correct the 19 photoacoustic signal representative of the desired analyte for variations in these interferants. Thus, 21 for example, the photoacoustic signal representative 22 of glucose could be corrected for variations in 23 haemoglobin concentration determined by optical 24 absorption techniques such as those taught in US Patent No 5,702,284.

26 27 For the reliable and reproducible determination of 28 glucose a signal to noise ratio of at least 10,000 29 is recommended. In this regard water is typically present in human tissue of a concentration of about 31 50 molar while glucose is present at a concentration 32 of about 5 millimolar in a normal individual.

29 1 Apparatus and method embodying the present invention 2 have been found to yield accurate and repeatable 3 results. In the case of blood glucose measurement, 4 the clinical range of glucose concentration is approximately 5-10 m mol/1 in healthy subjects, and 6 up to 40 m mol/1 in diabetics. An analysis based on 7 simple absorption models suggests that the change in 8 photoacoustic signal over this range might be as 9 little as 0.2%. The present invention has been found to provide a change in photoacoustic signal of 11 up to 140% for a change in.-flucose concentration of 12 15m M01/1. 13 14 The precise mechanisms involved are not at present is fully understood. It is believed, however, that 16 absorption occurs primarily in body plasma and is 17 modified by the presence of glucose, and that this 18 affects beam geometry. 19 20 Example 21 22 The blood glucose levels of three individuals, one 23 normal individual, one type 1 diabetic and one type 24 2 diabetic, were followed over a two hour period 25 following each individual taking about 75 grams of 26 glucose orally in an aqueous solution by both 27 photoacoustics and direct blood measurement. The 28 results are reported in Figures 17, 18 and 19. 29 Photoacoustic measurements were made every five 30 minutes and blood measurements were made very ten 31 minutes. The blood samples were venous blood samples analysed by the standard glucose oxidase 1 method using a Yellow Springs instrument. The error 2 bands for the blood measurements were derived from 3 the literature accompanying the testing instrument 4 while those for the photoacoustic results were based on the averages taken over 1000 pulses. The results 6 were obtained from a configuration similar to that 7 illustrated in Figure 1 in which 10 was an end of a 8 1 km multimode fibre optic cable which was placed 9 against the finger 12. The other end received 600 nanosecond pulses of 1040 nanometer light from a Q 11 switched Nd:YAG laser delivering 2,7 micro joules 12 per pulse for each measurement. Raman interactions 13 in the fibre caused the production of light an 14 additional wavelengths as set forth in the following is table:

16 wavelength in Average pulse Pulse width in Approximate nm energy in ns bandwidth in microjules 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 is 1390 0.3 350 20 1450 0.1 350 20 1500 0.2 350 20 1550 0.18 360 20 17 18 The resulting photoacoustic signal was detected by a 19 Smm disc transducer with a lead backing and fed to an amplifier and an oscilloscope.The transducer 31 1 was generally placed as 16 in Figure 1 but was not 2 precisely parallel to the beam axis; its detection 3 plane was at an angle of about 20 degrees to the 4 beam axis. The photoacoustic signal was evaluated 5 in terms of the difference in voltage signal from 6 the positive peak of the compression to the negative 7 peak of the relaxation of the acoustic pulse. 8 9 The change in photoacoustic response correlated well 10 with the change in blood glucose concentration over 11 the 'L--,rgo hour measurement period. A correlation of 12 0.89 was achieved on samples ranging from 4 to 35 m 13 M01/1.

14 is Other modifications and improvements may be made to 16 the foregoing embodiments within the scope of the 17 present invention as defined in the claims.

Cl 32

Claims

1 CLAIMS

2 3 1. A method of correcting measurement of an 4 analyte based on a photoacoustic signal obtained from a living being comprising 6 determining the concentration of other 7 constituents in the being which have a 8 significant effect on the photoacoustic signal 9 and tend to vary from individual to individual or over time, and adjusting the measurement to 1.1 remove the effect of variations in the 12 concentrations of said other constituents.

13 14

2. The method of claim 1 in which the analyte is is glucose.

16 17

3. The method of claim 1 or 2 in which the 18 concentration of haemoglobin is determined and 19 used to adjust the measurement.

21

4. The method of any preceding claim, including 22 the step of determining the absorbtion profile 23 of the photoacoustic signal at different depths 24 and/or locations of the living being.

26

5. The method of claim 4, wherein said profile is 27 determined using a time-gating technique or an 28 array of detectors.

29

6. A sensor head for use in photoacoustic in vivo 31 measurement, comprising a housing shaped to 32 engage a selected body part, light transmission 33 1 means terminating in said housing so as to 2 transmit light energy from a light source to 3 enter the body part along a beam axis, and 4 acoustic transducer means mounted in the housing to receive acoustic waves generated by 6 photoacoustic interaction within the body part, 7 the acoustic transducer means being disposed in 8 the housing to receive said acoustic wave in a 9 direction of high acoustic energy.

11

7. A sensor head according to claim 6, in which 12 the acoustic transducer means is arranged at 13 least partially perpendicular to the optical 14 beam axis.

is 16

8. A sensor head according to claim 7, for use 17 where the selected body part is the distal 18 portion of a finger, in which the housing 19 includes a generally half-cylindrical depression in which the finger may be placed 21 with the light transmission means aimed at the 22 end of the finger.

23 24

9. A sensor head according to any of claims 6 to 8, in which the acoustic transducer means 26 comprises a piezoelectric transducer which is 27 of a semi-cylindrical shape.

28 29

10. A sensor head according to any of claims 6 to 9, in which the acoustic transducer means 31 comprises a piezoelectric transducer which is 34 1 provided with a backing of lead or other dense 2 material.

3 4

11. A sensor head according to claim 10, in which said backing has a rear surface shaped to minimise internal acoustic reflection.

7 8

12. A sensor head according to any of claims 6 to 9 10, in which the transducer means comprises a capacitor-type detector.

11 12

13. A sensor head according to any of claims 6 to 13 10, in which the transducer means comprises a 14 piezoelectric transducer arranged generally is perpendicular to the optical axis to detect the 16 acoustic wave which is propagating in a 17 direction opposite to the direction of 18 propagation of the light beam.

19

14. A sensor head according to claim 13, in which 21 the transducer is part-spherical with an 22 aperture to allow access for the light beam.

23 24

15. A sensor head according to any of claims 6 to 14, including a surface wave detector for 26 characterizing tissue properties.

27 28

16. A sensor head according to any of claims 6 to 29 15, including means for ensuring a consistent contact pressure between a selected body part 31 and the acoustic transducer means.

32 1

17. A sensor head according to claim 16, for use 2 where the selected part is the distal portion 3 of a finger, said means being provided by 4 mounting a portion of the housing engaged by the finger in a resiliently biased fashion 6 against the remainder of the housing, and 7 providing means to ensure that measurement is 8 effected when a predetermined force or pressure 9 is applied by the subject against the resilient bias.

11 12

18. A sensor head according to claim 17, for use 13 where the selected part is the earlobe, said 14 means being provided by two plates, between is which the earlobe may be placed, and means for 16 pressing the plates together to apply pressure 17 to the ear.

18 19

19. A sensor head for use in photoacoustic in-vivo measurements, comprising a housing shaped to 21 receive a removable insert; a removable insert 22 that engages a selected body part, the insert 23 being fitted to an individual, allowing for a 24 range of sizes of body parts to be used; light transmission means terminating in or near said 26 removable insert so as to transmit light energy 27 from a light source to enter the body part 28 along a beam axis; and an acoustic transducer 29 means mounted in the housing or in the removable insert to receive acoustic waves 31 generated by photoacoustic interaction within 32 the body part, the acoustic transducer means 36 1 being disposed in the housing or insert to 2 receive said acoustic waves in a direction of 3 high acoustic energy.

4

20. An in vivo measuring system comprising in 6 combination: a sensor head as claimed in any of 7 claims 6 to 19; a light source coupled with the 8 light transmission means; and signal processing 9 means connected to receive the output of the acoustic transducer means and to derive 11 therefrom a measurement of a selected 12 physiological parameter.

13 ill

21. The system of claim 20, in which the light is transmission means is a fiber optic 16 distribution system.

17 18

22. The system of claim 21, in which there is a 19 plurality of light sources each connected to an individual fiber and the respective fibers are 21 joined by a wavelength division multiplexer or 22 a fiber coupler.

23 24

23. The system of claim 21 or claim 22, in which the fiber optic distribution system terminates 26 in contact with the body part.

27 28

24. The system of claim 21 or claim 22, in which 29 the fiber optic distribution system communicates with the body part via optical 31 elements such as lenses and beamsplitters.

37 1

25. The system of claim 20, in which the light 2 transmission means comprises optical elements 3 mounted in mechanical holders and arranged to 4 convey the light from the light source to a location in proximity to the body part.

6 7

26. The system of claim 24 or claim 25, in which 8 the light transmission means includes at least 9 one beamsplitter arranged in the light path to direct a portion of the light to a respective 11 reference detector te measure the energy of the 12 light entering the body part.

13 14

27. The system of any of claims 20 to 26, in which is the signal processing means is adapted to 16 perform a multi-dimensional processing method.

17 18

28. The system of claim 27, in which the signal 19 processing means is adapted to perform one of Classical Least Squares or Partial Least 21 Squares.

22 23

29. The system of any of claims 20 to 26, in which 24 the signal processing means comprises a Neural Network.

26 27

30. The system of any of claims 20 to 29, in which 28 the signal processing means is operable to 29 analyse the signals for their frequency content using one of Fourier Analysis and Frequency 31 Filtering.

32 38 1

31. The system of any of claims 20 to 30, in which 2 the signal processing means additionally 3 applies techniques that use time information.

4

32. The system of claim 31, in which the time 6 information processed is the time delay from 7 source trigger.

8 9

33. The system of any of claims 20 to 30, in which the signal processing means additionally 11 applies techniques that combine both frequency 12 and time information.

13 14

34. The system of claim 33, in which the signal is processing means performs wavelet analysis.

16 17

35. The system of any of claims 20 to 34, in which 18 the light source is a laser light source.

19

36. The system of claim 35, in which said laser 21 light source is selected from a pulsed diode 22 laser, a set of pulsed diode lasers, and a 23 tunable laser source.

24

37. The system of claim 36, for use in measuring 26 blood glucose concentration, in which the light 27 source is a laser diode with a wavelength in 28 the range of approximately 600 nm to 10,000 nm 29 and a pulse duration of the order of 5 to 500 ns.

31 39 1

38. The system of any of claims 35 to 37, in which 2 the 'light transmission means is arranged to 3 produce a spot size of the order of 0.05 mm to 4 0.50 mm.

6

39. The system of any of claims 20 to 34, in which 7 there are multiple light sources and means are 8 provided for time multiplexing the multiple 9 sources such that: each source is switched on and generates an optical pulse, or a set of 11 optical pulses, the pulse, or set of pulses 12 generates an acoustic signal that is detected 13 by the detector, and each source is pulsed in 14 sequence until all sources have been used tu generate their own signals.

16 17

40. The measuring system of any of claims 20 to 39, 18 in the form of a self contained system 19 including a power supply and a readout, which may be carried on the person and used at any 21 convenient time.

22 23

41. The system of claim 40, including facilities 24 for connection to a cellular telephone, two-way pager or other communication device for routine 26 transmission of measurements taken to a central 27 data collection point.

28 29

42. The system of any of claims 20 to 41, further including means for manipulating the body part 31 under measurement and for performing additional 32 measurement of the tissue to obtain other information about the state of the physiology of the issue.

4

43. The system of claim 42, in which said manipulating means includes means for squeezing 6 a body part, such as an earlobe, and means for 7 making photo acoustic measurements at several 8 different pressures.

9

44. The system of claim 42 or claim 41, including 11 temperature measurement means for measuring the 12 temperature of the body site, and in which the 13 signal processing means is arranged to apply a 14 correction to the measurements based upon the is temperature of the body site.

16 17

45. The system of claim 44, further including means 18 for inducing temperatures above and below 19 ambient in the body part.

21

46. The system of any of claims 20 to 45, 22 comprising a means for storing one or both of 23 calibration coefficients and operational 24 parameters in order to calibrate the instrument and to set critical operational parameters.

26 27

47. The system of claim 46, in which the signal 28 processing means is operable to adjust the 29 calibration coefficients and operational parameters to be specific to a particular 31 person.

32 41 1

48. The system of claim 47, when dependent upon 2 claim 19, in which the calibration coefficients 3 and operational parameters specific to a 4 particular person are contained in a storage site located in the removable insert.

6 7

49. The system of claim 48, in which additionally 8 calibration coefficients and operational 9 parameters specific to the reader system are stored in the non-removable housing.

11 12

50. The measuring system of any of claims 20 to 49, 13 further including connection means for 14 connecting the measuring system to an invasive is measuring system for the purpose of calibrating 16 or adjusting the operational parameters of the 17 non-invasive measuring system.

18 19

51. The system of claim 50, in which the connection means is selected from a cable link, IR link or 21 radio waves.

22 23

52. A method of operating a measurement system as 24 claimed in claim 39 to remove instrument drift from the measurement, the method comprising the 26 steps of:

27 28 1) placing a calibration standard in the 29 reader in place of the body part; 42 1 2) measuring the signal from the standard for 2 each wavelength and storing the values in 3 the calibration storage location; 4 3) before making a measurement of a body 6 part, placing the calibration standard in 7 the reader; 8 9 4) measuring the signal from the standard for each source; 11 12 5) comparing the just measured standard 13 values to the stored calibration values; 14 is 6) calculating correction factors for each 16 source wavelength.

17 18 7) removing the standard and placing the body 19 part in the reader; 21 8) measuring the signal from the body part 22 for each source; and 23 24 9) adjusting the measured values using the calculated correction factors.

26 27

53. The method of claim 52, in which a further 28 correction factor is calculated for the 29 instrument temperature.

31

54. A method of measuring a biological parameter in 32 a subject, the method comprising the steps of:

43 1 directing one or more pulses of optical 2 energy from the exterior into the tissue 3 of a subject along a beam axis, the 4 optical energy having a wavelength selected to be absorbed by tissue 6 components of interest, thereby to produce 7 a photoacoustic interaction; 8 9 detecting acoustic energy resulting from said photoacoustic reaction by means of a 11 transducer positioned to intercept 12 acoustic energy propagating in a direction 13 other than the forward direction of said 14 beam axis; and is 16 deriving from said detected acoustic 17 energy a measure of the parameter of 18 interest.

19

55. The method of claim 54, in which the parameter 21 of interest is blood glucose, and the optical 22 energy has a wavelength in the range of 23 approximately 600 mm to 10,000 mm and a pulse 24 duration of the order of 5 to 500 ms.

26

56. The method of claim 54 or claim 55, in which a 27 train of pulses is applied and the detected 28 signals are averaged to derive said measure.

29

57. The method of any of claims 54 to 56, in which 31 said measure is derived from the energy of the 32 detected signal.

44 1

58. The method of any of claims 54 to 57, in which 2 the optical energy is directed into a body part 3 which is substantially composed of soft tissue 4 and free of bone.

6

59. Apparatus for measuring a biological parameter 7 in a subject, the apparatus comprising:

8 9 means for directing one or more pulses of optical energy from the exterior into the 11 tissue of a subject along a beam axis, the 12 optical energy having a wavelength selected to 13 be absorbed by tissue components of interest, 14 thereby to produce a photoacoustic interaction; is 16 transducer means arranged to detect acoustic 17 energy resulting from said photoacoustic 18 reaction by intercepting acoustic energy 19 propagating in a direction other than the forward direction of said beam axis; and 21 22 means for deriving from said detected acoustic 23 energy a measure of the parameter of interest.

24

60. Apparatus according to claim 59, in which said 26 directing means incudes means for receiving a 27 selected body part such that the optical energy 28 is directed into a portion of the subject's 29 body which is substantially free of bone.

31

61. A method of establishing a photoacoustic signal 32 obtained from a living being comprising using the ratio of the acoustic signal obtained to 2 the optical signal which generated the acoustic 3 signal to determine the concentration of an 4 analyte present in said being.

6

62. The method of claim 61 in which the analyte is 7 glucose.

8 9

63. A method of normalizing a photoacoustic signal obtained from directing an optical beam on the 11 tissue of a.living being comprising determining 12 the dependence of the photoacoustic signal on 13 the energy of the optical beam from a series of 14 measurements at different energies for the type is of tissue involved.