CA2282855A1 - Biological measurement system - Google Patents

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. The resulting acoustic signal is detected by a transducer (14) and analysed to provide the desired parameter.

Description

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1 Biolocrical Measurement System 3 This invention relates to apparatus for use in non-4 invasive in vivo monitoring of physiological substances such as blood and the like.

7 One particular, but not exclusive, application of the 8 present invention is in the monitoring of blood 9 glucose, for example in the management of diabetes mellitus. It is accepted that the management of 11 diabetes can be much improved by routine monitoring of 12 blood glucose concentration and clinicians suggest that 13 monitoring as often as four times per day is desirable.

The monitoring technique currently available for use by 16 patients involves using a spring loaded lancet to stab 17 the finger to obtain a blood sample which is 18 transferred to a glucose test strip. The concentration 19 is derived either by reading the test strip with a reflectance meter or by visual comparison of colour 21 change against a colour scale. Many diabetics find the 22 testing onerous as the technique is painful, 23 inconvenient, messy, potentially embarrassing and 24 offers a site for the transmittance and acceptance of infection.

1 Techniques have also been developed for non invasive 2 measurement using transmittance or reflectance 3 spectroscopy. However the required instruments are 4 expensive and it is difficult to obtain accurate and repeatable measurements.

7 There are also known various types of in vivo chemical 8 sensors. These rely on implanting minimally invasive 9 sensors under the skin surface, but such sensors have ZO poor long term reproducibility and bio-compatibility 11 problems.

13 There is therefore a need for improved means for 14 routine monitoring of blood glucose in a manner which is simple and straightforward to use.

17 The present invention makes use of photoacoustic 18 techniques. The fundamentals of photoacoustic 19 techniques are well known per se. A pulse of light, typically laser light, is applied to a substance 21 containing an analyte of interest in solution or 22 dispersion, the wavelength of the applied Light being 23 chosen to interact with the analyte. Absorption of the 24 light energy by the analyte gives rise to microscopic localised heating which generates an acoustic wave 26 which can be detected by an acoustic sensor. These 27 techniques have been used to measure physiological 28 parameters in vitro.

US Patents 5348002 and 5348003 (Caro) propose the use 31 of photoacoustics in combination with photoabsorption 32 for the measurement of blood components in vivo.
33 However, the arrangement proposed by Caro has not been 34 demonstrated as a workable system and may suffer from interference to a degree which would preclude useful 36 acoustic signals, and since they would also suffer from 1 interference and resonance effects from hard structures 2 such as bone.

- 4 It has also been proposed by Poulet and Chambron in Medical and Biological Eng~ineering~ and Computi,~cr, 6 November 1985, Page 585 to use a photoacoustic 7 spectrometer in a cell arrangement to measure 8 characteristics of cutaneous tissue, but the apparatus 9 described would not be suitable for measuring blood analytes.

12 Published European Patent Application 0282234A1 13 (bowling) proposes the use of photoacoustic 14 spectroscopy for the measurement of blood analytes such as blood glucose. This disclosure however does not 16 show or suggest any means which would permit the 17 required degree of coupling to body tissues for use in 18 vivo.

Accordingly, the present invention provides a sensor 21 head for use in photoacoustic in vivo measurement, 22 comprising a housing shaped to engage a selected body 23 part, light transmission means terminating in said 24 housing so as to transmit light energy from a light source to enter the body part along a beam axis, and 26 acoustic transducer means mounted in the housing to 27 receive acoustic waves generated by photoacoustic 28 interaction within the body part, the acoustic 29 transducer means being disposed in the housing to receive said acoustic wave in a direction of high 31 acoustic energy.

33 The expression "direction of high acoustic energy" is 34 used herein to denote a direction other than the forward direction of the light beam. Preferably, the 36 transducer means is disposed so as to intercept 1 acoustic energy propagating at right angles to the 2 optical beam axis, or at an angle to the optical beam 3 axis which may be down to about 20°, typically about 4 45°.
6 An exact measure of the angle of high acoustic energy 7 can be worked out but is dependent upon the specific 8 geometry of the light source, the properties of the 9 tissue and the absorption coefficient of the tissue.
IO One model for understanding the propagation of the 11 acoustic energy in any homogenous media was developed 12 by Huyghens and is called the principle of 13 superposition. In this model each volume element that 14 is illuminated by the light generates an acoustic pressure wave that radiates outward in a spherical 16 manor. The magnitude of the pressure wave at each 17 volume element depends on the intensity of the optical 18 beam at that location, the absorption coefficient of 19 the material at that location, the wavelength of light and on several other physical properties of the 21 material such as the speed of sound and the specific 22 heat. The signal measured at the detector is just the 23 superposition of all pressure waves from all points 24 that are illuminated by the source light. An analytical solution for the pressure wave has been 26 worked out for a few cases in aqueous material. The 27 analytical case that best matches the in-vivo 28 measurements is that of a cylindrical optical beam 29 propagating in a weekly absorbing material. In this case the direction of highest acoustic energy is 31 perpendicular to the optical axis. The base detector 32 location is with the plane of the detector 33 perpendicular to the acoustic energy, or parallel to 34 the optical axis. This is because the acoustic detector has the highest sensitivity when the acoustic 36 energy strikes the detector perpendicular to the plane 1 of the detector. This analytical model is not 2 completely accurate for the in-vivo measurement case 3 because of scattering of the tissue and because the - 4 tissue absorbs more than the model predicts. These 5 differences indicate that a different position for the 6 detector will be optimal. A detailed numeric model is 7 required to determine the best detector location and. is 8 dependent upon the beam properties (focused to a point, 9 colligated, etc.), body site (finger, earlobe, arm etc.) and wavelength. One skilled in the art can 11 readily develop an appropriate mode. However, suitable 12 locations for a detector will generally be at an angle 13 to the optical axis. Angles between 40 and 90 degrees 14 should be suitable.
16 In one preferred arrangement, the acoustic transducer 17 means is arranged parallel to the optical beam axis.
18 This arrangement is particularly suitable for use where 19 the selected body part is the distal portion of a finger, in which case the housing may include a 21 generally half-cylindrical depression in which the 22 finger may be placed with the light transmission means 23 aimed at the end of the finger.

Preferably, the acoustic transducer means comprises a 26 piezoelectric transducer which most preferably is of a 27 semi-cylindrical shape. This transducer may be 2B provided with a backing of lead or other dense 29 material, and the backing may have a rear surface shaped to minimise internal acoustic reflection.

- 32 Alternative transducer means include a capacitor-type 33 detector, which is preferably small and disk-shaped; an 34 integrated semiconductor pressure sensor; and an optical pressure sensor, for example based on an 36 optical fibre.

1 In an alternative arrangement, the plane of the 2 transducer may be arranged to be perpendicular to the 3 optical axis to detect the acoustic wave which is 4 propagating in a direction opposite to the direction of the light beam. For example, the acoustic transducer 6 means may be part-spherical with an aperture to allow 7 access for the light beam. This may be particularly 8 suitable for engagement with a body part other than the 9 finger, for example the back of the arm.
11 The generation of a surface acoustic wave is an 12 inherent aspect of the in vivo pulsed photoacoustic 13 generation in tissue and may be used to characterize 14 tissue properties such as density. A surface wave detector may be provided in the sensing head assembly.

17 Preferably means are provided for ensuring a consistent 18 contact pressure between the selected body part and the 19 acoustic transducer means. In the case where the selected part is the distal portion of the finger, said 21 means may be provided by mounting the portion of the 22 housing engaged by the finger in a resiliently biased 23 fashion against the remainder of the housing, and 24 providing means to ensure that measurement is effected when the predetermined force or pressure is applied by 26 the subject against the resilient bias. In the case 27 where the selected part is the earlobe, said means may 28 be provided by placing the ear between two plates and 29 applying pressure to the ear with springs or weights or other force method. The two plates holding the ear may 31 contain a removable insert. The two plates may be fiat 32 or may be of another shape to optimally position the 33 detector with respect to the beam axis.

In addition, the present invention provides a sensor 36 head for use in photoacoustic in-vivo measurements, T

WO 98138904 . PCT/GB98100702 1 comprising a housing shaped to receive a removable 2 insert, a removable insert that engages a selected body 3 part, the insert being fitted to an individual, 4 allowing for a range of sizes of body parts to be used, . 5 and further comprising light transmission means 6 terminating in or near said removable insert so as~to 7 transmit light energy from a light source or sources to 8 enter the body part along a beam axis, and an acoustic 9 transducer means mounted in the housing or in the removable insert to receive acoustic waves generated by 11 photoacoustic interaction within the body part to I2 receive said acoustic waves in a direction of high 13 acoustic energy.

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

23 Preferably, the light transmission means is a fiber 24 distribution system where each light source is connected to an individual fiber and when multiple 26 light sources are used the multiple fibres are joined 27 by some standard fiber combining method, such as a 28 wavelength division multiplexer or a fiber coupler.
29 The fiber that comes from the light source, or contains the combined light for a multiple source system, is 31 then terminated in proximity to the body part being 32 measured. The fiber could be in contact with the body 33 part or alternatively standard optics, such as lenses, 34 beamsplitters and such, could be employed to convey the light from the end of the fiber to the body part. A
36 reference detector or several reference detectors and 1 beamsplitters can be added to the optical distribution 2 system to determine the energy of the light entering 3 the body part.

Alternatively, the optical distribution system may 6 contain mechanical holders, lenses and such to convey 7 the light from the source, or sources, to a location in 8 proximity to the body part being measured. A reference 9 detector or several reference detectors and beamsplitters can be added to the optical distribution 11 system to determine the energy of the light entering 12 the body part.

14 The acoustic signal from the detector contains information in both time and frequency, and there may 16 be information from several sources. The processing 17 means is preferably a multi-dimensional processing 18 method, such as Classical Least Squares (CLS) or 19 Partial Least Squares (PLS). Alternatively the processing method may be more flexible, such as a 21 Neural Network. In addition to these methods the 22 signals may be analysed for their frequency content 23 using such techniques as Fourier Analysis or Frequency 24 Filtering In addition techniques may be employed that use time information such as the time delay from source 26 trigger. Techniques that combine both frequency and 27 time information may be employed, such as Wavelet 28 analysis.

The light source is preferably a laser light source and 31 is most suitably a pulsed diode laser, but may utilise 32 a set of such lasers or utilise a tunable laser source.
33 In a particularly preferred form, suitable for use in 34 measuring blood glucose concentration, a laser diode is used with a wave length in the range of approximately 36 600 nm to 10,000 nm and a pulse duration of the order T..

WO 98/38904. PCT/GB98/00702 1 of 5 to 500 ns.

3 The delivery to the measurement site may be either 4 directly or by optical fibre with a suitable optical element to focus the beam into the tissue.

4 _ 7 Preferably means are provided for time multiplexing 8 multiple sources when multiple sources are used. Each 9 source is switched on, and it generates an optical pulse, or a set of optical pulses. This pulse, or set 11 of pulses, generates an acoustic signal that is 12 detected by the detector. Each source is pulsed in 13 sequence until all sources have been used to generate 14 their own signal.
16 The measuring system may conveniently be in the form of 17 a self contained system including a power supply and a 18 readout, which may be carried on the person and used at 19 any convenient time.
21 It is also possible for such a self contained system to 22 incorporate, or to be provided with facilities for 23 connection to, a cellular telephone, two-way pager or 24 other communication device for routine transmission of measurements taken to a central data collection point.

27 In addition the measuring system may have provision for 28 manipulating the body part under measurement and for 29 performing additional measurement of the tissue to get other information about the state of the physiology of 31 the issue. It is well-known in the art that squeezing 32 a section of tissue to increase the pressure and then 33 releasing the pressure will cause changes in the total 34 blood volume in the measurement site. The present invention may allow for this type of manipulation 36 including the squeezing of a body part, such as an 1 earlobe, and making photo acoustic measurements at 2 several different pressures. The present invention may 3 also allow for the measurement of the temperature of 4 the body site and to apply a correction to the 5 measurements based upon the temperature of the body 6 site.

8 Another type of physiological manipulation is body 9 temperature. It is known in the art that several 10 parameters involved in the detection of the photo 11 acoustic signal, such as the speed of sound, are 12 dependent upon the temperature of the medium the signal 13 is propagating through (the tissue}. Also the 14 profusion of the blood in the small capillaries is dependent upon the temperature of the tissue.
16 Additional information about the tissue can be obtained 17 if the photo acoustic measurement is made at several 18 temperatures, both higher and lower than ambient 19 temperature. This additional information is used to better eliminate interferences to the determination of 21 the analyte under investigation. These are only two 22 examples of manipulating the body site and are not 23 intended to be an exhaustive list, and they can be used 24 in combination with other manipulation techniques.
26 The in-vivo measuring system may comprise a means for 27 storing calibration coefficients or operation 2g parameters or both calibration coefficients and 29 operational parameters, in order to calibrate the instrument and to set critical operational parameters.

32 Another aspect of the present invention provides a 33 means for adjusting the calibration coefficients and 34 operational parameters to be specific to a particular person and may be used to adjust for such things as 36 body part size, skin color, skin condition, amount of T___ _ T.

_ WO 98/38904 PCT/GB98/00702 1 body fat, efficiency of the detector and efficiency of 2 the source(s).

4 In addition the present invention may provide for having the specific calibration coefficients and 6 operational parameters be contained in a storage site _ 7 located in the removable insert. This allows for the 8 system to be both mechanically and operationally 9 configured to a particular individual. Additionally the invention may allow for the calibration 11 coefficients and operational parameters to be stored in 12 two locations, one in the non-removable housing and one 13 in the removable insert with some of the coefficients 14 and parameters stored in each location. This allows for reader system coefficients to be stored in the 16 reader and coefficients specific to an individual to be 17 stored in the removable insert for that person, 18 enabling many people to use the same reader.

Another aspect of the present invention provides means 21 for connecting the non-invasive measuring system to an 22 invasive measuring system for the purpose of 23 calibrating or adjusting the operational parameters of 24 the non-invasive measuring system. Such connection may be accomplished, but is not limited to, communication 26 by a wire, IR link or radio waves.

28 Another aspect of the present invention provides a 29 method for removing instrument drift from the measurement comprising the steps of:

32 1. Placing a standard in the reader in place of the 33 body part.

2. Measuring the signal from the standard for each 36 wavelength and storing the values in the 1 calibration storage location.

3 3. Before making a measurement of a body part, 4 placing the calibration standard in the reader.
6 4. Measuring the signal from the standard for each 7 source.

9 5. Comparing the just measured standard values to the stored calibration values.

12 6. Calculating correction factors for each source 13 wavelength.

7. Removing the standard and placing the body part in 16 the reader.

18 8. Measuring the signal from the body part for each 19 source.
21 9. Adjusting the measured values using the calculated 22 correction factors.

24 In addition to the signal correction factors a correction factor can be calculated for the instrument 26 temperature. This can be applied to each signal with a 27 different correction coefficient.

29 The invention further provides a method of measuring a biological parameter in a subject, the method 31 comprising the steps of:

33 directing one or more pulses of optical energy 34 from the exterior into the tissue of a subject along a beam axis, the optical energy having a 36 wavelength selected to be absorbed by tissue 1 components of interest, thereby to produce a 2 photoacoustic interaction;

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

Embodiments of the invention will now be described, by 16 way of example only, with reference to the accompanying 17 drawings in which:-19 Figs. lA,lB and 1C are side views illustrating the principle of operation of one embodiment of the 21 present invention;

23 Fig. 2 is a schematic perspective view showing a 24 sensor head for use in carrying out the measurement illustrated in Fig. 1;

27 Fig 3. is a cross section view of the sensor head 28 of Fig. 2;

Fig. 4 is a side view of the sensor head of Fig.
31 2;

33 Fig. 5 is a schematic perspective view of an 34 apparatus incorporating the sensor head of Figs. 2 to 4;

1 Fig. 6 is a perspective view illustrating an 2 alternative form of sensor head;

4 Fig. 7 is a schematic end view showing another form of sensor head;

7 Figs. 8a and 8b are a cross-sectional side view 8 and a plan view, respectively, of a further sensor 9 head;

11 Fig. 9 is a cross-sectional side view of one more 12 embodiment of sensor head;

14 Fig. 10 is a perspective view of one type of ear interface apparatus;

17 Fig. 11 is a schematic of a multiple laser optical 18 distribution system using lenses, mechanical 19 mounts and a reference detector;

21 Fig. 12 is a schematic of a multiple laser optical 22 distribution system using fiber optic cables and a 23 fiber Wavelength Division Multiplexer (WDM), a 24 beam splitter and a reference detector;

26 Fig. 13 is a perspective view of a finger 27 interface apparatus with removable inserts that 28 are moulded to fit one individual;

Fig. 13A shows part of the apparatus of Fig. 13 in 31 greater detail;

33 Fig. 14 is a schematic of a semi-spherical 34 detector that contains a hole for the light beam, with a vacuum system and a fiber distribution 36 system;

.T....... ..... T...

2 Fig. 15 is a perspective view showing one form of 3 the instrument utilizing the vacuum body 4 interface, a semi-spherical detector and the 5 multiple laser source with lenses and mechanical 6 housing;
7 ,, 8 Fig. 16 is a perspective view showing one form of 9 the instrument using an ear lobe body interface, 10 with the added feature of being able to manipulate 11 the pressure on the ear lobe; and 13 Figs. 17, 18 and 19 are graphs illustrating an 14 example.
16 Referring to Fig 1, an important feature of the present 17 invention lies in introducing light energy along an 18 axis into an area of soft tissue and detecting the 19 resulting acoustic response transverse to that axis.
Accordingly, in the arrangement of Fig lA light energy 21 from a diode laser (not shown) is transmitted via a 22 fibre-optic guide 10 to the tip of a finger 12. The 23 photoacoustic interaction occurs in an approximately 24 cylindrical region indicated at 14 from which acoustic energy is radiated in a generally cylindrical manner 26 and is detected by a transversely arranged acoustic 27 transducer 16.

29 In Figs 1B and 1C, the principle is similar. The finger 12 is pressed against a support with force F.
31 In Fig 1B, the incident light beam indicated at L is 32 directed as in Fig lA, and the transducer 16 is at an 33 angle of 45 degrees thereto. In Fig 1B, the angle is 34 90 degrees as in Fig lA, but the incident beam is directed differently into the fingertip.

1 In the present embodiment, the laser wavelength is 2 chosen to achieve high degree of absorption by glucose 3 present in the blood. A suitable wavelength is in the 4 range approximately 1000 to 3000 nm. The laser pulse duration is chosen to be short, typically of the order 6 of 5 to 500 ns, in order to minimise thermal diffusion a .
7 and thus to optimise the acoustic waveform. For the 8 same reasons, it is desirable to use a spot size which 9 is sufficiently small to minimise thermal diffusion, typically a spot size of the order of 0.05 mm to 11 0.50 mm.

13 The efficiency of the photoacoustic detection is also 14 influenced by the positioning and dimensions of the acoustic transducer in relation to the characteristic 16 extinction length of the tissue at the principal 17 wavelengths chosen for measurement. in the fingertip 18 arrangement of Fig. 1, the system efficiency will be 19 improved by optimising the length of the transducer crystal parallel to the axis of the finger, but the 21 length should not be so great as to give rise to 22 undesired signals which would occur at the point of 23 entry of the optical energy into the finger and by 24 reason of interaction of the acoustic energy with bone or other hard tissue.

27 A second limit on the size of the acoustic detector 28 derives from the wavelength of the acoustic wave in the 29 tissue. Again making use of Huyghens principal of superposition we view each point of tissue, that is 31 illuminated by the incoming light, as a point source 32 that generates a spherical pressure wave. The signal 33 measured at the detector is just the superposition of 34 all pressure waves from all points that are illuminated by the source light. Normally if the size of the 36 detector is increased then the signal should also T _. __ _.___._ ~~

1 increase because more energy is received by the 2 detector. However if the acoustic detector is too 3 large then a pressure wave generated from a tissue - 4 element will create a pressure wave that will strike the both ends of the detector. If the paths length 6 from the tissue element to the first end of the 7 detector is different than the path length to the 4 8 second end of the detector and if this difference in 9 path length is about one half of the acoustic signal wavelength then the signal will destructively interfere 11 with itself and will reduce the magnitude of the 12 measured signal.

14 Referring to Fig 2, one manner of carrying out the arrangement shown in Fig 1 makes use of a sensor head 16 having a finger rest 18 which is slidably moveable 17 within housing 20 closed by a front plate 22. The user 18 inserts his finger in a semi-cylindrical depression 24 19 in the finger rest 18 with the finger tip engaged against an end surface 28 which includes an exit face 21 26 of the optical fibre 10. The finger is then pressed 22 downwardly against a resilient bias to enable a 23 standardised contact to be obtained between the skin 24 and the acoustic transducer. The finger tip may first be dipped in water or coated with an aqueous gel to 26 improve the acoustic coupling.

28 Referring to Figs 3 and 4, in this preferred 29 arrangement the acoustic transducer comprises a semi-cylindrical piezoelectric transducer 30. The 31 transducer 30 is provided with a backing member 32 of 32 lead or another dense substance, the rear face 34 of 33 which is shaped in irregular curves. The use of the 34 semi-cylindrical transducer 30 maximises the area for reception of acoustic energy from the finger, while the 36 use of a dense backing material minimises ringing 1 effects within the transducer. Additionally, the rear 2 face 34 is shaped as shown to reduce reflection of 3 acoustic energy back towards the piezo crystal.

Fig 3 also shows the finger rest biased upwardly by the 6 use of constant tension springs 38.
a -8 Fig 5 illustrates schematically the apparatus of Figs.
9 2 and 3 embodied in a self-contained, portable blood monitoring apparatus including a user readout 40. An 11 apparatus of this nature allows a diabetic to monitor 12 blood glucose concentration in a convenient manner, as 13 frequently as may be desired, and in a painless and 14 discreet manner.
16 Other forms of photoacoustic sensor head are possible 17 within the scope of the present invention. For 18 example, Fig. 6 shows an arrangement in which a light 19 guide 50 and an acoustic transducer 52 are applied to a finger 54 by means of a hinged clamp member 56. Fig. 7 21 shows a finger 60 engaged by a light guide 62 and an 22 acoustic transducer 64 which are carried on a moveable 23 assembly 66 with the finger 60 being trapped between 24 the moveable assembly 66 and a fixed anvil 68.
26 It is also possible to arrange the sensor head to co-27 operate with a soft tissue surface of the body, for 28 example a soft part of the abdomen. Figs. 8a and 8b 29 show an arrangement in which a cup shaped member 70, suitably of rubber, causes a light guide 72 and an 31 acoustic transducer 74 to be contacted with a bulge of 32 soft tissue 76 which may for example be drawn into 33 contact by means of a partial vacuum within the member 34 70 caused by suction through a conduit 78, or by other mechanical or adhesive means.

_ _ T _ _ ____ T _ 1 A somewhat similar arrangement is shown in Fig. 9 in 2 which a planar mount 80 carrying a light guide 82 and 3 acoustic transducer 84 is secured to a soft area of 4 body by means of surgical adhesive 86.
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 88.
9 The acoustic detector 89 is mounted partially perpendicular that is at an acute angle, to the beam 11 axis defined as line going from the center of a lens 90 12 to the center of a window 91. It has been found that 13 the system works satisfactorily with the detector 89 at 14 an angle or 45° to the beam axis. The window 91 and the detector 89 are placed in direct contact with the 16 ear and the opposite plate 88 places pressure on the 17 ear using a suitable mechanism (not shown). This 18 particular embodiment of the ear interface apparatus i9 incorporates an alignment ring 92 which is temporarily attached to the ear and fits over the window housing 91 21 to aid in aligning ear into the same location every 22 time.

24 Referring to Fig. 11, one method of combining light sources into the instrument is to use a mechanical 26 housing 93 with several holes used to align lenses 95 27 and laser diodes 94. The housing shown uses a 28 hexagonal array of seven holes. The sources and lenses 29 are arranged in such a way that they all focus to the same location 96 which could be on the surface of the 31 body part. This design does not show the inclusion of 32 beamsplitters and reference detectors but they can be 33 added in an alternative arrangement.

An alternative method of combining several sources into 36 one beam is shown in Fig. 12. Several laser diodes 97 1 are shown coupled to individual fiber optic cables 131.
2 These cables 132 are combined using a fiber Wavelength 3 Division Multiplexer (WDM) 98. Alternative combination 4 methods exist including couplers and multi-fiber 5 bundles. The combined light exits the WDM 98 in a 6 single fiber 104 and terminates at the focal point of a 7 lens 131. This end of the fiber is imaged to the end 8 of the finger 103 to a spot 102 using another lens 130.
9 Some of the light is split off the main beam using a 10 beam splitter 100 and focused onto a reference detector 11 101 using another lens 99. Additional reference 12 detectors and/or beamsplitters can be added to the 13 distribution system without changing its function.
14 Alternatively a reference detector could look directly 15 at the body part to measure the light reflecting off 16 the surface, as a measure of the overall light energy 17 entering the body part.

19 Referring to Fig. 13, another method of using a finger 20 as the body part and including removable inserts is 21 shown. A finger 105 is inserted into an insert 106 22 that is used to customize the finger holder to a 23 particular finger. The moulded insert 106 is placed 24 into a housing 107. The finger 105 is placed against a semi-cylindrical acoustic detector in a module108 which 26 is also attached to the housing 107. A cover 109 for 27 the housing 107 contains a mechanism 111 to apply 28 constant force to the finger 105. The light beam 110 29 is introduced into the finger 105 using a suitable optical distribution system (not shown). Fig. 13A shows 31 the module 108 in greater detail. A base 200 carries a 32 part-cylindrical piezo transducer 202 on a support 204.
33 206 indicates a coaxial connector to communicate the 34 transducer signal.
36 Fig. 14 shows a schematic of an alternative to the T __ I
__ _._ __ __ _ _ .

1 vacuum arrangement shown in Figs. 8 and 9. In this 2 system a photoacoustic reader 121 is placed against the 3 skin 113 with a semi-spherical detector 112 in contact 4 with the skin 113. A vacuum pump 115 and vacuum seal 116 create a negative pressure and pull the skin 113 6 against the detector 112. Processing electronics 119 7 energizes light sources 118 and an optical distribution 8 system 117 routes the light to the body part through a 9 hole in the top of the semi-spherical detector 112.
The optical distribution system 117 directs a small 11 portion of the light to a reference detector 114. The 12 processing electronics 119 measures the signal from the 13 acoustic detector 112 and the reference detector 114 14 for each optical source 119 and calculates the glucose value. The value is displayed on a display 120.

17 Fig. 15 shows a similar system 125, only using another 18 type of optical distribution system 127. Again a 19 vacuum pump 123 creates a negative pressure which draws the skin up to an acoustic detector 122. Processing 21 electronics 124 signals light sources in optical 22 distribution system 127 to illuminate and a signal is 23 generated at acoustic detector 122. The processing 24 electronics 124 calculates the proper value and displays it on a display 126.

27 Fig. 16 shows an alternative arrangement of a photo-28 acoustic reader. In this system 128, the vacuum system 29 is replaced with an ear squeeze mechanism 129 which applies pressure to the ear. An acoustic detector 130 31 detects the signals from the ear lobe.

33 In the most straightforward forms of the invention, a 34 single analyte such as glucose in blood can be measured by using light of selected wavelengths and by measuring 36 the area or the amplitude of the received acoustic _ WO 98/38904 PCT/GB98/00702 1 pulse. It is preferable to make each measurement by 2 using a train of pulses, for example about 100 pulses, 3 and averaging the results in order to minimise the 4 effects of noise and pulse effects in the blood flow.
6 The accuracy of the detection system is governed, in 7 part, by the Signal to Noise Ratio (SNR) of the system.
8 Variations in the intensity and duration of the light 9 ~ source can cause the acoustic signal to contain variations. A normalization technique, such as taking 11 the ratio of the acoustic signal to the optical signal, 12 can significantly reduce the effect of the source 13 variations, thereby improving the signal to noise ratio 14 of the system. The optical signal can be measured with a reference detector, or several reference detectors, 16 one far each source or one for a wavelength range. An 17 equation describing this type of normalization follows:

19 Acoustic Signal Normalized Signal -21 Optical Signal 23 In some cases the relationship between the optical 24 signal land the acoustic signal changes with wavelength and light intensity. When this is the case the 26 accuracy of the measurement can be further enhanced by 27 determining the energy dependence of the photoacoustic 28 signal. This may be determined by establishing the 29 specific relationship between the photoacoustic signal land the incident energy from a set of measurements and 31 using this relationship to compensate for the non 32 linear response. An equation describing this type of 33 normalization is as follows:

Acoustic Signal 36 Normalized Signal -T _.__ __..____.__.

- WO 98/38904 , PCT/GB98/00702 1 Scaling Factor *Optical Signal +
2 Offset 4 Other normalization methods can also apply. The time interval between the optical pulse and the detection of 6 the acoustic signal may be used to characterise 7 physical properties such as the velocity of sound in 8 the tissue. In addition, in another embodiment of the 9 device the damping of the acoustic oscillations may be used to monitor the elastic properties of the tissue 11 and, in particular, the compressibility. Both of these 12 aspects may be used in the person to person calibration 13 of the photoacoustic response.

More complex analysis of the received acoustic energy 16 is possible. For example, a time-gating technique may 17 be used to derive measurement at varying depths within 18 the tissue being examined. Alternatively, an array of 19 detectors can be employed to determine the profile of the absorption of the acoustic signal at different 21 depths and locations. This depth profile will change 22 with the absorption coefficient and could be used as 23 additional information to determine the analyte 24 concentration. It is also possible to derive information relating to a number of analytes of 26 interest by more sophisticated analysis of the received 27 acoustic energy wave forms, for example by analysis of 28 the frequency spectrum by Fourier transform or wavelet 29 analysis techniques.
31 Alternatively, or in combination with the frequency 32 techniques and multiple detectors, multiple light 33 sources can aid in the determination of the 34 concentration of a number of analytes.
36 There are a number of tissue features which may vary 1 from person to person or with in the same person over 2 time which impact the photoacoustic signal observed.
3 To obtain an accurate measurement of a given analyte, 4 such as glucose, it may be helpful to also determine the concentration of other analytes such as haemoglobin 6 which may act as interferants. One approach is to y 7 generate several distinct photoacoustic signals using 8 excitation light of several different wavelengths. For 9 example, excitation light of a wavelength of which haemoglobin absorbs strongly but glucose has little if 11 any absorption could be sued to obtain a measure of the 12 haemoglobin concentration with which to normalize the 13 effect of haemoglobin on measurements made on different 14 persons or on the same person at different times.
These measurements which are to be normalized might be 16 based on the photoacoustic signal generated by light of 17 a wavelength at which glucose absorbs.

19 It is also possible to measure the concentration of such interferants by other means, such as infrared 21 light absorption, and thus normalize or correct the 22 photoacoustic signal representative of the desired 23 analyte for variations in these interferants. Thus, 24 for example, the photoacoustic signal representative of glucose could be corrected for variations in 26 haemoglobin concentration determined by optical 27 absorption techniques such as those taught in US Patent 28 No 5,702,284.

For the reliable and reproducible determination of 31 glucose a signal to noise ratio of at least 10,000 is 32 recommended. In this regard water is typically present 33 in human tissue of a concentration of about 50 molar 34 while glucose is present at a concentration of about 5 millimolar in a normal individual.

r _ ____ z 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, the 4 clinical range of glucose concentration is 5 approximately 5-10 m mol/1 in healthy subjects, and up 6 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 little 9 as 0.2~. The present invention has been found to 10 provide a change in photoacoustic signal of up to 140 11 for a change in glucose concentration of 15m mol/1.

13 The precise mechanisms involved are not at present 14 fully understood. It is believed, however, that 15 absorption occurs primarily in body plasma and is 16 modified by the presence of glucose, and that this 17 affects beam geometry.

19 Example 21 The blood glucose levels of three individuals, one 22 normal individual, one type 1 diabetic and one type 2 23 diabetic, were followed over a two hour period 24 following each individual taking about 75 grams of glucose orally in an aqueous solution by both 26 photoacoustics and direct blood measurement. The 27 results are reported in Figures 17, 18 and 19.
28 Photoacoustic measurements were made every five minutes 29 and blood measurements were made very ten minutes. The blood samples were venous blood samples analysed by the 31 standard glucose oxidase method using a Yellow Springs 32 instrument. The error bands for the blood measurements 33 were derived from the literature accompanying the 34 testing instrument while those for the photoacoustic results were based on the averages taken over 1000 36 pulses. The results were obtained from a configuration _ WO 98/38904 PCT/GB98100702 13 wavelength Average pulse Pulse width Approximate in nm in ns 14 energy in bandwidth in nm microJoules 17 1064 2.7 600 4 18 1120 2.25 500 6 1176 2.0 450 8 21 1240 1.5 425 12 2 1308 0.85 400 15 1390 0.3 350 20 1450 0.1 350 20 2 1500 0.2 350 20 2 1550 0.18 360 20 ~

33 The photoacoustic resulting signal was detected by a 34 5mm disc transducer with a lead backing and fed to an 35 amplifier an oscilloscope.
and The transducer was 36 generally placed as in Figure but was not similar to that illustrated in Figure 1 in which 10 was an end of a 1 km multimvde 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:
__ T

- WO 98/38904, PCT/GB98100702 1 precisely parallel to the beam axis; its detection 2 plane was at an angle of about 20 degrees to the beam 3 axis. The photoacoustic signal was evaluated in terms 4 of the difference in voltage signal from the positive peak of the compression to the negative peak of the 6 relaxation of the acoustic pulse.
d 8 The change in photoacoustic response correlated well 9 with the change in blood glucose concentration over the two hour measurement period. A correlation of 0.89 was 11 achieved on samples ranging from 4 to 35 m mol/1.

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

Claims (61)

1. 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 from 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.

2. A sensor head according to claim 1, in which the acoustic transducer means is arranged at least partially perpendicular to the optical beam axis.

3. A sensor head according to claim 2, for use where the selected body part is the distal portion of a finger, in which the housing includes a generally half-cylindrical depression in which the finger may be placed with the light transmission means aimed at the end of the finger.

4. A sensor head according to any preceding claim, in which the acoustic transducer means comprises a piezoelectric transducer which is of a semi-cylindrical shape.

5. A sensor head according to any preceding claim, in which the acoustic transducer means comprises a piezoelectric transducer which is provided with a backing of lead or other dense material.

6. A sensor head according to claim 5, in which said backing has a rear surface shaped to minimise internal acoustic reflection.

7. A sensor head according to any of claims 1 to 4, in which the transducer means comprises a capacitor-type detector.

8. A sensor head according to any of claims 1 to 4, in which the transducer means comprises a piezoelectric transducer arranged generally perpendicular to the optical axis to detect the acoustic wave which is propagating in a direction opposite to the direction of propagation of the light beam.

9. A sensor head according to claim 8, in which the transducer is part-spherical with an aperture to allow access for the light beam.

10. A sensor head according to any preceding claim, including a surface wave detector for characterizing tissue properties.

11. A sensor head according to any preceding claim, including means for ensuring a consistent contact pressure between a selected body part and the acoustic transducer means.

12. A sensor head according to claim 11, for use where the selected part is the distal portion of a finger, said means being provided by mounting a 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 a predetermined force or pressure is applied by the subject against the resilient bias.

13. A sensor head according to claim 11, for use where the selected part is the earlobe, said means being provided by two plates, between which the earlobe may be placed, and means for pressing the plates together to apply pressure to the ear.

14. 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; light transmission means terminating in or near said removable insert so as to transmit light energy from a light source 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, the acoustic transducer means being disposed in the housing or insert to receive said acoustic waves in a direction of high acoustic energy.

15. An in vivo measuring system comprising in combination: a sensor head as claimed in any preceding claim; 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.

16. The system of claim 15, in which the light transmission means is a fiber optic distribution system.

17. The system of claim 16, in which there is a plurality of light sources each connected to an individual fiber and the respective fibers are joined by a wavelength division multiplexer or a fiber coupler.

18. The system of claim 16 or claim 17, in which the fiber optic distribution system terminates in contact with the body part.

19. The system of claim 16 or claim 17, in which the fiber optic distribution system communicates with the body part via optical elements such as lenses and beamsplitters.

20. The system of claim 15, in which the light transmission means comprises optical elements mounted in mechanical holders and arranged to convey the light from the light source to a location in proximity to the body part.

21. The system of claim 19 or claim 20, in which the light transmission means includes at least one beamsplitter arranged in the light path to direct a portion of the light to a respective reference detector to measure the energy of the light entering the body part.

22. The system of any of claims 15 to 21, in which the signal processing means is adapted to perform a multi-dimensional processing method.

23. The system of claim 22, in which the signal processing means is adapted to perform one of Classical Least Squares or Partial Least Squares.

24. The system of any of claims 15 to 21, in which the signal processing means comprises a Neural Network.

25. The system of any of claims 15 to 24, in which the signal processing means is operable to analyse the signals for their frequency content using one of Fourier Analysis and Frequency Filtering.

26. The system of any of claims 15 to 25, in which the signal processing means additionally applies techniques that use time information.

27. The system of claim 26, in which the time information processed is the time delay from source trigger.

28. The system of any of claims 15 to 25, in which the signal processing means additionally applies techniques that combine both frequency and time information.

29 The system of claim 28, in which the signal processing means performs wavelet analysis.

30. The system of any of claims 15 to 29, in which the light source is a laser light source.

31. The system of claim 30, in which said laser light source is selected from a pulsed diode laser, a set of pulsed diode lasers, and a tunable laser source.

32. The system of claim 31, for use in measuring blood glucose concentration, in which the light source is a laser diode with a wavelength in the range of approximately 600 nm to 10,000 nm and a pulse duration of the order of 5 to 500 ns.

33 The system of any of claims 30 to 32, in which the light transmission means is arranged to produce a spot size of the order of 0.05 mm to 0.50 mm.

34. The system of any of claims 15 to 29, in which there are multiple light sources and means are provided for time multiplexing the multiple sources such that: each source is switched on and generates an optical pulse, or a set of optical pulses, the pulse, or set of pulses, generates an acoustic signal that is detected by the detector, and each source is pulsed in sequence until all sources have been used to generate their own signals.

35. The measuring system of any of claims 15 to 34, 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.

36. The system of claim 35, including 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.

37. The system of any of claims 15 to 36, further including means for manipulating the body part under measurement and for performing additional measurement of the tissue to obtain other information about the state of the physiology of the issue.

38. The system of claim 37, in which said manipulating means includes means for squeezing a body part, such as an earlobe, and means for making photo acoustic measurements at several different pressures.

39. The system of claim 37 or claim 36, including temperature measurement means for measuring the temperature of the body site, and in which the signal processing means is arranged to apply a correction to the measurements based upon the temperature of the body site.

40. The system of claim 39, further including means for inducing temperatures above and below ambient in the body part.

41. The system of any of claims 15 to 40, comprising a means for storing one or both of calibration coefficients and operational parameters in order to calibrate the instrument and to set critical operational parameters.

42. The system of claim 41, in which the signal processing means is operable to adjust the calibration coefficients and operational parameters to be specific to a particular person.

43. The system of claim 42, when dependent upon claim 14, in which the calibration coefficients and operational parameters specific to a particular person are contained in a storage site located in the removable insert.

44. The system of claim 43, in which additionally calibration coefficients and operational parameters specific to the reader system are stored in the non-removable housing.

45. The measuring system of any of claims 15 to 44, further including connection means for connecting the measuring system to an invasive measuring system for the purpose of calibrating or adjusting the operational parameters of the non-invasive measuring system.

46. The system of claim 45, in which the connection means is selected from a cable link, IR link or radio waves.

47. A method of operating a measurement system as claimed in claim 34 to remove instrument drift from the measurement, the method comprising the steps of:
1) placing a calibration 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; and 9) adjusting the measured values using the calculated correction factors.

48. The method of claim 47, in which a further correction factor is calculated for the instrument temperature.

49 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.

50 The method of claim 49, in which the parameter of interest is blood glucose, and the optical energy has a wavelength in the range of approximately 600 mm to 10,000 mm and a pulse duration of the order of 5 to 500 ms.

51 The method of claim 49 or claim 50, in which a train of pulses is applied and the detected signals are averaged to derive said measure.

52 The method of any of claims 49 to 51, in which said measure is derived from the energy of the detected signal.

53 The method of any of claims 49 to 52, in which the optical energy is directed into a body part which is substantially composed of soft tissue and free of bone.

54 Apparatus for measuring a biological parameter in a subject, the apparatus comprising:
means for 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;
transducer means arranged to detect acoustic energy resulting from said photoacoustic reaction by intercepting acoustic energy propagating in a direction other than the forward direction of said beam axis; and means for deriving from said detected acoustic energy a measure of the parameter of interest.

55 Apparatus according to claim 54, in which said ~
directing means incudes means for receiving a selected body part such that the optical energy is directed into a portion of the subject's body which is substantially free of bone.

56 A method of correcting measurement of an analyte based on a photoacoustic signal obtained from a living being comprising determining the concentration of other constituents in the being which have a significant effect on the photoacoustic signal and tend to vary from individual to individual or over time, and adjusting the measurement to remove the effect of variations in the concentrations of said other constituents.

57 The method of claim 56 in which the analyte is glucose.

58 The method of claim 57 in which the concentration of haemoglobin is determined and used to adjust the measurement.

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

39~

60 The method of claim 59 in which the analyte is glucose.

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