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A PO TABLE: NON-INVASIVE BLOOD GLUCOSE MONITOR

John Hannigan, Scott S Freeborn, Peter WH Rae*, Bryan McIver# ,Eion M Johnston+ ,David T Einnie' & Hugh A MacKenzie Physics, Heriot-Watt University, Edinburgh, EH14 4AS, U.K. Biochemistry, The Royal Infirmary of Edinburgh, Edinburgh, U.K. The Royal Infirmary of Edinburgh, Edinburgh, U.K. and Computer Engineering, Napier University, Edinburgh, U.K. visible colour change is observed which may be viewed or, if the strip is placed in a meter, can be read from a digital panel. Within the typical blood glucose range these strips are sufficiently accurate (-+lo%),but they require careful use, take approx. 2 minutes to give a result and cost the diabetic subject around &50 per month [3]. The multiple daily finger stabs required for adequate monitoring are not only painful they also leave a site for possible infection. As a result many subjects apply minimal control, risking periods of hyper- and hypo- glycaemia and consequently increase the risk of microangioplasty. Non-invasive measurement techniques for blood glucose are now being actively pursued. Much of the work in non-invasive monitoring is based around near infra-red spectroscopy. In the wavelength range 750-1700nm there exists an 'optical transmission window' in tissue, originating from the fact that water absorption is at a minimum and absorption from other blood analytes are significant enough to be distinguishable. This technique has been successfully utilised for monitoring cerebral haemodynamics as the spectral features of haemoglobin and oxyhaemoglobin are sufficiently strong and different in appearance [4]. However, the same cannot be said for glucose. Spectral variations are subtle and advanced chemometric calibration techniques have to be applied to provide [51. Specmscopic adequate error values instrumentation based on measurements of light traversing through the finger and from diffuse reflectance measurements on the finger have already hut the marketplace (Diasense 1000, Futrex 500, Glucontrol), but their clinical performance has yet to be fully established. Pulsed laser photoacoustic spectroscopy (PLPAS) has been successfully utilised for the measurement of analytes in low concentrations of liquids and gases [ ] It relies on a more complex 6. mechanism than current near infra-red spectroscopy. Instead of measuring the transmitted or scattered light from the medium, an optically generated acoustic pressure wave is created within the medium and
detected at any other point. A pulse of laser light is fiied

s is an important ect. This presently le finger stabs and

tic and normal subjects, monitor changes in blood e physiological range. In

Around 5% of the

tion are estimated to have

Normal levels of blood

measurements of

ioplasty it increased the episodes. Frequent e level are therefore

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into the medium, the consequent temperature increase causes localised heating and thermal expansion, resulting in the generation of an acoustic pressure wave. The magnitude of the PLPA pressure, lPl, has previously been shown to have the form [7]: IPI = ( E P.\lV)lCP where E is the laser pulse energy, a is the optical absorption coefficient, p is the thermal expansion coefficient,v is the velocity of sound in the medium and Cp is the specific heat. From this, photoacoustic spectra can be generated. Most spectra will have the same form as its absorption spectra, but the relative strength will be dependent on the combination of the physical parameters. For glucose the specific heat decreases whilst the acoustic velocity increases with concentration, providing a favourable spectral response [8]. In contrast water has a relatively high specific heat and consequently the spectra is small in magnitude. This suggests glucose, and other analytes in low concentrations, may be detected in tissue. We have previously demonstrated that PLPAS on human blood plasma samples is sensitive to glucose concentration changes within the physiological range [9].

of Lhe detected signal. The entire measurement takes less than 5 seconds to perform. An IBM compatible PC (486DX, 66MHz) is used to control the system. It contains a multi-function I/O card (Amplicon PC30) to allow programming of the lascr firing, RS232 control of the monochromator and a high speed analogue acquisition card (Amplicon PC29) for the photoacoustic and input energy signals. All operational control and signal processing is performed within the PC (Turbo Pascal).

PRELIMINARY IN VIVO RESULTS

Standard oral glucose tolerance tests were performed on ninc volunteers, 4 normal subjects, 3 Type I1 and 2 Type I subjects. This test requires the individual to fast overnight and then consume 75g of D-glucose after the first measurement of blood glucose has been recorded. In this case a photoacoustic measurement was taken, using the right index finger, every five minutes. In addition a standard venous blood sample was drawn off every ten minutes for later sampling in the hospital laboratory. The photoacoustic measurements were made using the laboratory set-up. Laser pulse energies of -50 pJ were fired in and signals averaged over 1024 simultaneous measurements. Each complete photoacoustic trace took 5 seconds to acquire and the amplitude of the pressure waveform recorded in volts. Figure 1 shows typical results for (a) a normal subject and (b) a type I diabetic subject. In case (b) a small glucose dose (30g) was initially given, followed by two insulin doses at 35 and 150 minutes. In both cases the photoacoustic results have been overlayed on the clinical (hospital test) results i.e. no fitting algorithm was applied. A correlation plot was graphed, figure 2, at all points were a clinical and photoacoustic result were measured together using the data of all nine volunteers. As the voltage range of the photoacoustic response varied between individuals an equivalent blood glucose concentration (EBGC) was derived by taking the corresponding true blood glucose concentration representative of the voltage obtained for the individual during the measurement. This plot shows an overall correlation of 0.967 [lll.

INSTRUMENTATION
The instrumentation used [lo] was originally placed on a laboratory bench were the multi-wavelength source was a Q-switched Nd:YAG laser (Spectron, model SLSOQ) coupled into a doped Raman fibre (STC CA1618/392F) and passed through a monochromator (SPEX MINIMATE). For a portable unit the source was two laser diodes (EG&G) and the instrumentation was packaged in a 19 rack. The remaining instrumentation described is identical to both system. A small portion (approx. 4%) of the input energy is separated and measurcd on a pyroelectric detector (Mullard A869 1503) to provide a monitor for input pulse energy. The remaining light is coupled into a 400pm fibre and brought to the perspex sampling head, 25x35~90 in size. Micro-.optics focus the beam into the finger, while an orthogonally placed piezoelectric element OYZ;T-SA) is used to detect the photoacoustic pulse generated. A metal clip is used to hold the finger in place and reduce movement artifacts. The detected signal is amplified at a value preset by the operator to ensure maximum range is applied to the ADC input (Amplicon PC29) in order to maintain eight bit accuracy in digitisation. For each laser pulse the generated photoacoustic trace is recorded and, typically, 1024 traces are averaged for a single measurement. This averaging is necessary due to the random noise present on each photoacoustic trace. The averaged photoacoustic trace is displayed along with values of the input energy and the normalised amplitude

LASER DIODE BASED RESULTS

In order to make the blood glucose measurement system portable, the laser source, raman fibre and monochromator must be replaced with one or more laser diodes. As a preliminary investigation a laser diode (STC) at 904nm was selected with a pulse energy

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3.6 1 3.5

ff,f
20
40

60

80

100

3.1 120

3.4

3.3

3.2

I I

I
I

I 0.09
200

50

100

150

TIME (minutes)
Figure I . Oral Glucc e Tolerance Test performed on a (a) normal and (b)diabetic (Type I ) subject. The filled circles ( ) represent the p >toacoustic response and the results of a standard hospital glucose test performed on venous s blood samples and SI Iwn by crosses (x).

40

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I I
I 1

1.35

13 .

1P
0

0.95

L-H-4
0
10
20

30 rRUE BGC (mmoVL)

1
20

40

30

40

50

GLUCOSE CONCENTRATION (mmoUL)

Figure 2. Correl 'ion plot between photoacoustic response (EBGC) a, I the blood glucose concentration measured from the 3spital rest3 on the venous blood samples (TRUEBG( . The correlntion is 0.967.

Figure 3. Glucose concentration dependence of phoioacoustic signal over the physiological range (0SOrwmollL). The data has been normalised to the photoacoustic signal of water and a bestfit straight line attached.

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CONCLUSIONS
We have demonstrated that pulsed laser photoacoustic spectroscopy is a viable technique for the in vivo monitoring of blood glucose. Using a laboratory based instrument, oral glucose tolerance tests have been performed on a range of subjects demonstrating the techniques ability to monitor changes in blood glucose levels across the entire physiological range. These results show a correlation to the standard hospital blood test procedure for glucose measurement of 0.967. Further, we have demonstrated that low power laser diodes can yield both a photoacoustic response through tissue in vivo and operate at suitable wavelengths were a variation in PA signal with glucose concentration is distinguishable. Oral glucose tolerance tests are now being performed using the portable system in order to determine its performance in comparison to the laboratory based system.

Figure 4. Photoacoustic response j?om a finger. The time base was set at 2p sldiv and the photoacoustic waveform occured 5p s after the laser pulse was fired.

of 2yJ and duration of 20011s. Laser pulses at a rep. rate of 200Hz were continuously fired through focusing the optics, producing a 230ym spot size 5mm into the sample. The piezoelectric dctector was placed orthogonally to the optics at an identical distance from the interaction point. Suitable amplification was applied to the detected signal and simple averaging (256 or 2048) performed on an oscilloscopc. An initial investigation was performed to determine if glucose could be detected within the pathological range at this wavelength and power. A lOmm diameter cylindrical glass cuvette was placed into the photoacoustic interaction region. Solutions of Dglucose in water at room temperature where measured across the range 0-SOmmolL at 10mmolL intervals. In each case the signal recorded was the pk-pk of the photoacoustic waveform after 2048 averages (HP 54504A). Fifty consecutive measurements were recorded for each concentration Figure 3 shows the mean and standard deviation for each result obtained. The general trend of the graph suggests a linear relationship exists between the PA signal and the glucose concentration (y = 0.0053~ 1.0129, r2 = 0.9215). Previous results have + shown that for greater glucose concentrations, the relationship is linear [12]. In vivo determination of blood glucose is only possible if a photoacoustic response is detectable from skin. As a result of the low energy output obtainable from the laser diode, 21.1J cf. 50pJ from the Nd:YAG laser, an experiment was conducled to determine if a response could be seen. Using the set-up described above, the finger of a normal subject was placed between the laser diode and piezoelectric detector in place of the cuvette. The photoacoustic response
obtained over 256 sample%(Tektronix 2430A), is shown

ACKNOWLEDGEMENTS
This work is primarily funded through a grant from the British Diabetic Association. Further assistance has been obtained from The Paul Instrument Fund and Shell Expro Ltd.

REFERENCES
[ I ] National Centre for Health Statistics (1993). [2] The Diabetes Control and Complications Trial

Research Group. N. Engl. J. Med. 329 (1993) 977-986. [3] Burritt, MF; Hanson, E; Munene, NE; and Zimmerman, BR. Postgraduate Medicine. 89 (1991) 7584. [4] Wyatt, JS: Cope, M, Delpy, DT; Edwards, AD: Wray, SC; and Reynolds, EOR. Lancet ii. (1986) 10631066. [51 Heise, HM,Marbach, R Janatsch, G; and KruseJarres, JD. Anal. Chem. 61 (1989) 2009-2015. [61 Tam, AC. Rev. Mod. Phys. 58 (1986) 381-431. [7] Lai, HM;and Young, K. J. Acoust. Soc. Am. 72 (1982) 2000-2007. [81 Christison, GB. PhD Thesis. (1992) Heriot-Watt University, Edinburgh. 191 Christison,GB; and MacKenzie, HA. Med. Biol.
Eng. Comput. 31 (1993) 284-290. [lo] Greig, F; Johnston, EM; Binnie, TD; and

in Figure 4. The initial ringing is a result of 'pick-up' from the laser diode power supplies. A strong photoacoustic response is seen and if we consider that this is representative of a normal subject with a glucose level of 3-8mmol/L, then the system should be capable of monitoring glucose changes on both normal and diabetic subjects.

MacKenzie, HA. IEEE Conf. Ultrasonics (Cannes, Nov 2-4 1994). [ 111 MacKenzie, HA; Rae, PWH; Duncan, A; McIver B; Quan, KM; and Freeborn, SS. submitted to BMJ. [121 Quan, KM; Christison, GB; MacKenzie, HA; and Hodgson, P. Phys. Med. Biol. 38 (1993) 1911-1922.

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