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Advanced photoacoustic and thermoacoustic sensing and imaging beyond pulsed absorption contrast

This content has been downloaded from IOPscience. Please scroll down to see the full text. 2016 J. Opt. 18 074006 (http://iopscience.iop.org/2040-8986/18/7/074006) View the table of contents for this issue, or go to the journal homepage for more

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Journal of Optics J. Opt. 18 (2016) 074006 (20pp)

doi:10.1088/2040-8978/18/7/074006

Advanced photoacoustic and thermoacoustic sensing and imaging beyond pulsed absorption contrast Fei Gao, Xiaohua Feng and Yuanjin Zheng1 School of Electrical and Electronic Engineering, Nanyang Technological University, Singapore E-mail: yjzheng@ntu.edu.sg Received 20 January 2016, revised 22 March 2016 Accepted for publication 31 March 2016 Published 31 May 2016 Abstract

In this paper, we review the recent progress in the photoacoustic (PA) and thermoacoustic (TA) imaging domain. Going beyond the conventional investigation of optical/microwave absorption contrast, this review will focus more on the new developments of PA and TA imaging towards multi-contrast mechanisms, such as multimodal PA/TA imaging, viscosity imaging, temperature monitoring, Doppler detection of flow speed, etc. In addition, several interesting techniques utilizing PA/TA will be reviewed, including photoacoustic-guided optical focusing, electrical circuit modeling of PA/TA effect, TA imaging with coherent continuous-wave (CW) magnetic and radiofrequency (RF) excitations, as well as its nonlinear effect. Finally, some prospects about the further improvement of PA/TA imaging techniques are suggested, followed by the conclusion. Keywords: photoacoustics, thermoacoustics, sensing, imaging (Some figures may appear in colour only in the online journal) 1. Introduction

detection. Applying laser illumination under different wavelengths, PA imaging demonstrates the spectroscopic optical contrast of chemical compositions, including endogenous contrast such as hemoglobin [9–11], melanin [12–17], lipid [18– 25], and exogenous contrast such as various nanoparticles [26– 32]. In addition, the unique fusion of optics and ultrasound also extends its multi-scale imaging capability from optical-resolution PA microscopy (PAM) [33] to ultrasound-resolution PA tomography (PAT) [8]. Based on the spectroscopic optical contrast and multi-scale imaging capability, the biomedical imaging applications of the PA technique span from micro-scale organelle (e.g. melanosome) to macro-scale organs (e.g. breast) [2]. However, the above-mentioned achievements majorly explore the conventional optical absorption contrast of PA imaging. In recent years, several new aspects of PA imaging have been studied going beyond the optical absorption contrast, including multimodal imaging, viscosity imaging, temperature monitoring, and Doppler detection of flow speed, etc, which will be fully reviewed in this paper. Similarly, microwave-induced TA imaging has also been extensively explored recently to reveal the dielectric contrast with ultrasound resolution for cancer detection, such as breast

Laser-induced photoacoustic (PA) effect, or more generally thermoacoustic (TA) effect induced by other spectra of electromagnetic (EM) wave (microwave, RF, magnetic field, etc), is related to energy conversion from EM wave to acoustic wave through absorption, heating, temperature rising, thermoelastic expansion, and finally acoustic emission [1]. Although the PA/TA effect was discovered early in 1880, its intensive research in the biomedical sensing and imaging field was dramatically increasing from late 1990. With pulsed laser or microwave illumination, wideband PA/TA signal could be generated through the absorption of the object, and detected by the ultrasound transducer to reconstruct the image. Bridging the beauty of the two worlds (EM and acoustics), PA/TA imaging is capable of providing rich EM contrast and preserving fine ultrasound resolution in deep biological tissue [2–8]. More specifically, PA imaging enables the optical absorption contrast in deep scattering biological medium by breaking through the optical diffusion limit with ultrasonic 1

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PA with existing ultrasound imaging [72–88], or various optical imaging approaches, such as optical coherence tomography (OCT) [89–94], diffusion optical tomography [95], fluorescence microscopy [96–101], Raman spectroscopy [102–104], and elastic scattered photons to form phasoscopy image [105, 106]. In addition, numerous multi-functional contrast agents are designed to enable multi-contrast enhancement beyond optical absorption [26, 27, 29, 30]. Figure 2(a) shows the PA-ultrasound dual-modal probe design for endoscopic imaging. Figure 2(b) is the signal processing scheme of coherent PAultrasound correlation to improve the signal-to-noise ratio (SNR) and image contrast. Figure 2(c) demonstrated the combined PA and OCT images of subcutaneous vasculature, which show complementary information and improved performance. Figure 2(d) shows the triple-modality nanoparticle design of magnetic resonance imaging (MRI), PA imaging, and Raman spectroscopy, as well as its application in tumor localization, surgery and margin confirmation. Figure 2(e) is the working process of a nanoparticle droplet with vaporization enhanced contrast beyond thermoelastic expansion. Meanwhile, the vaporization generated micro-bubble also works as a good ultrasound imaging contrast to render dual-contrast performance. The current PA multimodal imaging has almost covered the different ways of combining PA imaging and other imaging modalities, the further development of which could be its dedicated engineering development for a compact integrated medical imaging device for real clinical trials and commercialization. One example is the work of Philips to push PAUltrasound dual-modal imaging based on existing ultrasound machines to the market [107].

Figure 1. Advanced PA techniques beyond pulsed optical absorption

contrast.

tumor [34–40]. However, the majority of the TA imaging research focuses only on the pulse-mode microwave illumination and absorption under different wavelengths and pulse widths [34–71]. In recent years, several novel investigations of TA imaging have been conducted to push TA research beyond conventional pulse-mode microwave absorption. More specifically, this paper will review the circuit modeling of the TA effect, correlate TAs with microwave scattering, TA imaging with CW magnetic and RF excitation, TA imaging with exogenous contrast, TA nonlinear effect, etc. In this review, we revisit these recent developments of PA and TA imaging techniques going beyond the conventional absorption contrast. This review is organized into two categories: PA and TA. Within each category, several advanced methods are introduced, summarized, and key results are demonstrated. At the end, prospects and conclusions are given to discuss the potential new directions and potential problems. This review paper is distinct from the existing reviews of PA and TA that focus more on the fundamentals and linear absorption contrast. Therefore, it will be interesting to broader readers to encourage the interdisciplinary study of PA/TA with other subjects.

2.2. PA viscosity sensing and imaging

As a hybrid phenomenon of optical absorption and mechanical vibration, the PA effect intrinsically includes optical and mechanical contrast. However, the majority of the conventional PA imaging research focuses on the optical absorption characterization of the object. In recent years, several studies have shown the feasibility of mechanical property characterization, e.g. elasticity and viscosity, based on time-domain measurement [108, 109], frequency-domain measurement [110, 111], and phase measurement [112, 113]. Figure 3(a) is the equivalent resonance modeling of the PA effect, which could be in the form of a mechanical mass-spring oscillator, or an electrical resistance-inductance-capacitance (RLC) oscillator. Figure 3(b) shows the time-domain waveform of the PA oscillation signal, which is characterized by its peak number (Pn) and relaxation time (Tr). Figure 3(c) is the muscle characterization results using the peak ratio (first positive peak to second positive peak) of the PA oscillation signal, where red muscle and pink muscle are differentiated obviously. Figure 3(d) is the frequency-domain PA resonance spectroscopy characterization by sweeping the modulation frequency of the CW laser, where different phantoms show different spectrum central frequency and bandwidth. Figure 3(e) is the PA signal when it is in resonance and nonresonance. Figure 3(f) is the experimental setup of the phaseresolved PA measurement of viscoelasticity using CW laser

2. PA sensing and imaging beyond pulsed optical absorption In this section, several aspects of PA imaging techniques beyond the linear absorption-only contrast will be reviewed. As shown in figure 1, these techniques majorly include PA multimodal imaging, PA viscosity sensing and imaging, PA temperature sensing and imaging, PA Doppler sensing and imaging, PA sensing and imaging with chirping source, PAguided optical focusing and nonlinear PA sensing. 2.1. PA multimodal sensing and imaging

The first straightforward idea to extend conventional PA imaging beyond optical absorption contrast is to directly combine PA with other kinds of imaging modalities, achieving multimodal imaging. As a hybrid imaging method combining optical illumination and ultrasound detection, it is simple to combine 2

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Figure 2. (a) The design of a dual-modal PA-ultrasound endoscopic probe. (b) Working principle of coherence PA-ultrasound correlation for

enhanced SNR. (c) The overlapped imaging results of combined PA and OCT modalities. (d) The multi-functional nanoparticle design and usage of MRI-PA-Raman triple-modality imaging. (e) The nanoparticle design of droplet vaporization for enhanced contrast beyond thermoelastic expansion. Reprinted with permission from [27, 29, 78, 84, 94].

for measuring the oxygen saturation (SO2) of a sheep [114] with a resolution capable of differentiating the SO2 in the artery (SaO2) with that in the vein (SvO2). The achieved measurement accuracy is 7.5%, as shown in figure 4(a). A photoacoustic microscopy can further render a detailed map of SO2 values in capillaries and color-code the veins and arteries according to the SO2 values (figure 4(b)) [11]. More reports of photoacoustic SO2 measurement can be found in [115, 116] and the references therein. As most materials exhibit distinct optical absorption characteristics [117], it is expected that photoacoustics could measure other biological analytes as well. Blood glucose is one such analyte that could potentially be measured by the photoacoustic technique and indeed it has attracted both academic and industrial attention. In [118], a compact mid-infrared photoacoustic spectroscopy system was reported, which measures the glucose concentration in the epidermis layer with a promising accuracy of 10 mg dl−1 (shown in figure 4(c)), indicating its potential for clinical applications. Except for optical absorption, PA signal is also proportional to the Gruneisen coefficient, which is

excitation and lock-in detection. Figure 3(g) is the phantom imaging results, where four phantoms with different optical absorption and viscoelasticity properties are well imaged with high contrast. The PA viscosity imaging technique is still in the early stage with experimental results using phantom in most of the literature. To further push this technique towards real applications, the CW laser power and detection sensitivity need to be further improved, because the limited output power of the CW laser used is always the bottleneck for deep in vivo imaging. On the other hand, optimized exogenous nanoparticles could be designed with significantly distinct viscosity parameters to further improve the contrast. 2.3. PA oxygen saturation and temperature sensing and imaging

Since blood is a major optical absorber, photoacoustics is inherently sensitive and tremendously useful for imaging blood vessels and probing physiological parameters therein at a high resolution. For instance, photoacoustics has been used 3

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Figure 3. (a) The equivalent oscillator model of the PA effect. (b) Typical PA oscillation signal from a tube phantom. (c) Red muscle and pink muscle characterization results from the PA oscillation signal’s peak ratio. (d) Frequency-domain PA resonance spectroscopy of different phantoms, (e) and their waveforms at resonance and non-resonance. (f) The experimental setup of phase-resolved PA measurement of viscoelasticity. (g) Imaging results of both optical absorption and viscoelasticity. Reprinted with permission from [108, 110, 112].

tagging that was imaged by PA tomography. Figures 4(h)–(i) are the measurement results, achieving flow speed detection as low as 0.24 mm s−1. Figure 4(j) is the working principle of Gruneisen relaxation PA imaging, where the thermal tagging of the first pulse laser perturbs the Gruneisen parameter that is sensed by the second pulse laser-induced PA. The difference in the two PA signals could render improved axial resolution confined in the perturbation focus. Figures 4(k)–(l) are the lateral and axial profiles of conventional PA microscopy and Gruneisen relaxation PA microscopy, showing that the axial resolution is greatly improved by 20 times. Although lots of papers have studied the functional PA imaging by detecting the blood oxygenation using two or more wavelengths, the unknown fluence distribution of different wavelengths’ light is still awaiting a solution for more accurate quantitative measurement of SO2. Regarding glucose detection using the PA technique, the major challenge is the low signal amplitude and SNR due to the low concentration of glucose in blood, leading to measurement variations with low correlation. One

related to temperature change. Several research works have been conducted to explore the temperature sensing and imaging capability based on the PA effect [97, 119–123]. By monitoring the temperature in real time, a closed-loop controlled hyperthermia controller has been reported for tight temperature control and effective treatment [124]. By actively modulating the temperature of the object, flow speed could be measured accurately [125], and image resolution could be improved significantly [126]. Figure 4(d) shows the system setup based on magnetic hyperthermia and PA temperature monitoring, where the controller is implemented based on an FPGA board. Figures 4(e)–(f) show the temperature increase under an open-loop (black line), a closed-loop with a pre-set temperature increase of 3.6 °C (red line), and pre-set temperature increase of 5.8 °C (yellow line). The closed-loop system achieves quite accurate and stable temperature control during the hyperthermia process. Figure 4(g) is the system diagram of ultrasonically encoded TA flow speed imaging, where high-intensity focused ultrasound provides the thermal 4

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Figure 4. (a) SO2 measurement in a sheep SSS. (b) SO2 map of subcutaneous blood vessels by photoacoustic microscopy. (c) Blood glucose

concentration measurement by a mid-infrared photoacoustic spectroscopy system. (d) System setup of closed-loop PA temperature controller, (e)–(f) and its temperature control experiments compared with open-loop results. (g) The system setup of ultrasonically encoded PA flow speed monitoring, (h)–(i) and its flow speed measurement results. (j) The working principle of Gruneisen relaxation PA imaging, (k)-(l) and its profiles with much-improved axial resolution. Reprinted with permission from [11, 114, 118, 124–126].

Doppler effect was demonstrated to monitor the flow speed by several groups, including both time and frequency-domain methods [129–134]. Figure 5(a) shows the principle of the PA Doppler effect by employing CW-modulated laser illumination, where the moving particles will generate the PA signal with shifted frequency depending on its velocity, as shown in figure 5(b). Figure 5(c) is the system setup of time-domain PA Doppler detection based on cross-correlation, where two consecutive laser pulses are used to generate two PA signals for cross-correlation. The time shift of the correlated signal, as shown in figure 5(d), is proportional to the flow speed of the particles. Figures 5(e)–(f) are the PA Doppler broadening of the bandwidth for flow speed detection, where both flow speed and flow direction could be monitored (figure 5(f)). Although PA Doppler sensing and imaging have found some

way to solve it could be the fusion of multi-technologies to minimize the measurement variation and improve the accuracy, e.g. the GlucoTrack device from Integrity Applications [127, 128]. Lastly, PA sensing of temperature opens the possibility of temperature measurement in deep tissue, which has triggered the multiple interesting applications mentioned above. However, it still needs to be further developed towards in vivo and clinical validation. 2.4. PA Doppler sensing and imaging

The Doppler effect refers to the detection of frequency shift caused by the moving of the target. Flow speed detection is an important application of the Doppler effect, which is usually done by ultrasound Doppler imaging. In recent years, the PA 5

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Figure 5. (a) The principle of the PA Doppler effect and (b) its measurement results using CW laser. (c) The system setup of PA Doppler

detection based on time-domain cross-correlation, (d) and the correlated signal with time shift annotated. (e)–(f) PA Doppler detection based on bandwidth broadening and its imaging results. Reprinted with permission from [130, 131, 134].

advantages for measuring blood flow speed, it still needs to be studied systematically and compared with the well-established ultrasound color Doppler imaging. One of the challenges could be the limited penetration depth of light in some opaque tissues, while conventional ultrasound color Doppler imaging could be used in deep tissues.

signal. However, this kind of high-power pulsed laser suffers from bulky size, high cost, and inconvenience. The lowpower laser diode is an alternative to induce PA signal, which is too weak due to its low peak power. To achieve high PA SNR with low peak power, several studies have demonstrated the potential by modulating the laser illumination in terms of chirping frequency [135–146]. After matched filtering processing, PA SNR could be significantly improved. Figure 6(a) is the system setup of frequency-domain PA based on chirping modulation of CW laser using an acousto-optic modulator (AOM). Figure 6(b) is the frequency-domain PA

2.5. PA sensing and imaging with CW chirping source

The majority of the PA sensing and imaging systems are based on high-power pulsed laser to generate strong PA 6

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Figure 6. (a) The system setup of frequency-domain PA imaging based on AOM modulation of CW laser. (b) The ultrasound probe-based

frequency-domain PA imaging. (c) The PA signal from coded excitation laser illumination, (d) and its cross-correlation signal. (e) The system setup of laser-shared PA temperature sensing and photothermal treatment. Reprinted with permission from [137, 138, 146, 147].

imaging based on an ultrasound array probe. Figure 6(c) is the measured PA signal using coded excitation, and its crosscorrelation signal with the template signal in figure 6(d). Figure 6(e) shows single-laser-diode-based PA temperature sensing and photothermal treatment using chirping modulation, which could achieve both effective treatment and realtime temperature monitoring in a compact and low-cost way. It is true that by utilizing the chirp modulation with CW laser, the sensitivity could be improved. However, the achievable SNR is still not as high as the conventional high-power pulsed laser system. Another challenge is the EM coupling from the excitation to the ultrasound transducer, which may limit the laser illumination duration to avoid the overlapping of coupling noise with detected signals. Further development of the chirp-based PA imaging may include the higher-power CW laser source, a dedicated laser-driven circuit design, as well as proper chirp pulse duration and bandwidth selection.

modalities, optical manipulation and photothermal therapy. In recent years, several optical focusing techniques based on ultrasonic tagging of scattered light have been proposed to achieve acoustic resolution focusing inside scattering medium [148–153]. Moreover, PA signal has also been utilized to guide optical focusing for better performance [154–157]. Figure 7(a) is the system setup of nonlinear PA signal-guided optical focusing to achieve single optical speckle grain on the scale of 5–7 μm. Figure 7(b) is the optical focusing based on PA transmission matrix, which could selectively focus light on absorbing targets through diffusive medium. Figures 7(c)– (e) are the PA imaging results of a sweat bee wing based on uniform (figure 7(c)), random (figure 7(d)), and wavefront optimization (figure 7(e)) optical illumination utilizing the spatially non-uniform sensitivity of an ultrasound transducer. Figure 7(f) is the proof-of-concept work of PA-guided depthresolved Raman spectroscopy, which could maximize the Raman signal in deep medium. Lastly, figure 7(g) shows the stimulated Raman PA principle to achieve Raman sensing in deep tissue, which explores the non-radiation relaxation closely related to the Raman emission. Figure 7(h) exhibits the well-agreed Raman and PA spectroscopy of neat chloroform [158]. Although some of the PA-guided optical focusing techniques (e.g. figure 7(a)) utilized the temperature-dependent nonlinearity of the PA signal, there are some other interesting

2.6. PA-guided optical focusing and nonlinear PA sensing

Although PA imaging broke through the optical diffusion limit in deep scattering medium by detecting the acoustic signal, it still suffers from weak optical focusing in deep medium to achieve higher resolution beyond acoustic wavelength. More importantly, optical focusing in scattering medium is a long-standing challenge for breakthrough in many applications, such as various optical imaging 7

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Figure 7. (a) Experimental setup of nonlinear PA-guided optical focusing. (b) The experimental setup of optical focusing based on PA

transmission matrix. (c)–(e) PA imaging results of a sweat bee wing based on uniform (c), random (d) and wavefront optimization (e) optical illumination. (f) The experimental setup of the PA-guided depth-resolved Raman spectroscopy system. (g) The principle of stimulated Raman PA imaging, and (h) the reconstructed PA and Raman spectrum of neat chloroform. Reprinted with permission from [102, 154–156, 158].

applications by utilizing the nonlinear PA to visualize the target from highly absorption background by its nonlinear contrast, which could be caused by an enhanced thermal expansion coefficient [159–162], or nano/micro-bubble generations [163–165]. Figure 8(a) shows the thermal nonlinear PA signal from a single gold nanosphere with increasing laser fluence. Figure 8(b) is the fluence-dependent linear and nonlinear PA signal from RBCs and melanoma, where the nonlinearity originates form nanobubble formation and explosion. Figure 8(c) shows the nonlinear resonance from a gold nanorod for both photothermal and PA responses. Figure 8(d) shows the PA signal amplitudes from melanoma cells in blood as a function of laser energy fluence, where higher pigmented melanoma cells exhibit a stronger nonlinear effect. Compared with linear PA that has been extensively

studied, nonlinear PA generation from optimally designed nanoparticles deserves deeper exploration for contrastenhanced PA imaging from highly absorption background. To further push the nonlinear PA for real clinical applications, the threshold light fluence for nonlinear PA generation needs to be reduced by using dedicated nanoparticle design, so that the light fluence is safe enough for human use.

3. TA sensing and imaging beyond pulsed microwave absorption In this section, several aspects of TA imaging techniques beyond the conventional pulse-mode microwave absorption contrast will be reviewed. As shown in figure 9, these 8

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Figure 8. (a) Thermal nonlinear PA signal from gold nanosphere due to temperature-dependent thermal expansion coefficient increase. (b)

Linear and nonlinear PA signal dependency on energy fluence from RBCs and melanoma cells. (c) Nonlinear resonances of gold nanorods with plasmon resonances at 860 nm. (d) PA signal amplitudes from melanoma cells in blood as a function of laser energy fluence. Reprinted with permission from [161, 163, 164].

frequency magnetic/RF illuminations, TA imaging with exogenous contrast, and TA nonlinear effect. 3.1. TA equivalent circuit modeling

As a hybrid physical phenomenon combining EM absorption and acoustic generation, the numerical study of the TA effect normally requires separate simulation of an EM and acoustic field based on the finite element method (FEM) [34, 43]. In addition, this kind of numerical simulation is not compatible with the hardware simulation of a TA imaging circuit, e.g. SPICE. Therefore, the equivalent circuit model has been proposed recently to bridge the gap between TA numerical simulation and circuit simulation [166, 167]. Figure 10 shows the overall circuit model of one unit (figure 10(a)), a 2D circuit network and its co-simulation with hardware (figure 10(b)), and the 2D numerical simulation results of two tumors (figure 10(c)). Good agreements have been achieved comparing the circuit simulation and numerical simulation

Figure 9. Advanced TA techniques beyond the conventional pulsed microwave absorption contrast.

techniques majorly include TA circuit modeling, TA-correlated imaging with scattered microwave, TA imaging with spectroscopic and CW excitations, TA imaging with low-

9

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Figure 10. (a) The equivalent circuit model of the TA effect in a single unit. (b) The co-design and co-simulation of the TA effect and the

microwave-acoustic transceiver, and (c) the simulation results based on the 2D circuit model of the TA effect. Reprinted with permission from [166].

results. This study opens a new way of co-simulating the TA effect and hardware circuit to achieve optimized system design. The immediate step to optimize this model is to extend its equivalent circuit to 3D simulation, which is closer to the real case. In addition, silicon verification of the circuit model is also expected to build the TA phantom for the TA experiments and testing. This kind of TA phantom on silicon chip may enable quick and convenient emulation of the real TA generation scenario.

microwave signal is usually ignored. Some recent studies showed that both the microwave absorption-induced TA signals and the microwave scattered signals could be collected for complementary image reconstruction [168–170]. Moreover, the microwave-acoustic phasoscopy has been proposed for tissue characterization with enhanced sensitivity [171]. Figures 11(a)–(d) show the reconstructed images from both scattered microwave signals (figure 11(b)) and TA signals (figure 11(c)), as well as the correlated microwaveacoustic imaging results (figure 11(d)). Figure 11(e) illustrates the phasoscopy concept by mapping the microwave-acoustic phase on an ellipse chart. Figure 11(f) is the preliminary ex vivo porcine tissue characterization based on the

3.2. TA-correlated imaging with scattered microwave

In the conventional TA imaging setup, microwave is transmitted and ultrasound is received, where the scattered 10

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microwave imaging, (c) TA imaging, and (d) correlated microwave-acoustic imaging. (e) The concept of microwave-acoustic phasoscopy for tissue characterization, and (f) the preliminary results using four kinds of porcine tissues. Reprinted with permission from [169, 171].

phasoscopy concept. These results demonstrated the improved image contrast and sensitivity of the TA sensing or imaging only. To implement the correlated microwaveacoustic imaging system, the challenge comes from the highpeak power (kW) microwave source with narrow pulsed width (nanosecond), which is usually bulky and high cost. One way to circumvent it is to utilize chirp-modulated CW excitation of the microwave source with lower peak power, which will be discussed further in the section below.

3.3. TA imaging with spectroscopic and CW excitations

The majority of the developed TA imaging systems up to now are based on the pulse-modulated microwave illumination to induce wideband TA signal under single-carrier frequency. In recent years, spectroscopic TA sensing and imaging have been proposed to experimentally demonstrate the feasibility of imaging water/fat composite with enhanced sensitivity [53]. Moreover, TA imaging based on CW or chirp modulation has also been proposed recently to improve the SNR and lower the 11

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Figure 12. (a) The TA spectroscopy of water/fat samples under microwave illumination with three difference frequencies. (b) The SFCW TA

imaging setup with low-power microwave source. (c)–(d) The time and frequency domain of TA resonance signal compared with conventional pulse TA signal. Reprinted with permission from [47, 48, 53].

peak microwave power [42, 47, 48]. Figure 12(a) shows the TA spectroscopy of four water/fat composite samples using three microwave frequencies (2.7, 2.9, 3.1 GHz), where different samples exhibit different positive slope. Figure 12(b) is the stepped-frequency continuous-wave (SFCW) TA imaging setup, where the envelope of the microwave carrier is modulated with different frequencies to induce CW TA signal in frequency domain, followed by coherent processing to extract time-domain information for imaging with much lower microwave peak power. Figures 12(c) and (d) are the waveform and spectrum of the TA resonance signal, where the TA resonance signal under multiple microwave illumination achieved enhanced SNR and narrower bandwidth for high-sensitivity detection. The challenge of implementing the CW microwave excitation for TA imaging is its low peak power output, because there is a trade-off on the power and bandwidth of the RF amplifier. Further development of the CW TA imaging requires

the demonstration of in vivo animal results, as well as system integration for a portable cancer screening device. Multi-contrast imaging (microwave absorption and mechanical resonance) could also be expected by analyzing the TA resonance spectrum through the chirp-modulated frequency [110].

3.4. TA imaging with low-frequency near-field magnetic/RF illuminations

The existing TA imaging systems usually employ the narrowband microwave source with frequency range from 100 MHz to 3 GHz, which is radiated from a horn or helical antenna to achieve far-field uniform illumination. In recent years, lower frequency magnetic mediation for TA generation has been proposed for deeper penetration TA imaging with potentially lower peak power [44, 46, 49]. Furthermore, its closed-loop integration with magnetic hyperthermia using nanoparticles has 12

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Figure 13. (a) The system setup of magnetically mediated TA imaging, and the imaging results of (b) time-domain and (c) frequency-domain

methods. (d) The system setup of near-field impulse TA imaging, and (e) its simulation and experimental results. Reprinted with permission from [49, 51, 57].

also shown its feasibility [41]. Near-field TA imaging with impulse source for higher RF energy coupling and spatial resolution has also been demonstrated [50, 51, 55, 57, 172]. Figure 13(a) shows the setup of magnetically mediated TA with both time and frequency-domain illumination (pulsed and chirping), together with the imaging results of a metal strip with pulsed (figure 13(b)) and chirping magnetic illumination (figure 13(c)). Figure 13(d) is the system setup of near-field impulse TA imaging. Figure 13(e) shows the simulated electrical field distribution, measured electrical signal and reconstructed image of phantom. Figures 13(f) and (g) are the reconstructed images by conventional wide and proposed ultrashort microwave pulses, where image resolution was greatly improved [51]. Some challenges still exist for magneticmediated TA imaging, especially the low absorption coefficient at such low RF frequencies. On the other hand, although nearfield illumination could improve the microwave energy coupling into tissue with higher efficiency, its uniform distribution cannot be easily controlled compared with horn-antenna-based far-field illumination. Therefore, further development of nearfield illumination-based TA imaging needs to improve the coupling efficiency, while keeping a uniform microwave energy deposition.

173, 174], iron oxide magnetic nanoparticles [175] and microbubbles [176] have been used as contrast agents for TA imaging due to their distinct microwave absorption from biological tissue. Figure 14 demonstrates several experimental examples of TA signal and image contrast improvement by carbon nanotubes (figures 14(a)–(b)), microbubbles (figure 14(c)), and iron oxide magnetic nanoparticles (figures 14(d)–(f)). An obvious increase of more than double was observed from these results. However, a recent study [177] investigated the fundamental source of exogenous TA contrast, concluding that the carbon nanotube provides no dielectric contrast due to its non-ionic and nonpolar properties, and the magnetic nanoparticle is also inefficient due to the low magnetic loss at microwave range. Although some published results seem contradictory, the importance of using exogenous contrast for TA imaging improvement is attracting more researchers to maximize its potential on a larger scale. Another way to develop exogenous contrast agents for TA imaging is to go beyond the microwave absorption improvement by incorporating other TA generation mechanisms. One possible example is to utilize nano/micro-bubble generation from the nanoparticles that could be triggered by microwave illumination, which could significantly enhance TA pressure due to the explosion of the bubbles.

3.5. TA imaging with exogenous contrast 3.6. TA nonlinear effect

Conventional TA imaging exploring the endogenous contrast of microwave absorption relies on the dielectric difference of biological tissue, which usually suffers from small permittivity/ conductivity and weak TA signal generation. In recent years, the usage of contrast agents for TA imaging signal enhancement has gained increasing interest. Carbon nanotubes [34, 43,

Conventional TA signal based on microwave absorption is proportional to the modulation envelope of the microwave carrier. More specifically, the envelope modulation frequency of microwave carrier determines the generated TA signal frequency, while the carrier frequency of microwave (300 MHz to 13

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Figure 14. Contrast-enhanced TA signal improvement and imaging results using (a)–(b) carbon nanotubes, (c) microbubbles, and (d)–(f) non-

targeted and targeted magnetic nanoparticles. Reprinted with permission from [43, 173, 175, 176].

3 GHz) is too high to generate detectable TA signal due to significant acoustic attenuation at this frequency range. However, when reducing the microwave frequency to a lower RF frequency range (∼MHz), the TA signal generating from the RF carrier frequency is detectable with second-order harmonic response [172]. Figure 15(a) shows the experimental setup of RF-induced TA generation with quasi-CW illumination. The RF excitation signal and measured TA signal are shown in figure 15(b), which demonstrates that the generated TA signal (4 MHz) doubles the frequency of the RF excitation signal (2 MHz). Besides frequency doubling, a mixing effect based on acoustic radiation force has been recently reported by generating TA and magnetoacoustic (MA) signals simultaneously on the same target [45]. Figure 15(c) shows the setup of generating TA and MA with a coil and static magnet, and the typical measured time-domain signal is shown in figure 15(d). By setting the carrier frequency to be 3.5 MHz and envelope frequency to be 0.2 MHz, the mixing frequency components (3.3 and 3.7 MHz) show up clearly to verify the nonlinear mixing effect of TA and MA. The most promising application of the TA nonlinear effect may be its capability of visualizing the weak target with nonlinear property from strong linear absorption background to enhance the sensitivity and contrast. In addition, the nonlinear effect could render more information beyond absorption, such as the elastic property characterization by TA and MA mixing [45]. More studies deserve to be done in

the nonlinear TA domain, which has been rarely tapped up to now.

4. Prospects and conclusions This review comprehensively summarizes the recent progress in the PA and TA imaging area, focusing on the techniques beyond conventional pulse absorption contrast. These techniques broaden the applications of PA and TA imaging on a much larger scale, and facilitate the interdisciplinary research at the boundaries between PA/TA and other subjects. Although many interesting studies have been done extending the potential of PA/TA imaging, there are still some topics which deserve further exploration and development in three aspects: fundamental methods, biomedical applications, and system development. 4.1. Fundamental methods

In this part, a deeper exploration and comprehensive study of the optic-acoustic interaction is required to inspire new imaging modalities in future work. For example, the intrinsic correlation between PA generation and Raman/fluorescence scattering may introduce advanced imaging techniques that combine both merits of PA’s deep penetration and Raman spectroscopy’s molecular specificity. Another example is the intelligent integration of PA/TA imaging with elastography,

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Figure 15. (a) The system setup of RF-induced second harmonic TA generation, and (b) the measured RF excitation waveform (blue line) and

TA waveform (red line). (c) The setup of generating TA and MA simultaneously with designed excitation pattern and expected mixed TA/ MA signal. (d) The measured time-domain mixed TA/MA signal, and (e) its spectrum. Reprinted with permission from [45, 172].

which is potentially able to provide dual-contrast deep tissue imaging for challenging clinical applications. Lastly, the nonlinear properties of both PA and TA imaging techniques are opening the way to further enhance the sensitivity and image contrast beyond the conventional TA/PA imaging based on linear absorption [178].

work. The high-end direction is to develop a high frame-rate PA/TA imaging system, which could enable real-time monitoring of oxygen delivery and epilepsy [179–182]. For the low-end direction, a portable, low-complexity and low-cost PA/TA imaging device is highly desired to extend its utility to small clinics and developing countries, even homecare. To achieve this, a dedicated PA/TA imaging system integration employing advanced technologies, such as microelectromechanical systems (MEMS), integrated circuit (IC) design, and silicon photonics could be developed. To develop a truly compact PA imager, a low-cost laser diode should be selected as the light source. To overcome the disadvantages of the laser diode, especially its low peak power, an advanced high-sensitivity ultrasound receiver is required. In conclusion, although PA/TA sensing and imaging has been intensively studied in recent decades, to demonstrate its potential for rich absorption contrast with deeper penetration, a much wider research scope could be undertaken by exploring the interdisciplinary boundary of the PA/TA effect with other research areas. A more impactful outcome will be generated in the future.

4.2. Biomedical applications

In this part, more interesting clinical applications could be explored. To go beyond the phantom and simple ex vivo studies, in vivo animal testing and even human trials are expected in future work to further validate the potential of the new PA/TA techniques for real clinical applications. For example, these applications could be, but not limited to, SO2/ temperature/glucose monitoring, early-stage cancer detection, brain imaging, early stroke/shock prevention monitoring. 4.3. System development

In this part, more advanced and integrated multi-wave imaging systems are required for commercialization in future

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