Photoacoustic measurement

Abstract

A method of photoacoustic measurement is provided. The method comprises generating a series of pulses of electromagnetic radiation, each pulse having a predetermined wavelength, and the series of pulses being transmitted into a target. The series of pulses are timed such that a first transition between a first pair of pulses generates a first differential acoustic signal from the target; and a second transition between a second pair of pulses generates a second differential acoustic signal from the target. The predetermined wavelength of at least one pulse of the second pair of pulses is different to the predetermined wavelengths of the first pair of pulses. The method further comprises measuring the first and second differential acoustic signal. A photoacoustic measurement system is also provided.

Description

[0001] PHOTO ACOUSTIC MEASUREMENT

[0002] Technical Field

[0003] The present invention relates to a method of photoacoustic measurement, and a system for performing such a method.

[0004]

[0005] Photo-acoustics, also known as opto-acoustics or thermo-acoustics, is a technique which can be used to visualise and study subjects such as biological tissues and materials. A sample is irradiated with short pulses of probe light. Constituent parts of the sample absorb the probe light pulses, undergoing thermal expansion to generate propagating photoacoustic waves. Measurement of these photoacoustic waves, referred to herein as acoustic signals, using acoustic sensors can reveal information about the sample, such as the properties of light-absorbing components within the sample and / or their locations within the sample.

[0006] A challenge of photoacoustic imaging and spectroscopy is that components of a sample which are not of particular interest, such as e.g. water, may still absorb probe light and produce unwanted photoacoustic waves, generating noise in the photoacoustic measurement system. The components of interest therefore may exhibit weak contrast with respect to the background noise, if being detectable at all.

[0007] In view of the above, it is desirable to improve photoacoustic measurement methods and systems.

[0008] Summary

[0009] It is an object of the present disclosure to provide a method photoacoustic measurement which can generate high signal-to-noise ratio signals in noisy environments.

[0010] According to a first aspect, there is provided a method of photoacoustic measurement. The method comprises generating a series of pulses of electromagnetic radiation, each pulse having a predetermined wavelength, the series of pulses being transmitted into a target. The series of pulses are timed such that: a first transition between a first pair of pulses generates a first differential acoustic signal from the target; and a second transition between a second pair of pulses generates a second differential acoustic signal from the target. The predetermined wavelength of at least one pulse of the second pair of pulses is different to the predetermined wavelengths of the first pair of pulses. The method further comprises measuring the first and second differential acoustic signal.

[0011] According to a second aspect, there is provided a system for photoacoustic measurement. The system comprises an emission system configured to generate a series of pulses of electromagnetic radiation for transmission into a target, with each pulse having a predetermined wavelength. The emission system comprises at least one source of the electromagnetic radiation, and a controller for determining the series of pulses of electromagnetic radiation from the at least one source. The controller determines the series of pulses of electromagnetic radiation such that: a first transition between a first pair of pulses generates a first differential acoustic signal from the target; a second transition between a second pair of pulses generates a second differential acoustic signal from the target; and the predetermined wavelength of at least one pulse of the second pair of pulses is different to the predetermined wavelengths of the first pair of pulses. The system for photoacoustic measurement further comprises an acoustic measurement system configured to detect a first differential acoustic signal and a second differential acoustic signal originating from the target.

[0012] According to a third aspect, there is provided a wearable device. The wearable device comprises the system of the second aspect, and an analyser configured to determine a presence or absence of a component in the target based on the first and second differential acoustic signals detected by the acoustic measurement system. The wearable device is operable to determine, as a component, the presence and / or amount of a biomarker in the target.

[0013] By selecting at least one wavelength for the second pulse pair which is not used in the first pulse pair, the first differential acoustic signal corresponds to a first property of the target whereas the second differential acoustic signal corresponds to a second, different property of the target. For example, the first differential acoustic signal corresponds to the difference in a wavelength-dependent absorption parameter of at least one component of the target between (i) a first wavelength and (ii) a second wavelength, whereas the second differential acoustic signal may correspond to the difference in the wavelength-dependent absorption parameter of at least one component of the target between (iii) the first or second wavelength and (iv) a third wavelength, or between (v) a third wavelength and (vi) a fourth wavelength. The first and second differential acoustic signal in combination can facilitate measurement of a presence or an amount of a particular component which may not be detectable from just the first or second differential acoustic signal alone. This can allow components in the target to be detected, even in the presence of background photoacoustic noise at any particular wavelength of the transmitted electromagnetic radiation.

[0014] Furthermore, due to the use of differential acoustic signals, which typically have lower amplitude than other photoacoustic signals, more sensitive sensors can be used with reduced risk of saturation. This can enhance accuracy of the measurement.

[0015] In some examples, the first differential acoustic signal has a first set of characteristics, and the second differential acoustic signal has a second set of characteristics different from the first set of characteristics, the characteristics including amplitude, polarity, magnitude, duration, bandwidth, and / or frequency. Characteristics of the differential acoustic signals may be used to determine properties of a component in the target and / or the presence or amount of a component in the target. Characteristics between differential acoustic signals may be compared against each other or against threshold values, for example, to help determine properties of a component in the target and / or the presence or amount of a component in the target.

[0016] In some examples, a predetermined wavelength of the first pair of pulses is the same as a predetermined wavelength of the second pair of pulses, a second pulse of the first pair of pulses being a first pulse of the second pair of pulses. In other words, the first pair of pulses is formed of a first pulse and a second pulse, and the second pair of pulses is formed of the second pulse (which is thus a first pulse of the second pair of pulses) and a third pulse (which is thus a second pulse of the second pair of pulses). This can generate two differential acoustic signals with three transmitted pulses. In some other examples, a predetermined wavelength of the first pair of pulses is the same as a predetermined wavelength of the second pair of pulses, but the first and second pair of pulses do not share a common pulse.

[0017] In some examples, the predetermined wavelengths of the first pair of pulses are different to the predetermined wavelengths of the second pair of pulses. That is, the first pair of pulses is formed of a first pulse at a first wavelength and a second pulse at a second wavelength, and the second pair of pulses is formed of a third pulse at a third wavelength and a fourth pulse at a fourth wavelength.

[0018] In some examples, the first and / or second transition comprises, respectively, a first pulse of the pair temporally overlapping a subsequent, second pulse of the pair.

[0019] In some examples, the first and / or second transition comprises, respectively, a trailing edge of the first pulse of the pair temporally overlapping a rising edge of the subsequent, second pulse of the pair.

[0020] In some examples, the first and / or second transition comprises a trailing edge of a respective first pulse of the pair temporally separated from a rising edge of a subsequent, second pulse of the pair.

[0021] In some examples, respective durations of each pulse are between 100 ns and 30 ps. Pulse durations in this range can facilitate effective separation of differential signals from between 150 micrometres deep to 4.5 centimetres deep, for example.

[0022] In some examples, the method further comprises determining a presence or absence of a component of the target based on the first and second differential acoustic signals. The method may comprise determining a binary indicator of whether a component is present in the target, for example. The method may comprise determining a continuous metric related to an amount of the component in the target without being linked to a specific quantity such as volume, weight, and / or concentration, for example.

[0023] In some examples, determining a presence or absence of a component of the target comprises determining an amount of the component of the target such as a quantity, or discrete number of, a concentration, a mass, or a volume. The method may comprise determining a presence of a component in the target based on a measured value being above or below a threshold value, for example.

[0024] In some examples, the target comprises biomarkers. That is, the component detected by the method may be a biomarker. The biomarker may be bilirubin, creatine, glucose, a ketone, or a lactate, for example. The target may be biological tissue.

[0025] In some examples, the method comprises determining a presence, absence or amount of a further component in the target based on at least some of the measured differential acoustic signals. That is, the method comprises generating a further pair of pulses, each having a predetermined wavelength, a wavelength of the further pair of pulses being different to wavelengths of the first and second pairs of pulses to generate a third differential acoustic signal from the target, and measuring the third differential acoustic signal, and determining a presence, absence, or amount of (i) a component in the target based on at least some of the measured differential acoustic signals and (ii) a further component based on at least some other of the measured differential acoustic signals.

[0026] In some examples, the acoustic measurement system comprises an acoustic imaging system. An acoustic imaging system can identify a spatial information regarding a component, such as its position, based on received acoustic signals, including differential acoustic signals.

[0027] In some examples, the acoustic measurement system comprises an acoustic spectroscopy system. An acoustic spectroscopy system can identify properties of a components based on received acoustic signals, including differential acoustic signals.

[0028] In some examples, the system further comprises an analyser configured to determine a presence or absence of a component in the target based on the first and second differential acoustic signals detected by the acoustic measurement.

[0029] Brief Description of the Drawings

[0030] The above, as well as additional objects, features, and advantages, may be better understood through the following illustrative and non-limiting detailed description, with reference to the appended drawings. In the drawings, like reference numerals will be used for like elements unless stated otherwise.

[0031] Figure 1 shows a photoacoustic measurement system according to an example. Figures 2-5 show series of pulses according to respective examples.

[0032] Figures 6a, 6b show a pair of pulses according to respective examples.

[0033] Figure 7 shows a differential unmixer according to an example.

[0034] Figure 8 shows a photoacoustic measurement method according to an example. Figure 9 shows a photoacoustic measurement method according to a further example.

[0035] Figures 10 and 11 shows photoacoustic measurement systems according to respective further examples. Figure 12 shows a wearable device comprising a photoacoustic measurement system according to an example.

[0036] Detailed

[0037]

[0038] A photoacoustic measurement system 100 according to the present disclosure is illustrated, schematically, by Figure 1. The acoustic measurement system 100 is used to perform a method 800 of photoacoustic measurement according to the present disclosure. Figure 1 depicts a general arrangement of the photoacoustic measurement system 100, and further specific examples of photoacoustic measurement systems 100-1, 100-2 are depicted in Figures 10 and 11 and described later. The systems and methods described herein are applicable across numerous use cases. In particular, the method and system described herein can be used to determine the existence of biomarkers within biological tissue, but it will be appreciated that the system and method of the present disclosure are not limited to that particular use, and can be used to detect non-biological components in non-biological settings.

[0039] The photoacoustic measurement system 100 comprises an emission system 110 and an acoustic measurement system 120. The emission system 110 is configured to generate a series of pulses 105 of electromagnetic radiation into a target 130. These pulses generate differential acoustic signals 115 within the target 130. A differential acoustic signal 115 is a signal which arises from a transition between pulses 105 of different wavelengths due to a difference in an optical absorption parameter at the respective wavelengths; differential acoustic signals 115 are described in further detail in view of Figure 2, later. The acoustic measurement system 120 is configured to detect these differential acoustic signals 115. In particular, the series of pulses 105 may be absorbed by components 135 of the target 130. Detecting the resulting differential acoustic signals 115 can reveal a presence or amount of a particular component 135, or particular components 135, within the target 130.

[0040] The emission system 110 comprises one or more optical sources 112. The optical sources 112, collectively, are operable to produce three or more different wavelengths of pulsed light. The optical sources 112 are typically lasers sources, since lasers can produce bright, or high-power, pulsed light at a given wavelength (e.g. a pulse with a spectral bandwidth centered on a given wavelength). The optical sources 112 typically comprise three or more fixed wavelength sources, described in more detail in connection with Figure 10, or two or more variable wavelength sources, described later in connection with Figure 11. However, the skilled person will appreciate that a single variable wavelength source may be used, if operable to produce the three or more different wavelengths of pulsed light, such that a suitable series of pulses 105 can be generated.

[0041] The emission system 110 comprises a differential pulse generator 114. The differential pulse generator 114 generally represents processing capabilities for control of the optical sources 112, including determining the order and timing of pulses from the optical sources 112 to form the series of pulses 105. The differential pulse generator 114 may also output wavelength control information which determines a wavelength produced by an optical source, for example. In examples, the differential pulse generator 114 may be a single processor or distributed across multiple processors.

[0042] The acoustic measurement system 120 comprises acoustic sensors 122. The acoustic sensors 122 are configured to detect the differential acoustic signals 115 originating from the target 130. In the example of Figure 1, the acoustic sensors 122 comprise an ultrasound transducer array.

[0043] The acoustic measurement system 120 comprises an analyser 124. Measurements of the differential acoustic signals 115 by the acoustic sensors 122 are provided to the analyser 124. The analyser 124, based on the differential acoustic signals 115, determines a presence or absence of a component 135 in the target 130. The acoustic measurement system 120 may be configured as a spectroscopy system, wherein wavelength-dependent properties of a component can be measured. The acoustic measurement system 120 may alternatively or additionally be configured as an acoustic imaging system, in which position-information of a component can be measured, to e.g. determine the location of a component in a target.

[0044] Turning now to consider the series of pulses 105 produced by the emission system 110, Figures 2-6b illustrate various facets of the series of pulses 105 by way of examples which aid explanation.

[0045] Figure 2 illustrates generation of a single differential acoustic signal 101a by a series of pulses 105-1. A first plot represents light produced by the emission system 110, having vertical axis I, indicative of intensity of light produced by the emission system 110, and horizontal axis t, indicative of time.

[0046] The plot illustrates a first pair of pulses 101 consisting of a first pulse Pl at a first wavelength of light and a second pulse P2 at a second wavelength of light λ2, the first wavelength being different to the second wavelength λ2. For clarity, these pulses are offset with respect to the intensity axis I, each going from a respective value of “0” to “1”. The units of the intensity axis I are arbitrary, and the plot should be generally understood to represent when each wavelength of light is “off’ or “on”; each pulse Pl and P2 may deliver different amounts of energy and have different intensity and / or power values, for example. Additionally, for simplicity, pulses herein are depicted as having uniform maximum intensities. The skilled person will appreciate that the teaching herein is not limited to such idealised pulse profiles. In particular, a “maximum” intensity described herein refers more generally to elevated intensity between rising and falling edges of a pulse, rather than e.g. a global maximum value for the pulse intensity.

[0047] The first pulse Pl lasts from a first time

[0048]

[0049] to a second time t2, having an intensity value of zero outside of this time window. The second pulse P2 follows the first pulse Pl, lasting from a third time t3to a fourth time t4, also having an intensity value of zero outside of this time window. In this example, the third time t3is after the second time t2, but as will be explained in view of Figure 6a, the first and second pulses Pl, P2, or pulses in the series of pulses 105 more generally, may overlap such that e.g. the second time t2is after the third time t3. A transition 101t represents a time window encompassing the first pulse Pl ending and the second pulse P2 starting. A transition between pulses, as described herein, is a period of time corresponding to the ending of a first pulse and the starting of a second pulse. A transition may correspond to the first pulse and the second pulse overlapping in time, or the first pulse and the second pulse being separated in time. A transition may span between the first pulse reducing from a maximum intensity to e.g. zero intensity and then second pulse growing from e.g. zero intensity to a maximum intensity. A transition between pulses can be understood to refer to a timing arrangement of pulses which produces a measurable differential acoustic signal, for example. A second plot represent temperature of a component 135 within the target. The component 135 absorbs energy from the series of pulses 105 based on an optical absorption parameter a, which in general is wavelength-dependent. Light is absorbed more or less strongly depending on its wavelength. At the first time t1, the first pulse Pl is turned on and the component 135 absorbs the first pulse Pl. The temperature of the component 135 increases by an amount AT as energy is delivered by the first pulse Pl to the component 135. The component 135 absorbs the first pulse Pl according to the value of the optical absorption parameter a (A) of the component 135 at the first wavelength and so the temperature increase AT of the component 135 is determined at least partly by the first wavelength of the first pulse Pl.

[0050] In the transition 101t, the first pulse Pl ends and the second pulse P2 starts. Energy is no longer provided to the component 135 from the first pulse Pl. The component 135 absorbs the second pulse P2. Absorption of the second pulse P2 is determined by the value of the optical absorption parameter a (A) at the second wavelength A2of the second pulse P2. The second wavelength A2of the second pulse P2 is selected such that the absorption parameter a(A2) at the second wavelength A2is different than the absorption parameter α(λ1) at the first wavelength

[0051] Accordingly, the component 135 receives different amounts of energy from the first pulse Pl compared to the second pulse P2. In this example, the component 135 absorbs the second pulse P2 more weakly than the first pulse Pl, and so less energy is delivered to the component 135. Accordingly, the temperature of the component 135 drops by an amount AT,, which results from the transition between the first pulse Pl and the second pulse P2. Finally, when the second pulse P2 ends at the fourth time t4, the component 135 ceases absorbing any light and its temperature drops back to some lower “ground state” value, which is a temperature absent illumination by the series of pulses 105.

[0052] A third plot represents acoustic signals 115 generated by the component 135 within the target 130. These acoustic signals are measured by the acoustic measurement system 120.

[0053] The increase in temperature AT of the component 135 caused by absorption of the first pulse Pl produces a first acoustic pressure wave 400. However, other components of the target 130 may absorb the first pulse Pl, each of which undergo a respective temperature change and produce a respective acoustic pressure wave. Accordingly, the first acoustic pressure wave 400 can generally comprise contributions from more than one component within the target: from a component of interest (a target component), and from other components within the target. This can make the first acoustic pressure wave 400 non-specific, and it may be hard to determine the existence of any particular component from the detection of the first acoustic pressure wave 400 alone.

[0054] When the pulse transition lOlt between the first pulse Pl and the second pulse P2 occurs, and a temperature change AT, of the component 135 is brought about, a second acoustic pressure wave 101a is produced. This second acoustic pressure wave 101a is based on the difference a ( ) in the optical absorption parameter a( ) at the first wavelength of the first pulse Pl, and at the second wavelength A2of the second pulse P2, as described previously. The second acoustic pressure wave 101a is accordingly a first differential acoustic signal 101a.

[0055] This difference in the optical absorption parameter a( ) at the first and second wavelength is typically specific to the component of interest 135, since each component (e.g. biomarker, molecules, material) generally exhibits a unique optical absorption spectra. In particular, if respective absorption parameters a( ) for other components within the target are relatively similar, or the same, at the first wavelength of the first pulse Pl and at the second wavelength A2of the second pulse P2, then a relatively small temperature change, or no temperature change, will occur for these other components. This will result in them producing no differential acoustic signals (where no temperature change of the other components occurs) or relatively small differential acoustic signals (where only a relatively small temperature change of these other components occurs). In contrast, if a relatively large temperature change occurs for the target component 135, then the differential acoustic signal 101a can be attributed to a presence of the target component 135 with more certainty compared with the first acoustic signal 400, which has originated from multiple components within the target 130. Accordingly, the differential signal 101a can indicate the presence or amount of a target component 135 even in complex environments which may contain other components. The wavelengths of the series of pulses 105, and in particular of the pairs of pulse forming the series of pulses 105, are selected, based on the absorption spectra of the components in the target 130, to bring about this effect.

[0056] A first differential acoustic signal 101a generated by a first pair of pulses 101 has been explained in view of Figure 2. Figures 3 and 4 show how this approach is extended to introduce a second pair of pulses 102-1, 102-2. Figures 3 and 4 comprise plots displaying the same relationships as Figure 2, namely a first plot with intensity information for the series of pulses 105, a second plot with temperature of a component within the target 135, and a third plot of acoustic signals 115 measured from the target. For clarity, some labels present in Figure 2 are removed from Figures 3 and 4, but the description of Figure 2 still applies to Figures 3 and 4 where appropriate, i.e. unless specified otherwise.

[0057] Figure 3 illustrates a first example of how a series of pulses 105-2 comprising a second pair of pulses 102-1 can be generated by the emission system 110. As per Figure 2, a second pulse P2 ends at a fourth time t4. A third pulse P3 at a third wavelength3is produced by the emission system 110, starting at a fifth time t5which, in this example, follows the fourth time t4, and ending at a sixth time t6. The third wavelength A3is different to either of the first wavelength

[0058]

[0059] or the second wavelength 12. The second pulse P2 and the third pulse P3 form the second pair of pulses 102-1. A second transition 102t represents a time window encompassing the second pulse P2 ending and the third pulse P3 starting.

[0060] In accordance with the discussion in view of Figure 2, the transition 102t between the second pulse P2 and the third pulse P3 brings about a temperature change in the component 135. This originates from the absorption parameter a(A) of the component 135 having a value a(2) at the second wavelength A2different to a value a(3) at the third wavelength 13. The temperature change of the component 135 due to the transition between the second pulse P2 and the third pulse P3 of the second pair of pulses 102-1 produces a second differential acoustic signal 102a.

[0061] The first differential acoustic signal 101a may be different to the second differential acoustic signal 102a. For example, the first differential acoustic signal 101a may have a different characteristic, or set of characteristics, to the second differential acoustic signal 102a. The first differential acoustic signal 101a may have one or more of a different amplitude, polarity, magnitude, duration, bandwidth and / or frequency to the second differential acoustic signal 102a. The first differential acoustic signal 101a may also have entirely comparable characteristics to the second differential acoustic signal 102a, but, nevertheless, since each differential acoustic signal 101a, 102a results from a different pulse pair, they are still usable to determine useful information regarding components in the target.

[0062] In this example, therefore, the second pair of pulses 102-1 and the first pair of pulses 101 share the second pulse P2 in common. In the example of Figure 4, a series of pulses 105-3 comprises a second pair of pulses 102-2 which does not share a pulse with the first pair of pulses 101.

[0063] A third pulse P3-2 at a third wavelength3is generated by the emission system 110. The third pulse P3-2 starts at a seventh time t7and ends at an eight time t8. The seventh time t7is at some point after the fourth time t4where the second pulse P2 of the first pair of pulses 101 ends. The second P2 and third pulse P3-2 may be sufficiently spaced that the component 135 returns to some “ground state” temperature, i.e. a temperature absent absorption of pulses in between the fourth time t4and the seventh time t7, i.e. between the second pulse P2 and the third pulse P3-2. A fourth pulse P4 at a fourth wavelength A4starts a ninth time t9and ends at a tenth time t10. The fourth wavelength A4is different to any of the first

[0064]

[0065] second 12,orthird wavelength 13. The third pulse P3-2 and the fourth pulse P4 form a second pair of pulses 102-2. A transition 102t encompasses the end of the third pulse P3-2 and the start of the fourth pulse P4. Again, in accordance with the description of Figures 2 and 3, the transition between the third pulse P3-2 and the fourth pulse P4 generates a second differential signal 102a due to the absorption parameter a( ) having a value a(3) at the third wavelength3different to a value a(4) at the fourth wavelength 14.

[0066] By using two differential acoustic signals 101a, 102a, a component 135 can be more effectively measured in a target 130. A single differential signal based on pulses at a first and second wavelength may be help distinguish a component of interest from one particular background component, for example, but there may be other components which have a similar difference in absorption parameter at these wavelengths. Using two or more differential signals can allow a component of interest to be distinguished from these other components, by utilising differences in the respective absorption parameters at different wavelengths. In one case, two differential acoustic signals can arise from use of three wavelengths, such as that described in Figure 3. In another case, two differential acoustic signals can arise from use of four different wavelengths, such as that described in Figure 4. Additionally, pairs of pulses can share a common pulse, such as described in Figure 3, or not share a common pulse, such as described in Figure 4. The configurations of pulses described in Figures 2, 3, and 4 can be considered building blocks in which more complex sequences of pulse pairs can be formed, utilising (i) different wavelengths and (ii) different combinations of wavelengths, for example.

[0067] Figure 5 illustrates an example of a series of pulses 105-4 which comprises a first pair 101 and second pair 102-1 of pulses in accordance with Figure 3, and additionally a third pair of pulses 103. The first pair of pulses 101 is formed of the first pulse Pl at the first wavelength

[0068]

[0069] and the second pulse P2 at the second wavelength 12. The second pair of pulses 102 is formed of the second pulse P2 and the third pulse P3 at the third wavelength 13. A fourth pulse P4 follows the third pulse P3. The fourth pulse P4 is a pulse at the first wavelength

[0070] The third pair of pulses 103 is formed of the third pulse P3 and the fourth pulse P4. A transition 103t encompasses an end of third pulse P3 and the start of the fourth pulse P4. The transition from the third pulse P3 to the fourth pulse P4 brings about temperature change AT3in the component 135 which in turn produces a third differential acoustic signal 103a, again based on a difference in absorption parameter a (A) having different values at the third and first wavelengths. Accordingly, the series of pulses 105-4 of Figure 5 exploits differences in absorption parameter Aa between the first wavelength and the second wavelength A2to generate a first differential acoustic signal 101a, the second wavelength A2and the third wavelength A3to generate a second differential acoustic signal 102a, and the third wavelength A3and the first wavelength

[0071] to generate a third differential acoustic signal 103 a.

[0072] Figures 6a and 6b illustrate characteristics of the pulses of the series of pulses 105, and in particular illustrate examples of transitions between pulses. Figure 6a illustrates an example pair of pulses 101Z comprising a first pulse PA and a second pulse PB. The plot illustrates intensity, I, on a vertical axis and time, t, on a horizontal axis. The first pulse PA starts at a first time T1 and rises to maximum intensity at a second time T2. This rise in intensity defines a rising edge T1of the first pulse PA. The first pulse PA continues at maximum intensity until a third time T3, where it falls in intensity until a fourth time T4. This fall in intensity defines a falling edge T2of the first pulse PA. In total, the first pulse PA has a duration T3between the first time T1 and the fourth time T4. The second pulse PB starts at a fifth time T5 which is before the fourth time T4. In other words, the second pulse PB is partially overlapped with the first pulse PA, as the second pulse PB starts before the first pulse PA has ended. The second pulse PB grows in intensity until a sixth time T6, defining a rising edge of the second pulse. The second pulse PB lasts until a seventh time T7.

[0073] The first pulse PA overlaps the second pulse PB by an overlap period T4, which is a transition between the pulses PA, PB. The overlap period T4is a period where the target 130 receives both the first pulse PA and the second pulse PB concurrently. In this example, the overlap period T4corresponds to the trailing edge of the first pulse PA overlapping the rising edge of the second pulse PB. In other examples, the overlap period may be arranged to overlap the rising edge of the second pulse PB with the first pulse PA being at maximum intensity (i.e. before the trailing edge of the first pulse PA). The overlap period can be selected based on the characteristics of the component being measured and / or other components in the target, for example.

[0074] Figure 6b illustrates a pair of pulses 101Y formed of a first pulse PA-2 and a second pulse PB-2. The first pulse PA-2 extends to an eighth time T8, and the second pulse PB-2 extends from a ninth time T9, which is after the eighth time T8. The first pulse PA2 therefore does not overlap the second pulse PB-2. Instead, the first pulse PA-2 is separated by the second pulse PB-2 by a separation time T5, which is a transition between the pulses PA-2, PB-2. The separation time can be selected based on the characteristics of the component being measured and / or other components in the target, for example.

[0075] According to the present disclosure, the differential photoacoustic measurement method can utilise pulses having pulse widths in excess of 100 ns, for example, but still relatively sharp rising and falling edges, so that the expansion-induced and contraction- induced photoacoustic signals for a single wavelength laser pulse can be separated in the time domain. The term “relatively sharp” refers to the duration of the rising and falling edges relative to the overall pulse duration. To effectively generate differential photo-acoustic signals by the temporal transition between the two consecutive laser pulses, it can be preferable for the rising time for the first / second pulse, the falling time of the first / second pulse, and the separation or overlap between the two pulses to together satisfy a stress confinement threshold rst.

[0076] In the case of overlapping pulses, such as those depicted in Figure 6a, this relationship is provided by equation (1):

[0077] Ti + T2- T4< Tst= ~ (1)

[0078]

[0079] Vs

[0080] In the case of separated pulses, such as those depicted in Figure 6b, this relationship is provided by equation (2):

[0081] T4+ T2+ T5< Vst= ~ (2)

[0082]

[0083] Vs

[0084] where dcis a desired spatial resolution and vsis the speed of sound, approximately equal to 1540 m / s if waves are propagating in tissue, r, in the above formulas is the rising edge of the second pulse (Figure 6a), T2is the falling edge of the first pulse (Figure 6a), T4is the overlap period (Figure 6a), and T5is the separation time (Figure 6b), as appropriate.

[0085] The duration of the two consecutive pulses themselves are preferably, in examples, longer than the time-of-flight TtOf between a furthest component in the target and the acoustic sensor to effectively separate the differential photoacoustic signal from the direct photoacoustic signals in the time domain, such that:

[0086] z

[0087]

[0088] > Ttof =~s> Tst (2)

[0089] where z is a distance of the furthest component in the target from the acoustic sensor (e.g. the depth of the component into the target), vsis the speed of sound. T3in the above formula is the pulse duration of the first / second pulse (Figure 6a). In other examples, shorter pulse durations, but longer than the stress confinement threshold, are usable by employing spatio-temporal analytics such as time-depth gating or filter-based feature selection.

[0090] The case where the trailing edge of the first pulse is overlapping with the rising edge of the second pulse is expected to give the most optimal results as wavelength transition is optimally aligned in time (Figure 6a), but both the overlapping and the separated pulse pair case are acceptable and most effective when condition (1) is satisfied. When generating a differential photoacoustic signal / image with a desired spatial resolution of 100 pm, stress confinement condition can be met by ensuring that the transition duration less than 65 ns. Generally, effective parameters for differential PA can be achieved with

[0091]

[0092] T4 and lying between 1 and 100 ns for biological tissue, for example, although it is anticipated that other ranges may be applicable.

[0093] In examples, the respective durations of each pulse are between 100 ns and 30 microseconds (30 ps). This can give sufficient time for resolution of differential acoustic signals generated by the series of pulses 105.

[0094] Having described how a series of pulses 105 comprising three or more wavelengths can be formed by the emission system 110, we now turn to how the differential acoustic signals 115, detected by the acoustic sensors 122, are processed to determine the presence or amount of one or more components 135 within the target 130. Figure 7 illustrates a differential unmixer 90, which forms part of the analyser 124.

[0095] The differential acoustic signals 101a, 102a, 103a produced by transmission of the series of pulses 105 into the target 130 are measured by the acoustic sensors 122. A degree of processing may occur at this stage, such as performing an analogue-to-digital conversion, data cleaning and denoising, normalisation, reformatting, and the like. The differential acoustic signals 101a, 102a, 103a are used as an input to the differential unmixer 90.

[0096] The differential unmixer 90 may be provided with component data 190 which describes a respective absorption spectrum for each component. In the example depicted by Figure 7, the component data 190 includes respective absorption spectra for a first biomarker BM1, a second biomarker BM2, and a background component B. The biomarkers BM1, BM2 could be glucose, bilirubin, lactate, ketones, or the like. The background component B could be water, for example. That is, the data for each component describes how the optical absorption spectrum a (A) varies with wavelength A for the component. The data may describe, for a given wavelength A, the respective optical absorption value a (A) for one or more components in the target 130. In other examples, the differential unmixer 90 does not receive particular component data 190, but nevertheless knowledge of the optical absorption spectrum a (A) may be utilised to perform processing of the differential acoustic signals 101a, 102a, 103a.

[0097] Based on the differential acoustic signals 101a, 102a, 103a, the differential unmixer 90 is configured to determine information related to the presence or amount of one or more components 135 in the target 130. For example, the first differential acoustic signal 101a may be compared to a threshold value. If a strength (e.g. a peak-to-peak amplitude) of the first differential acoustic signal 101a exceeds the threshold value, it may be determined that a first biomarker BM1 is present, as a component 135, in the target 130. The first differential acoustic signal 101a may be compared with another differential acoustic signal, such as the second differential acoustic signal 102a. If, for example, the strength of the first differential acoustic signal 101 a is stronger than the strength of the second differential acoustic signal 102a, then it may be determined that the first biomarker BM1 is present as a component 135 in the target 130 in a stronger concentration than a second biomarker BM2, for example. Determination of the presence of a component 135 in the target 130 may be conditional upon more than one differential acoustic signal 101a, 102a meeting a respective criterion or criteria. For example, the presence of a component 135 may be determined by the strength of the first differential acoustic signal 101a exceeding a threshold value, the strength of the second differential acoustic signal 101b being greater than the first differential acoustic signal 101a, and the strength of the third differential acoustic signal 103 a falling within a threshold range of the first differential acoustic signal 101a. A variety of processing methods are envisaged to process the differential acoustic signals 101a, 102a, 103 a to determine information about components 135 in the target 130.

[0098] It will be appreciated that only two differential acoustic signals 101a, 102a may be used in some examples, but this can be extended in other examples to take into account any number more differential acoustic signals. Moreover, in some examples, the presence or amount of only a single component 135 of the target 130 may be determined by the two or more differential acoustic signals, but in other examples multiple components of interest 135 may be determined as being in the target 130. Additionally, direct photoacoustic signals such as the photoacoustic signal 400 depicted in Figure 2 may be considered in combination with the differential acoustic signal(s) as part of the analysis of the differential unmixer 90.

[0099] As an output, the differential unmixer 90 may determine a presence of a component 135, such as a binary indicator of whether the component 135 exists or does not exist inside the target. This can be relative to a threshold, such that the binary indicator is whether a component exists at a defined level (such as at above a given concentration, mass, volume, or the like). The differential unmixer 90 may additionally or alternatively determine an amount of the component 135, such as a mass, concentration, volume, or quantity (e.g. discrete number of) a component 135. The differential unmixer 90 may determine different metrics (such as presence or amount) for different components, such as determining a first metric for a first component and a second, different metric for a second component.

[0100] Figure 8 depicts the method 800, which captures the method of photoacoustic measurement according to the present invention.

[0101] At item S801, the method 800 involves generating a series of pulses 105 of electromagnetic radiation, such as in accordance with the description of Figures 2-6b. Each pulse has a predetermined wavelength. The series of pulses 105 are transmitted into a target 130. The method of photoacoustic measurement 800 can reveal the presence of components of interest 135 in the target 130. The series of pulses 105 are timed such that: a first transition between a first pair of pulses generates a first differential acoustic signal 101a from the target, and a second transition between a second pair of pulses generates a second differential acoustic signal 102a from the target. The predetermined wavelength of at least one pulse of the second pair of pulses is different to the predetermined wavelengths of the first pair of pulses. The series of pulses of electromagnetic radiation are generated by the emission system 110.

[0102] At item S803, the method 800 involves measuring the first 101a and second 102a differential acoustic signals. The first 101a and second 102a differential acoustic signals are measured by the acoustic measurement system 120. The first and second differential acoustic signals 101a, 102a can indicate the presence or amount of a component 135 in the target 130.

[0103] Figure 9 depicts a specific example 900 of the method 800, illustrating further details of the method 800.

[0104] At item S901, a series of pulses 105 are determined based on a component 135 of interest in a target 130 and at least one other component in the target 130. This involves determining a pair of wavelengths A A2for which (i) for the component of interest, a first optical absorption parameter a^A^ at a first wavelength A is different from a second optical absorption parameter i(A2) at a second wavelength 12, having a difference in optical absorption parameter values

[0105]

[0106] = | at(At) — a^(A2) |; and (ii) for the other component, a first optical absorption parameter a0(A^) at the first wavelength A is similar to or the same as a second optical absorption parameter a0(A2) at the second wavelength 12, having a difference in optical absorption parameter Aa0= |a0(Ai) — a0(A2)|, which may be zero. In particular, the difference in optical absorption parameter

[0107]

[0108] for the component of interest should be greater than the difference in optical absorption parameter Aa0for the other component for the pair of wavelengths A1, A2. This same approach is applied for a second pair of wavelengths, which will include a third wavelength A which is not in the first pair of wavelengths A±, A2. This can ensure that differential acoustic signals are produced which are indicative of the component of interest in the target and not, or to a lesser extent than, the other component. Item S901 may also involve determining pulse duration, relative pulse timings including pulse overlap or pulse separation, for example.

[0109] In some examples, the series of pulses 105 are determined based on e.g. a predefined sequence of pulses which are stored in a look-up table or the like. In other examples, the series of pulses 105 are determined by analysing component data 190 and determining a suitable set of pulses based on the same.

[0110] At item S903, the series of pulses 105 are generated and transmitted into the target 130. This can be by operation of one or more optical sources in the emission system 110. In particular, laser driver units, pulse pickers, or other optical arrangements may be used to modulate output from the optical sources to construct the series of pulses 105. The skilled person will appreciate that various configurations can allow for the series of pulses 105 to be generated. In examples using variable optical sources which can be tuned between output wavelengths, instructions related to which predetermined wavelengths should be used can be provided to the variable optical sources to construct the series of pulses 105. Furthermore, optical operations such as beam steering, polarisation conversion, attenuation, diffusing, focussing, collimating, defocussing, and the like can be performed on output of the optical sources in order to prepare the series of pulses 105 for transmission onto the target 130.

[0111] At item S905, the two or more differential acoustic signals 115 originating from the target 130 are measured. These differential acoustic signals have been produced by the series of pulses 105 being incident up on the target 130, and in particular components within the target 130. The differential acoustic signals 115 are measured by an ultrasound transducer array 122, or similar arrangement of acoustic sensors. The output from the ultrasound transducer array 122 may undergo initial processing by a receive unit, which can include low noise amplifier, configured to amplify weak signal components whilst adding no or low amounts of noise to the signal, and an analogue-to-digital conversion, for example. The ultrasound transducer array 122 may further be controlled by a beamformer to optimise a measured signal from the target 130, for example. Techniques such as time-gated detection may be performed to help improve signal to noise ratio.

[0112] At item S907, a presence or amount of a component of interest in the target based on the two or more differential acoustic signals is determined. This can be performed by a differential unmixer, as described earlier in view of Figure 7.

[0113] Item S909 represents an optional further step. Based on a measurement of the differential acoustic signals from the target, a new series of pulses is determined for transmission into the target. This could be because e.g. the first series of pulses reveals that a particular component which interferes with measurement of a component of interest may be present in the target 130, and so a subsequent series of pulses may be modified to compensate for this. Figure 10 illustrates an example of the photoacoustic measurement system 100 described in view of and depicted by Figure 1. The photoacoustic measurement system 100-1 comprises an emission system 110-1 and an acoustic measurement system 120.

[0114] The emission system 110-1 comprises a plurality of single-wavelength solid state lasers 112a-d. These are each driven by respect laser drivers (not pictured) and operable to produce pulsed light at a respective wavelength1...N. The lasers 112a-d, via the laser drivers, are controlled by the differential pulse generator 114. The differential pulse generator 114 produces timing information 114a which is used by the lasers 112 to construct the series of pulses 105. The timing information 114a can comprise, for example, time series data indicating an “on” or “off’ state for each laser 112 (or optical source, more generally), such as data corresponding to the information depicted in the top plot of Figures 2-5. An optical arrangement 170 is used to transmit the series of pulses 105 from the lasers 112a-d to the target 130.

[0115] The acoustic measurement system 120 comprises an ultrasound transducer array 122 which is interfaced with a receive and processing unit 126. The receive and processing unit 126 performs signal processing and control of the ultrasound transducer array 122 as described for item S905. The receive and processing unit 126 sends received differential acoustic signal data to the analyser 124. Although depicted in a single unit here, for clarity, in other examples the control of the ultrasound transducer array 122 may be performed by a separate component to the signal processing of data measured by the ultrasound transducer array 122, for example.

[0116] The analyser 124 and differential pulse generator 114 each interface with a controller 160. Although depicted as separate entities in Figures 10 and 11, the analyser 124, differential pulse generator 114 and controller 160 can each be functions performed by a single processing unit, or distributed across several cooperating processing units, for example. The controller 160 can perform overall control of the emission system 110-1 and the acoustic measurement system 120, and can determine commands to be provided to the lasers 112 via the differential pulse generator 114 and to the ultrasound transducer array 122 via the receive and processing unit 126.

[0117] A user interface 165 is provided in the photoacoustic measurement system 100. The user interface 165 allows a user to input instructions, and / or to read out and interpret data. For example, the user may input instructions relating to a series of pulses 105 for the emission system 110 to transmit to the target 130. For example, the user may receive an indication of a presence or amount of a component 135 in the target 130, as determined by the analyser 124, through the user interface 165. The user interface 165 may comprise input devices such as a mouse, keyboard, and / or transparent touch display module, for example. The user interface 165 may comprise output devices such as display units or audio units, for example.

[0118] Figure 11 illustrates a second example of the photoacoustic measurement system 100 described in view of and depicted by Figure 1. The photoacoustic measurement system 100-2 comprises an emission system 110-2. The arrangement of the photoacoustic measurement system 100-2 of Figure 11 is comparable to the photoacoustic measurement system 100-1 of Figure 10, and so the description in view of Figure 10 applies here also, where applicable.

[0119] The emission system 110-2 of the photoacoustic measurement system 100-2 of Figure 11 differs from the emission system 110-1 of the photoacoustic measurement system 100- 1 of Figure 10 in that rather than a plurality of single-wavelength solid state lasers, the emission system 110-2 comprises two tunable lasers 112x, 112y. Each tunable laser 112x, 112y can be varied between two or more wavelengths. For example, a first tunable laser 112x can produce pulses at a first wavelength

[0120]

[0121] or a second wavelength λ2, and the second tunable laser can produce pulses at a third wavelength λ3or a fourth wavelength λ4. Accordingly, the differential pulse generator 114 transmits both timing information 114a but also wavelength information 114b to the tunable lasers, to inform which wavelengths of light each tunable laser 112x, 112y should produce in forming the series of pulses 105.

[0122] Figure 12 illustrates a person wearing a wearable device 1000. The wearable device 1000 comprises a photoacoustic measurement system 100-3 in accordance with the photoacoustic measurement system 100 of Figure 1. The photoacoustic measurement system 100-3 is miniaturised by using integrated photonic and electronic circuit components to realise the emission system 110 and acoustic measurement system 120. The wearable device 1000 is operable to measure biomarkers, which are components, within a region of the person, which is the target. For example, the wearable device 1000 may be operable to detect one or more of bilirubin, creatine, glucose, a ketone, or a lactate. In some examples, the wearable device 1000 is operable as a non-invasive blood sugar detector. In some examples, the wearable device is operable as an interstitial or intra-vascular molecule or biomarker detector.

[0123] It is to be understood that any feature described in relation to any one embodiment may be used alone, or in combination with other features described, and may also be used in combination with one or more features of any other of the embodiments, or any combination of any other of the embodiments. Furthermore, equivalents and modifications not described above may also be employed without departing from the scope of the invention, which is defined in the accompanying claims.

Claims

CLAIMS1. A method of photoacoustic measurement, comprising:generating a series of pulses of electromagnetic radiation, each pulse having a predetermined wavelength, the series of pulses being transmitted into a target;wherein the series of pulses are timed such that:a first transition between a first pair of pulses generates a first differential acoustic signal from the target; anda second transition between a second pair of pulses generates a second differential acoustic signal from the target;the predetermined wavelength of at least one pulse of the second pair of pulses being different to the predetermined wavelengths of the first pair of pulses; andmeasuring the first and second differential acoustic signal.

2. The method according to claim 1, wherein the first differential acoustic signal has a first set of characteristics, and the second differential acoustic signal has a second set of characteristics different from the first set of characteristics, the characteristics including amplitude, polarity, magnitude, duration, bandwidth, and / or frequency.

3. The method according to claims 1 or 2, wherein a predetermined wavelength of the first pair of pulses is the same as a predetermined wavelength of the second pair of pulses, a second pulse of the first pair of pulses being a first pulse of the second pair of pulses.

4. The method according to claims 1 or 2, wherein the predetermined wavelengths of the first pair of pulses are different to the predetermined wavelengths of the second pair of pulses.

5. The method according to any previous claim, wherein the first and / or second transition comprises, respectively, a first pulse of the pair temporally overlapping a subsequent, second pulse of the pair.

6. The method according to claim 5, wherein the first and / or second transition comprises, respectively, a trailing edge of the first pulse of the pair temporally overlapping a rising edge of the subsequent, second pulse of the pair.

7. The method according to any one of claims 1 to 4, wherein the first and / or second transition comprises a trailing edge of a respective first pulse of the pair temporally separated from a rising edge of a subsequent, second pulse of the pair.

8. The method according to any previous claim, wherein respective durations of each pulse are between 100 ns and 30 ps.

9. The method according to any previous claim, further comprising determining a presence or absence of a component of the target based on the first and second differential acoustic signals.

10. The method according to claim 9, wherein determining a presence or absence of a component of the target comprises determining an amount of the component of the target such as a quantity, a concentration, a mass, or a volume.

11. The method according to claim 10, wherein the target comprises biomarkers.

12. The method according to any previous claim, comprising generating a further pair of pulses, each having a predetermined wavelength, a wavelength of the further pair of pulses being different to wavelengths of the first and second pairs of pulses to generate a third differential acoustic signal from the target, and measuring the third differential acoustic signal.

13. The method according to claim 12 when dependent on claim 9, 10, or 11, comprising determining a presence, absence or amount of a further component in the target based on at least some of the measured differential acoustic signals.

14. A system for photoacoustic measurement comprising:an emission system configured to generate a series of pulses of electromagnetic radiation for transmission into a target, each pulse having a predetermined wavelength, the emission system comprising:at least one source of the electromagnetic radiation, and a controller for determining the series of pulses of electromagnetic radiation from the at least one source such that:a first transition between a first pair of pulses generates a first differential acoustic signal from the target;a second transition between a second pair of pulses generates a second differential acoustic signal from the target; and the predetermined wavelength of at least one pulse of the second pair of pulses is different to the predetermined wavelengths of the first pair of pulses; andan acoustic measurement system configured to detect a first differential acoustic signal and a second differential acoustic signal originating from the target.

15. A wearable device comprising the system of claim 14, and an analyser configured to determine a presence or absence of a component in the target based on the first and second differential acoustic signals detected by the acoustic measurement system, the wearable device operable to determine, as a component, the presence and / or amount of a biomarker in the target.

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