- Open Access
Concurrent photoacoustic and ultrasound microscopy with a coaxial dual-element ultrasonic transducer
© The Author(s) 2018
- Received: 1 April 2018
- Accepted: 25 June 2018
- Published: 5 September 2018
Simultaneous photoacoustic and ultrasound (PAUS) imaging has attracted increasing attention in biomedical research to probe the optical and mechanical properties of tissue. However, the resolution for majority of the existing PAUS systems is on the order of 1 mm as the majority are designed for clinical use with low-frequency US detection. Here we developed a concurrent PAUS microscopy that consists of optical-resolution photoacoustic microscopy (OR-PAM) and high-frequency US pulse-echo imaging. This dual-modality system utilizes a novel coaxial dual-element ultrasonic transducer (DE-UST) and provides anatomical and functional information with complementary contrast mechanisms, achieving a spatial resolution of 7 μm for PA imaging and 106 μm for US imaging. We performed phantom studies to validate the system’s performance. The vasculature of a mouse’s hind paw was imaged to demonstrate the potential of this hybrid system for biomedical applications.
- Photoacoustic microscopy
- Ultrasound microscopy
- Concurrent imaging
- Coaxial dual-element ultrasonic transducer
Photoacoustic (PA) imaging uses optical absorption as the contrast mechanism and can thus visualize the optical properties of tissue . One of the most widely imaged endogenous chromophores is hemoglobin in the red blood cells, which provides high contrast and high resolution PA images of vasculature in vivo [2–4]. However, the contrast mechanism of PA imaging limits that only selective biomolecules are visible, it is therefore useful to complement PA imaging with ultrasound (US) imaging, which can reveal tissue morphology at depths of up to tens of centimeters [5–7]. Since US imaging derives contrast from echogenicity and differing mechanical properties of tissue, it can provide general structural information that is typically absent from PA images [8–10]. Thus, concurrent PA and US imaging (PAUS) has gained increasing interest in the last decade for both preclinical and clinical applications [6, 8, 11–14].
As a dual-modality imaging system, the merits of PAUS imaging can be summarized as follows: 1) PA imaging provides functional and molecular information about tissue and US imaging enables anatomical localization [11, 13]. This allows the integrated PAUS system to identify structural and functional abnormalities and diseases , enhance the sensitivity and specificity of early stage cancer diagnosis and metastases detection [11, 13, 16], and guide interventional procedures such as needle injection and laser ablation with higher contrast [8, 13, 17]. 2) PA imaging is inherently compatible with US imaging, as both modalities acquire acoustic signals. With the commercial programmable US systems currently available, PA imaging can be readily integrated into an US system [12, 14, 18, 19], and PA and US images can be easily co-registered. 3) Moreover, morphologic information provided by US imaging such as tissue boundaries, speed of sound, and acoustic attenuation may aid in the reconstruction of PA images [18, 20–22].
However, the reported PAUS systems mostly rely on the commercially available ultrasound transducer probes for acoustic detection, which generally have frequencies below 10 MHz [8, 12–14]. The low frequency ultrasound leads to relatively deep penetration, at the expense of spatial resolution. For the other PAUS systems that use high-frequency ultrasound detection, the spatial resolution is much improved [23–25]. However, the detection of the PA and US signals is typically separated, resulting in a long imaging time.
In this work, we will present a truly concurrent photoacoustic and ultrasound (PAUS) microscopy system that provides automatically co-registered PA and US images using a novel coaxial dual-element ultrasonic transducer. This PAUS microscopy system can reveal detailed structural and functional information simultaneously, by acquiring the PA and US signals simultaneously at each lateral position. We have performed phantom and animal studies to demonstrate the hybrid imaging capability. For readers without access to the customized dual-element ultrasonic transducer, we have also provided an alternative engineering solution using two commercial focused ultrasonic transducers, at the expense of the system complexity and imaging depth.
The 20 MHz transducer element was connected to an ultrasonic pulser-receiver (5800PR, Olympus, Waltham, MA, USA) for ultrasound transmission and the 40 MHz transducer element was connected to an amplifier for receiving both US and PA signals. The lateral resolution of PA imaging is determined by the optical focus of 7 μm. The 40 MHz transducer element provides an axial resolution of 36 μm for PA and a lateral resolution of 106 μm for US. The 20 MHz transducer element was used for US transmission for a deeper penetration. Although the 20 MHz transducer element can be used for both US transmission and detection, it is preferable to receive the PA and US signals using the 40 MHz transducer element for the following two reasons: (1) The 40 MHz element naturally attenuates the reflected 20 MHz US signals, which are typically more than 100 times stronger than the PA signal, allowing both PA and US signals to be acquired in the same dynamic range without saturation or suppression; and (2) Both PA and US signals can be amplified and sampled by a single-channel amplifier and a single-channel data acquisition card (DAQ), reducing the cost of the imaging system.
To achieve simultaneous PA and US imaging, we implemented a controlling timing sequence using a FPGA card (myRIO-1900, NI instrument, Austin, TX, USA), as shown in Fig. 1e. In each cycle, four triggers were fired to acquire one time-resolved PA and US A-line at each point. For each cycle, the laser firing and PA signal acquisition were followed by US transmission and receiving. Two independent DAQ triggers for PA and US signal acquisition were added to improve the timing flexibility and to reduce the raw data size by avoiding acquiring unnecessary data. The A-lines were acquired at 1000 Hz, and the sampling frequency for each A-line was 250 MHz. Two-dimensional raster scanning was performed with a step size of 5 μm along the x-axis and 10 μm along the y-axis. The raw RF data was processed in MATLAB.
Integrated PA and US imaging has been demonstrated for needle guidance, identification of lymph nodes , and other in vivo structural imaging applications [26, 27]. However, the majority of existing integrated PAUS systems do not have a good enough resolution to qualify as microscopes. Here we have demonstrated a concurrent PAUS microscope that reveals optical and mechanical properties of the tissue simultaneously. Our PAUS system combines optical-resolution photoacoustic microscopy (OR-PAM) with US pulse-echo imaging, providing a high-resolution PA image that can reveal functional and anatomical information and a co-registered US pulse-echo image that can reveal general structural information [3, 28]. We have also implemented an alternative design with commercial focused ultrasonic transducer, for readers without access to the customized DE-UST. While hemoglobin was used as the endogenous chromophore for PA imaging in this study , multiple wavelengths could be incorporated into the system in the future for measuring oxygen saturation of hemoglobin (sO2) [29–31] and oxygen partial pressure (pO2) [24, 32, 33], as well as for molecular imaging of exogenous probes [2, 34, 35]. Our PAUS system can also be used to image microbubbles to provide blood flow velocity [36–38] and nonlinear mechanical properties [39–41]. We expect PAUS imaging to find a broad range of biomedical applications.
Nevertheless, our PAUS system still faces certain challenges. The depth of laser penetration in PA imaging is limited by the strong scattering of light in tissue. Though targeted nanoparticle contrast agents can be used to enhance the signal-to-noise ratio at greater depths [7, 42], the delivery efficiency of the targeted nanoparticles has to be further improved . In addition, incorporating PA imaging into a commercial US system may increase the cost of the overall system due to the typical requirement of high-energy laser excitation . Low-cost laser-diodes have been used for PA imaging [44–46], which might be a promising solution for low-cost concurrent PAUS systems.
This work was sponsored by a Duke MEDx grant. The authors would like to thank Yuan Zhou’s help on data processing and Emelina Vienneau’s close reading of the manuscript.
All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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- Xu M, Wang LV. Photoacoustic imaging in biomedicine. Rev Sci Instrum. 2006;77(4):041101.View ArticleGoogle Scholar
- Beard P. Biomedical photoacoustic imaging. Interface focus. 2011;1:602–31.Google Scholar
- Hu S, Wang LV. Optical-resolution photoacoustic microscopy: auscultation of biological systems at the cellular level. Biophys J. 2013;105(4):841–7.MathSciNetView ArticleGoogle Scholar
- Maslov K, Zhang HF, Hu S, Wang LV. Optical-resolution photoacoustic microscopy for in vivo imaging of single capillaries. Opt Lett. 2008;33(9):929–31.View ArticleGoogle Scholar
- Wang LV. Multiscale photoacoustic microscopy and computed tomography. Nat Photonics. 2009;3(9):503.View ArticleGoogle Scholar
- Hysi E, Saha RK, Kolios MC. Photoacoustic ultrasound spectroscopy for assessing red blood cell aggregation and oxygenation. J Biomed Opt. 2012;17(12):125006.View ArticleGoogle Scholar
- Li W, Chen X. Gold nanoparticles for photoacoustic imaging. Nanomedicine. 2015;10(2):299–320.View ArticleGoogle Scholar
- Wei C-W, Nguyen T-M, Xia J, Arnal B, Wong EY, Pelivanov IM, et al. Real-time integrated photoacoustic and ultrasound (PAUS) imaging system to guide interventional procedures: ex vivo study. IEEE Trans Ultrason Ferroelectr Freq Control. 2015;62(2):319–28.View ArticleGoogle Scholar
- Jia C, Huang SW, Jin Y, Seo CH, Huang L, Eary JF, Gao X, O’Donnell M. Integration of photoacoustic, ultrasound, and magnetomotive system. InPhotons Plus Ultrasound. Imaging and Sensing 2010. International Society for Optics and Photonics. 2010;7564:756416.Google Scholar
- Wells PN. Ultrasound imaging. Phys Med Biol. 2006;51(13):R83.View ArticleGoogle Scholar
- Garcia-Uribe A, Erpelding TN, Krumholz A, Ke H, Maslov K, Appleton C, et al. Dual-modality photoacoustic and ultrasound imaging system for noninvasive sentinel lymph node detection in patients with breast cancer. Sci Rep. 2015;5:15748.View ArticleGoogle Scholar
- Xu G, Rajian JR, Girish G, Kaplan MJ, Fowlkes JB, Carson PL, et al. Photoacoustic and ultrasound dual-modality imaging of human peripheral joints. J Biomed Opt. 2012;18(1):010502.View ArticleGoogle Scholar
- Yan Y, John S, Ghalehnovi M, Kabbani L, Kennedy NA, Mehrmohammadi M. Ultrasound and photoacoustic imaging for enhanced image-guided endovenous laser ablation procedures. InMedical Imaging 2018: Ultrasonic Imaging and Tomography. International Society for Optics and Photonics. 2018;10580:105800T.Google Scholar
- Kolkman RG, Brands PJ, Steenbergen W, van Leeuwen TG. Real-time in vivo photoacoustic and ultrasound imaging. J Biomed Opt. 2008;13(5):050510.View ArticleGoogle Scholar
- Strohm EM, Moore MJ, Kolios MC. High resolution ultrasound and photoacoustic imaging of single cells. Photo-Dermatology. 2016;4(1):36–42.Google Scholar
- Mallidi S, Luke GP, Emelianov S. Photoacoustic imaging in cancer detection, diagnosis, and treatment guidance. Trends Biotechnol. 2011;29(5):213–21.View ArticleGoogle Scholar
- Manohar S, Vaartjes SE, van Hespen JC, Klaase JM, van den Engh FM, Steenbergen W, et al. Initial results of in vivo non-invasive cancer imaging in the human breast using near-infrared photoacoustics. Opt Express. 2007;15(19):12277–85.View ArticleGoogle Scholar
- Yao J, Wang LV. Photoacoustic tomography: fundamentals, advances and prospects. Contrast Media Mol Imaging. 2011;6(5):332–45.View ArticleGoogle Scholar
- Dean J, Gornstein V, Burcher M, Jankovic L, editors. Real-time photoacoustic data acquisition with Philips iU22 ultrasound scanner. Photons Plus Ultrasound: Imaging and Sensing 2008: The Ninth Conference on Biomedical Thermoacoustics, Optoacoustics, and Acousto-optics: International Society for Optics and Photonics; 2008.Google Scholar
- Jose J, Willemink RG, Steenbergen W, Slump CH, van Leeuwen TG, Manohar S. Speed-of-sound compensated photoacoustic tomography for accurate imaging. Med Phys. 2012;39(12):7262–71.View ArticleGoogle Scholar
- Montilla LG, Olafsson R, Bauer DR, Witte RS. Real-time photoacoustic and ultrasound imaging: a simple solution for clinical ultrasound systems with linear arrays. Phys Med Biol. 2012;58(1):N1.View ArticleGoogle Scholar
- Xia J, Huang C, Maslov K, Anastasio MA, Wang LV. Enhancement of photoacoustic tomography by ultrasonic computed tomography based on optical excitation of elements of a full-ring transducer array. Opt Lett. 2013;38(16):3140–3.View ArticleGoogle Scholar
- Harrison T, Ranasinghesagara JC, Lu H, Mathewson K, Walsh A, Zemp RJ. Combined photoacoustic and ultrasound biomicroscopy. Opt Express. 2009;17(24):22041–6.View ArticleGoogle Scholar
- Needles A, Heinmiller A, Ephrat P, Bilan-Tracey C, Trujillo A, Theodoropoulos C, Hirson D, Foster FS. Development of a combined photoacoustic micro-ultrasound system for estimating blood oxygenation. InUltrasonics Symposium (IUS), 2010 IEEE: IEEE; 2010:390–93.Google Scholar
- Wang P-H, Li M-L, Liu H-L, Hsu P-H, Lin C-Y, Wang C-RC, et al. Gold-nanorod contrast-enhanced photoacoustic micro-imaging of focused-ultrasound induced blood-brain-barrier opening in a rat model. J Biomed Opt. 2012;17(6):061222.View ArticleGoogle Scholar
- Kim J, Park S, Jung Y, Chang S, Park J, Zhang Y, et al. Programmable real-time clinical photoacoustic and ultrasound imaging system. Sci Rep. 2016;6:35137.View ArticleGoogle Scholar
- Ma R, Söntges S, Shoham S, Ntziachristos V, Razansky D. Fast scanning coaxial optoacoustic microscopy. Biomedical optics express. 2012;3(7):1724–31.View ArticleGoogle Scholar
- Niederhauser JJ, Jaeger M, Lemor R, Weber P, Frenz M. Combined ultrasound and optoacoustic system for real-time high-contrast vascular imaging in vivo. IEEE Trans Med Imaging. 2005;24(4):436–40.View ArticleGoogle Scholar
- Liba O, de la Zerda A. Photoacoustic tomography: breathtaking whole-body imaging. Nature Biomedical Engineering. 2017;1(5):0075.View ArticleGoogle Scholar
- Hariri A, Wang J, Kim Y, Jhunjhunwala A, Chao DL, Jokerst JV. In vivo photoacoustic imaging of chorioretinal oxygen gradients. J Biomed Opt. 2018;23(3):036005.View ArticleGoogle Scholar
- Yao J, Maslov KI, Zhang Y, Xia Y, Wang LV. Label-free oxygen-metabolic photoacoustic microscopy in vivo. J Biomed Opt. 2011;16(7):076003.View ArticleGoogle Scholar
- Wang X, Xie X, Ku G, Wang LV, Stoica G. Noninvasive imaging of hemoglobin concentration and oxygenation in the rat brain using high-resolution photoacoustic tomography. J Biomed Opt. 2006;11(2):024015.View ArticleGoogle Scholar
- Wang Y, Hu S, Maslov K, Zhang Y, Xia Y, Wang LV. In vivo integrated photoacoustic and confocal microscopy of hemoglobin oxygen saturation and oxygen partial pressure. Opt Lett. 2011;36(7):1029–31.View ArticleGoogle Scholar
- Taruttis A, Ntziachristos V. Advances in real-time multispectral optoacoustic imaging and its applications. Nat Photonics. 2015;9(4):219.View ArticleGoogle Scholar
- Razansky D, Buehler A, Ntziachristos V. Volumetric real-time multispectral optoacoustic tomography of biomarkers. Nat Protoc. 2011;6(8):1121.View ArticleGoogle Scholar
- Ferrara K, Pollard R, Borden M. Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery. Annu Rev Biomed Eng. 2007;9:415–47Google Scholar
- Hu Y-z, Zhu J-a, Jiang Y-g HB. Ultrasound microbubble contrast agents: application to therapy for peripheral vascular disease. Adv Ther. 2009;26(4):425–34.View ArticleGoogle Scholar
- Stewart V, Sidhu P. New directions in ultrasound: microbubble contrast. Br J Radiol. 2006;79(939):188–94.View ArticleGoogle Scholar
- Lee RT, Richardson SG, Loree HM, Grodzinsky AJ, Gharib SA, Schoen FJ, et al. Prediction of mechanical properties of human atherosclerotic tissue by high-frequency intravascular ultrasound imaging. An in vitro study. Arterioscler Thromb Vasc Biol. 1992;12(1):1–5.View ArticleGoogle Scholar
- Krouskop T, Dougherty D, Vinson F. A pulsed Doppler ultrasonic system for making noninvasive measurements of the mechanical properties of soft tissue. J Rehabil Res Dev. 1987;24(2):1–8.Google Scholar
- Zheng Y-P, Mak AF. An ultrasound indentation system for biomechanical properties assessment of soft tissues in-vivo. IEEE Trans Biomed Eng. 1996;43(9):912–8.View ArticleGoogle Scholar
- Yang X, Stein EW, Ashkenazi S, Wang LV. Nanoparticles for photoacoustic imaging. Wiley interdisciplinary reviews: nanomedicine and nanobiotechnology. 2009;1(4):360–8.Google Scholar
- Albanese A, Tang PS, Chan WC. The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annu Rev Biomed Eng. 2012;14:1–16.View ArticleGoogle Scholar
- Upputuri PK, Pramanik M. Performance characterization of low-cost, high-speed, portable pulsed laser diode photoacoustic tomography (PLD-PAT) system. Biomedical optics express. 2015;6(10):4118–29.View ArticleGoogle Scholar
- Wang T, Nandy S, Salehi HS, Kumavor PD, Zhu Q. A low-cost photoacoustic microscopy system with a laser diode excitation. Biomedical optics express. 2014;5(9):3053–8.View ArticleGoogle Scholar
- Rabasović MD, Nikolić MG, Dramićanin MD, Franko M, Markushev DD. Low-cost, portable photoacoustic setup for solid samples. Meas Sci Technol. 2009;20(9):095902.View ArticleGoogle Scholar