This PDF file contains the front matter associated with SPIE Proceedings Volume 12379, Title Page, Copyright Information, Table of Contents and Conference Committee lists.

The non-invasive assessment of biomarkers is crucial to predict chronic molecular changes and subsequent complications. Here, an AI-assisted volumetric multi-spectral photoacoustic imaging framework has been designed for enhanced visualization of tissue biomarkers and their monitoring. Besides, the multi-frequency spectral photoacoustic imaging approach has enabled multi-scale and multi-contrast imaging. The performances have been tested via tissue mimicking phantoms, at multiple-frequency bandwidths of 5−10 MHz, 10−22 MHz, and 15−29 MHz. Besides the impact of the frequency response of the ultrasound transducer on the PAI depth and resolution has been evaluated in detail, laying the fundamentals for the translation of PAI in clinics.

In order for photoacoustic endoscopy to make a significant contribution to clinical gastroenterology, the relevant probes must be implemented in a form that can pass through the instrument channel of a clinical video endoscope or one that has its own camera-based self-steering capability at its distal section to effectively approach a target point. In line with the first direction, multiple probes with a diameter smaller than standard channel sizes have been reported in biomedical photoacoustics research thus far. However, no actual in vivo image acquisition via the instrument channel has been demonstrated yet. In this study, we developed a torque coil-based highly-flexible mini-probe that can provide co-registered optical resolution photoacoustic and ultrasonic images via the standard instrument channel of a video endoscope. With the probe, we were able to acquire in vivo photoacoustic and ultrasonic endoscopic images from a swine esophagus via the instrument channel of a clinical video endoscope, which is the first demonstration in biomedical photoacoustics to the best of our knowledge. In this paper, we describe several useful aspects that we learned from this study and discuss future hardware development directions that must be pursued for the full clinical translation of the mini-probe technology.

The minimally invasive application of photoacoustic (optoacoustic) tomography (PAT) has been mainly focused on gastrointestinal endoscopy and the imaging of cardiovascular and reproductive systems, such as the uterus, ovaries, and prostate, in relation to the diagnosis of atherosclerotic plaques (e.g., in coronary arteries) and reproductive cancers. However, the miniature probe technology involved could also make a considerable contribution to the diagnosis and post-treatment follow-ups of urinary diseases. PAT can provide a variety of anatomical, functional, and molecular information that is not producible with conventional imaging methods, such as MRI and ultrasound. Among the related clinical issues, the development of a new diagnostic paradigm for the early detection of bladder cancer is urgently needed, because it is known to be very aggressive and lethal if found after stage 2 (T2). In this study, we developed a transurethral photoacoustic and ultrasonic endoscopic probe with an outer diameter of 2.8 mm to contribute to the early diagnosis of bladder cancer in clinical urology. From a live rabbit, we successfully acquired the first high-resolution 3D vasculature map of more than 50% of the bladder wall, which we believe is a completely new type of image information never acquired before from a vertebrate urinary system.

Photoacoustic (PA) imaging has become one of the promising biomedical imaging technologies in the past decade, thanks to its advantages of structural, functional, imaging capabilities and seamless integration with conventional ultrasound imaging. Endoscopic photoacoustic and ultrasound (ePAUS) is the combination of PA imaging technology and endoscopic ultrasound (EUS). In the design of the ePAUS, it is ideal to align the optical beam of the laser and the acoustic beam of the transducer on the same axis to achieve high spatial resolution and long imaging range. Existing ePAUS uses a ring transducer or a beam combiner to obtain a coaxial or rather an off-axis arrangement. However, the ring transducer has a problem in that the diameter and acoustic side lobes are large, and the beam combiner has a disadvantage in that the structure is complicated and the acoustic loss due to multiple acoustic reflections is large. Our approach to solving this problem is the development of ePAUS based on a miniaturized transparent ultrasonic transducer (TUT). In this study, lead-magnesium- niobate lead-titanate and Indium Tin Oxide-based ultra-small TUT was fabricated, and the performance of center frequency of 28.1 MHz and bandwidth of 51.5% was obtained. Thereafter, quasi-focus was used by combining a multimode optical fiber and a gradient index lens, and coaxial alignment was achieved by arranging the optical axis perpendicular to the optically transparent TUT. This results in high spatial resolution and long imaging distances, and the imaging performance of the probe is demonstrated by imaging the rectum and vagina of the rat in vivo.

As the most prevalent hepatic disorder worldwide, non-alcoholic fatty liver disease strongly correlates to obesity and encompasses a broad spectrum from steatosis to carcinoma. Complementary to established diagnostic modalities, photoacoustic tomography (PAT) can provide high-speed images with endogenous optical contrast. However, none of the PAT systems has investigated fatty liver non-invasively with detailed angiograms. With the newly developed noninvasive PAT (termed 3D-PAT) system, we study the livers of multiple rats in vivo. The system provides isotropically high spatial resolution in 3D space, presenting clear anatomical and dynamical details of the rat livers. Moreover, we propose several PAT image features to quantify the difference between the livers of lean and obese rats. Statistical differences between the two groups have been observed, demonstrating the capabilities of 3D-PAT to provide hematogenous information for fatty liver diagnosis. The preclinical hepatic research using 3D-PAT warrants clinical translation towards human pediatric liver imaging.

Combining functional optical contrast with high spatiotemporal resolution, photoacoustic computed tomography (PACT) benefits mainstream cardiac imaging modalities for preclinical research. However, PACT has not revealed detailed vasculature or hemodynamics of the whole heart without surgical tissue penetration. Here, we present non-invasive imaging of rat hearts using the recently developed three-dimensional PACT (3D-PACT) platform. 3D-PACT utilizes optimized illumination and detection schemes to reduce the effects of optical attenuation and acoustic distortion through the chest wall, thus visualizing cardiac anatomy and intracardiac hemodynamics within a 10-second scan. We then applied 3D-PACT to investigate different structural and functional variations in healthy, hypertensive, and obese rat hearts. 3D-PACT provides high imaging speed and nonionizing penetration to capture the whole heart for diagnosing animal models, holding promises for clinical translation to human neonatal cardiac imaging without sedation or ionizing radiation.

Photoacoustic ophthalmoscopy in rodents is gaining research momentum, due to advancement in transducer shape and technology. Needle transducers emerged as most valuable tool for photoacoustic retinal imaging and have proven to be sensitive enough to resolve retinal vasculature in-vivo. Nevertheless, placement of the eye and screening of the retina remains challenging, since needle transducers must remain static during image acquisition, while the optical field of view is limited. Such restriction mandates movement of the mouse to rotate the eye and therefore the imaging area on the retina. The needle transducer needs to be temporarily detached during this process to avoid damage to the eye or the transducer. Re-attachment involves additional application of ultrasound gel and doesn’t guarantee ideal placement for optimized imaging performance. Additive manufacturing can help to tackle those challenges and allows to design novel rotational rodent holders for imaging. Hence, we present a fully 3D printable rotatable tip/tilt mouse platform with the eye in the center of rotation, combined with a printable needle transducer holder. Such system guarantees optimal placement of the needle transducer during imaging and rotation of the mouse eye, avoiding detachment of the transducer and effortless screening of the retina. The capabilities for retinal screening are demonstrated by a multimodal optical coherence photoacoustic ophthalmoscopy system employing two separated wavelengths, 1310 nm for optical coherence and 570 nm for photoacoustic ophthalmoscopy.

Photoacoustic (PA) imaging is a technique that visualizes the optical absorption characteristics with ultrasound-like spatial resolution. It has been demonstrated that molecular targeted contrast agents (CAs) have great potential in applying to the early detection of tumor. These CAs attach to the tissues of the subject of interest, i.e., the cancerous cells, and emit PA signals based on the absorbed light. Precise quantification of the CA expression is desired to identify the degree of the malignancies. The current quantification of the CA expression is based on the strength of the PA intensity with the assumption of its linearity between them. However, the estimation accuracy of such a method is limited because the PA intensity is affected by many factors including the light, sound, and tissue interactions and the use of CAs that do not present linearity. Here, we investigate a robust quantification method by using the spectroscopic relationship between the dye concentration and its corresponding PA variation. We introduce a spectroscopic decomposition algorithm considering multiple reference spectra to accommodate the non-linear behavior of sample concentrations. The in vitro validation of the concept was performed using the synthesized PA CA possessing the non-linear property. The concentration of the samples was successfully estimated with the algorithm. The introduced method improved the quantification accuracy by reducing the averaging estimation error from 15.89 𝜇M to 1.80 𝜇M, compared with the conventional estimation.

Two optical techniques and two ultrasound methods have been applied on an excised mouse tumor with the aim of estimating its microstructural properties. Enhanced Backscattering Spectroscopy, Light Scattering Spectroscopy, ultrasound Backscatter Coefficient parametrization and Envelope Statistics have been performed the same day on this biological sample. Thus, different quantitative light-based and ultrasound-based parameters that reflects the scattering properties have been estimated. Histological analyses were carried out to obtain morphological information about the cell structures. The scatterer size distribution extracted by the Backscatter Coefficient parametrization (mean radius = 9.2 µm) overestimates the cell size (mean radius = 4.6 µm). However, a good agreement have been observed between the experimental data and the models for Enhanced Backscattering Spectroscopy and Envelope Statistics (respectively R2 = 0.98, R2 env,HK = 0.98 ± 0.01 and R2 env,Nak = 0.90 ± 0.03). These two techniques brought quantitative parameters with difficult absolute value interpretations. Nonetheless, they could be of prime interest in studies with different type of tissue for classification purposes.

Two-dimensional and three-dimensional photoacoustic (PA) visualization is an emerging diagnostic procedure for investigation and research in vascular studies. Current manual/mechanized target scanning techniques involve sweeping the target along the elevation to generate 3D visuals. However, since the linear array probes exhibit poor resolution along the direction orthogonal to its focal plane, these techniques are prone to miss out on the organic structures parallel to the lateral direction. This could result in a misrepresentation of the target and is a critical shortfall of the method. We propose a multiview scanning and compounding technique to overcome the directionality bias and obtain more accurate and isotropic imaging performance. Using electromechanical translatory and rotary stages for multiview data acquisition, we generate a unified 3D visualization. A data processing pipeline illustrates an axial implementation of the Hilbert transform followed by spatial integration of the volumetric data to obtain the output. A 6-directional scanning approach improves the completeness of the structural details. We validated the technique using sub-millimeter-sized balls and wire phantoms. We first observed an enhanced resemblance of the outcome with the actual target in the ball phantom. Secondly, we observed imaging quality improvement with isotropic intensity distribution prominently in the wire phantom. A comparative analysis showed around a 50% reduction in the standard deviation of intensity distribution as compared to conventional unidirectional 3D PA imaging.

A photoacoustic 3D imaging system for animal experiments was made. This system is special because it has a hemispherical detector array. To test its performance, we used a chart from the field of optics as a sample. We checked the whole imaging range using the ISO 12233 chart, which is used to test digital camera images. We found that there was no distortion in the xy-plane and the system had high resolution. We also tested it using a high image quality mode with a different scanning sequence. In this study, live albino mice with white hairs were anesthetized and photographed. Using hair removal cream, we were able to visualize the vascular network throughout their bodies, including blood vessels in organs such as the liver and kidneys. The smallest vessels we were able to visualize were less than 0.1 mm in diameter. We used photoacoustic (PA) images to relatively estimate the oxygen saturation of the mice's blood at two different wavelengths, which we refer to as the S-factor. By analyzing the PA images, we were able to estimate the arterial and venous systems of the whole body, as well as the difference in S-factor between the two systems within the liver. When the mice were euthanized and examined post-mortem, we observed that the S-factor of the whole body decreased and the difference in S-factor between the two systems within the liver was lost.

Photoacoustic (PA) wavefront shaping (WFS; PAWS) could allow focusing light deep in living tissue, increasing the penetration depth of biomedical optics techniques. PAWS experiments have demonstrated focusing light through rigid scattering media. However, focusing deep in tissue is significantly more challenging. To examine the scale of this challenge, a computational model of the propagation of coherent light in tissue was developed to simulate the focusing of light via PAWS. To demonstrate the model, it was used to simulate focusing in an 800 µm thick tissue-like medium. To show the utility of the model, the focusing was repeated in different conditions illustrative of simplified PAWS experiments involving different spatial resolutions. As expected, a finer spatial resolution led to a brighter focus. By providing a simulation platform for studying PAWS, this work could pave the way to developing systems that can focus light in tissue.

The heart is the first essential organ that develops during organogenesis. Fetal impaired heart function correlates to functional cardiac anomalies and heart defects in adulthood. Therefore, noninvasive assessment of dynamic functional cardiac events during pregnancy is essential for early diagnosis of cardiac diseases. However, visualization and analysis of the small yet fast-beating embryonic heart require a high-resolution imaging platform to provide reliable volumetric analyses. Optoacoustic (OA) imaging provides excellent optical contrast along with high spatial resolution and has demonstrated an exclusive potential for noninvasive deep-tissue visualization. In this study, we used volumetric OA imaging to visualize the embryonic heart at gestational day (GD) 16.5. The anatomical structure of the embryonic heart and cardiac vasculature was visualized in three orthogonal imaging planes allowing for further quantification and structural measurements. Twenty-five volumes per second temporal resolution of OA imaging enabled assessment of embryonic cardiac dynamics. Using the temporal profile of the time-lapse OA data at different locations of the embryonic heart, the average heart rate of embryos was calculated. This study demonstrated the capability of volumetric OA tomography for noninvasive visualization of the embryonic heart and assessment of cardio dynamics at nearly video rate.

The ability to perform dynamic imaging of time-varying physiological processes in small animal models is critically needed to understand the progression of human diseases and develop new therapies. Photoacoustic computed tomography (PACT) has been recognized as a promising tool for small animal imaging because of its relatively low expense, high resolution, and good signal-to-noise ratio. By exploiting the optical absorption of hemoglobin or exogenous contrast agents, dynamic PACT holds excellent potential for measuring important time-varying biomarkers like tumor vascular perfusion. Nonetheless, current dynamic PACT technologies possess several limitations. Most three-dimensional (3D) PACT imagers employ a tomographic measurement process in which a gantry containing acoustic transducers is rotated about the animal. Such a rotating gantry is advantageous for limiting the cost of the system due to the decreased number of acoustic transducers and associated electronics and for enabling convenient delivery of the light to the object. However, this presents significant challenges for dynamic image reconstruction because only a few tomographic views are available to reconstruct each temporal frame. This work presents an efficient and accurate dynamic image reconstruction method that can be deployed with widely available 3D imagers using rotating gantries. In particular, a low-rank matrix estimation based spatiotemporal image reconstruction (LRME-STIR) algorithm is proposed. In a stylized virtual dynamic contrast-enhanced imaging study, the proposed LRME-STIR algorithm is shown to accurately recover a well characterized dynamic numerical murine phantom in which tumor vascular perfusion and breathing motion are modeled.

Small animal preclinical research is indispensable to study human disease progression and to monitor potential treatment therapies. Optoacoustic tomography has been recognized as a powerful imaging modality for preclinical whole-body imaging of rodents. In particular, spiral volumetric optoacoustic tomography (SVOT) capitalizes on the large angular coverage of a spherical transducer array to provide otherwise-unattainable optoacoustic images of mice. However, only thoracic and/or abdominal regions of the animal could be imaged with this approach. Efficient whole-body coverage indeed demands continuous acoustic coupling between the animal and the detector surface. In this work, we implement panoramic (3600) head-to-tail imaging of mice with SVOT combined with multi-beam illumination. For this, a dedicated animal holder enables uninterrupted acoustic coupling for whole-body scans. Proper coverage of cranial regions in addition to thoracic and abdominal regions is then feasible in a single set up. Self-gated motion rejection and dual speed-of-sound correction algorithms were employed to optimize the image fidelity. The developed system is highly suitable for label-free imaging of hemodynamics across individual organs, total body accumulation and clearance dynamics of molecular agents and drugs, as well as for monitoring responses to stimuli with unparalleled contrast and spatio-temporal resolution.

Photoacoustic tomography (PAT) is a valuable tool in characterizing ovarian lesions for accurate diagnosis. However, limited view problem degrades the quality of PAT reconstruction severely, especially for transvaginal transducer which only partially encloses the target. To address this issue, we compensated limited view information loss by co-registered PAT and US machine learning method. The simulation and phantom results showed that the details of the target were recovered by proposed method, compared with delay-and-sum reconstruction method.

Photoacoustic computed tomography (PACT) has emerged as a practical tool for fast 3D imaging with optical contrast that give morphological, functional, and molecular in vivo information. The spatiotemporal resolution of the PACT system are decided by the composed hardware specification. Hence, to achieve better image quality and faster imaging speed, the high-specification hardware should be supported, but it leads to huge costs. Here, we propose a new solution to overcome the inherently trade-offs between imaging speed and image quality based on a neural network, a 3D progressive U-shaped enhancement network (3D-pU-net). In our approach, a hemispherical transducer array-based PACT system was used for the system configuration, and we could obtain accurate high-quality reference images with all elements of the array. Cluster sampling, which was used for input data, is not affected by imaging speed degradation, but the image quality is degraded. We demonstrated that the trained 3D-pU-net enhanced the image quality of cluster-sampled data of static whole-body imaging. Furthermore, the network also performed a wide range of applications such as dynamic observation of contrast agent kinetics. In this study, we showed that the 3D-pU-net could improve the anatomical contrast and spatial resolution by overcoming the limited-view effect. This proposed approach can help a variety of PACT applications in practical settings, allowing for the development of useful and economical imaging equipment.

High-speed photoacoustic (PA) endomicroscopy imaging is desired for real-time guidance of minimally invasive surgery. However, the imaging speed of wavefront shaping-based endomicroscopy has been limited by the speed of spatial light modulators. In this work, a deep convolutional neural network was used to improve the imaging speed of a newly developed PA endomicroscopy system by enhancing sparsely sampled PA images. With a carbon fibre phantom, this method increased the imaging speed by 16 times without significantly affecting the image quality. With further validation on more complex datasets, this approach is promising to achieve real-time PA endomicroscopy imaging via wavefront shaping.

This paper reports a 2D surface-micromachined optical ultrasound transducer (SMOUT) array consisting of 350 × 350 elements based on Fabry-Perot interferometry. The uniformity of the SMOUT array is characterized by mapping the optical performance of the elements. The center frequency, acoustic bandwidth, and noise equivalent pressure (NEP) of the elements are determined to be 3.5 MHz, 5 MHz, and 20.7 Pa over a bandwidth of 10 MHz, respectively. PACT based on the SMOUT array is conducted to demonstrate the imaging capability. With these features, SMOUT array could provide a promising solution for achieving high-speed 3D PACT applications.

Unraveling the scientific and technological importance of the mid-infrared (mid-IR) region remains yet a long-standing challenge. Despite the significant efforts on mid-IR light sources, development of high-energy, narrow-linewidth and compact lasers still constitutes the main obstacle towards novel spectroscopic, imaging and sensing devices. Photoacoustic modality is known as one of the most powerful tools enabling high signal-to-noise ratio gas detection and albeit its wide use in the mature near-infrared (near-IR) region, further research has to be carried out in the mid-IR in order to “unlock” its full potential. In this work, we aim on tracing CO2 based on the innovative combination of the emerging gas-filled mid-IR silica anti-resonant hollow-core fiber (ARHCF) Raman laser technology with the powerful photoacoustic modality. The laser source adopts the stimulated Raman scattering effect of H2 filled in a piece of ARHCF, to enable the generation of first-order vibrational Raman Stokes from a 1533 nm Er-doped fiber laser pump. With this configuration, a nanosecond laser pulses with micro-joule level pulse energy is achieved at ~ 4.25 μm wavelength, which is located within the strongest absorption band of CO₂. The laser’s linewidth is estimated to be tens GHz level. This laser source is used to drive an in-house developed photoacoustic sensor, revealing a 1.78 ppm level CO₂ detection limit in laboratory condition. This work provides a valuable reference for the development of high-sensitivity gas detectors.

In this work, we have developed PVDF-TrFE/BaTiO₃ composite thin film-based highly sensitive ultrasound (US) and photoacoustic (PA) transducer. The synthesized nanocomposite polymer-based sensor film has been grown layer by layer on the flat surface of a 9.00 mm diameter aluminum substrate. The fabricated transducer has been tested in pulse-eco mode and it shows high sensitivity with a peak-to-peak voltage 800 mV. Preliminary US and PA experiments have been performed with the aluminum block and multi-layer ink coated phantom. The central frequency of the obtained acoustic signal was found to be 44 MHz with an acoustic bandwidth of 32 MHz (72% of central frequency at -6 dB). The PA signals have been detected with the fabricated transducer and the estimated frequency spectrum shows multiple sub-band central frequencies varying from 17 MHz to 55 MHz. Due to its high sensitivity and broad bandwidth, the developed transducer can be used for high-resolution US and PA microscope imaging (PAI).

The optical phase contrast technique in combination with camera technology is a promising ultrasound detection approach for photoacoustic imaging. However, sensitivity needs to be optimized to be competitive with piezo array detection approaches. This can be achieved without sacrificing resolution by substituting Fluorinert liquid for water. This liquid has a nearly four times larger piezo-optical coupling coefficient and a speed of sound (SoS) of 598 m/s. The overall performance of the proposed sensitivity improvement taking into account the spatial SoS inhomogeneities and reflecting walls in the reconstruction with the time-reversal method is examined in simulations and preliminary tests.

Photoacoustic computed tomography (PACT) utilizing a linear array ultrasound transducer that can be handheld is popular in clinical translation. However, in linear array PACT, one of the challenges is achieving homogenous light illumination of structures from the surface through deep structures within biological tissue with limited optical energy. A circular or rectangular optical fiber bundle attached to both sides of the elevation plane of the transducer at a fixed angle provides light delivery in linear array PACT, but this configuration does not provide optimum homogenous illumination. Therefore, it is essential to have accessibility to angular adjustment of the optical beam path to allow photons to create different pathways. Existing methods for implementing various beam paths are not flexible or require precise calibration for any changes in the angle of illumination. In this study, we propose a simple and effective adjustable-angle illumination scheme for linear array-based PACT to create different illumination focal points randomly within the imaging plane. This method, based on an adjustable angular illumination technique while acquiring photoacoustic signals, allows the incident photons to interact with the imaging targets for longer periods of time and diffuse further in all directions. We have investigated the effectiveness of the proposed method by imaging photoacoustic targets in biological tissues ex-vivo and demonstrated that deeper structures can be successfully identified.

Since hypoxia is an early marker for cancer and several microvascular disorders, imaging oxygen saturation with high resolution has profound importance in multiple preclinical and clinical imaging studies. In this work, we demonstrate the potential of dual-wavelength (690/850 nm) LED-based photoacoustic imaging in high resolution real-time oxygen saturation imaging in vivo. We performed two live rat imaging experiments in which the oxygen saturation of the blood vessels in the left hindlimb was imaged for 20 seconds while the animal was breathing pure nitrogen gas to induce hypoxia. For a comparison, we continuously monitored the oxygen level using a pulse oximeter connected to the forelimb. In another experiment, we performed imaging of oxygen saturation changes in the tail vein of the rat while hypoxia was induced over the period of 40 seconds. In this case also, pulse oximeter readings were recorded for a comparison. In all the experiments, photoacoustic-based oxygen saturation values measured over time followed the same trend as the reference values provided by the pulse oximeter. Also, our two wavelength LED-based photoacoustic imaging approach was found to be sensitive even for 3% change in oxygen saturation. Results give a direct confirmation about the potential of LED-based photoacoustic imaging in detection of oxygen saturation with high spatio-temporal resolution, making it an ideal tool for hypoxia detection in longitudinal preclinical and clinical imaging studies.

Approximately 19% of breast cancer patients undergoing breast conserving surgery (BCS) must return for a secondary surgery due to incomplete tumour removal. We propose a single sensor, low-frequency hand-held photoacoustic imaging (PAI) probe for detection of residual cancer tissue during BCS within the surgical cavity and on the excised specimen based on lipid content differences. The probe incorporated a single polyvinylidene fluoride acoustic sensor, a 1-to-4 optical fibre bundle and a polycarbonate axicon lens for light delivery. A phantom consisting of nylon strings was imaged to find an optimal scanning geometry and resolution of the probe. The effect of limited angular coverage was evaluated by comparing the PAI results of a phantom mimicking an ex-vivo breast cancer specimen obtained with the hand-held probe and near-full view PAI system. Translation of the probe with 4 mm steps and rotation over 6° steps resulted in lateral and axial resolution of 1.8 mm and 1 mm, respectively. Experiments with the prototype hand-held PAI probe at 930 nm resulted in excellent image contrast exclusively from lipids. Lipid-free gaps mimicking positive margins were clearly visible in the images. Compared to images from the near full-view PAI system, the hand-held PAI probe had a higher signal-to-noise ratio but suffered from more negativity image artefacts. Taken together, the results show that PAI with the hand-held probe has the potential for detection of residual breast cancer tissue during BCS.

Visualizing blood vessel networks in 3D is helpful in many superficial vascular imaging applications. We previously reported the feasibility of LED-based photoacoustic imaging in visualizing human vasculature in 3D by linear translation of combined photoacoustic/ultrasound imaging probe. In this work, we improved this 3D imaging functionality by 1) automatic removal of skin PA signal in different 2D slices by ultrasound-based lineation , 2) encoding depth information with different colors and 3)improving the grayscale and hot color maps. All these new features were implemented in the system software and we validated these using phantom and human in vivo imaging experiments. Results demonstrate that the newly implemented features significantly improved the 3D imaging capability in our LED-based photoacoustic and ultrasound imaging system. We believe that the improved 3D imaging functionality in the system will be potentially useful for multiple preclinical and clinical applications in which the visualization of vasculature in 3D is a prerequisite.

During medical investigations of the head, ultrasound measurements can offer information with simple, non-invasive, and real-time procedure. However, for human adult applications, the clinical treatment of transcranial acoustic imaging remains a challenge by the presence of the skull, results in acoustic aberrations caused by two main phenomena, i.e., attenuation and distortion. These aberrations may affect the signal understanding because of the induced artifacts and the inaccuracy of the imaging target structural information. Variations of the physical properties of the skull, its thickness and porosity, will strongly affect the mechanical properties of the medium and thus the acoustic response. We propose a method to understand the influence of these characteristics on the signal degradation. In order to mimic the human adult skull, a large quantity of epoxy resin-based phantoms is created to explore all the possible physical characteristic variation in the bone. Additional components, titanium dioxide and seeds, will be added to the samples to recreate the acoustic scattering effects of a skull bone. Signal features from pulse-echo mode ultrasound, such as signal attenuation or broadening, will be extracted and studied in the time and frequency domain. In this paper, we are looking for relationship between these physical parameters and the signal features, with the objective to determine bone characteristics without any direct access in later experiments; and going a step further into aberration correction during transcranial imaging procedure.

Laser scanning photoacoustic microscopy (LS-PAM) is one of the simplest implementations of photoacoustic microscopy (PAM) systems. In this work, we investigate how the sensitivity distribution of the transducer relates to its FOV, which in turn affect the imaging area. Furthermore, the relation between transducer active area and sensitivity distribution will be investigated. Transducers with varying diameters and sensitivity will be compared and their FOV will be evaluated. The results will be quantitatively compared in terms maximum sensitivity distribution, signal to noise ratio (SNR) of the signals received and peak signal to noise ratio (PSNR) of the images produced.

Conventional model-based algorithms are based on building the forward model and then minimizing the cost function with some constrain. In this study, a new approach is proposed, based on building the forward model, stabilizing it and then minimizing the cost function. The more stable system provides more stable solution. A small perturbation in the measurement matrix would not change the solution much if the proposed method is applied.

Microwave-induced thermoacoustic tomography has the advantage of a high spatial resolution and a deep imaging depth. This method has been extensively explored over the past decade to find an alternative of existing imaging techniques. In this study, we have developed a compact microwave-induced thermoacoustic tomography (MI-TAT) with a waveguide antenna and a rotating ultrasound transducer unit. We performed a characterization study of the system in terms of pulse width, selection of microwave frequency and resolution. Then the optimized parameters were used to image in-vitro complex structure phantoms. Later, we expanded our system capability for spectroscopic study by imaging different concentrations of methanol and water to mimic the tissue properties and analyze them based on the absorption characteristics of these materials. We hope, this spectroscopic capability broadens the capability of thermoacoustic system to separate the diseased tissue from the healthy one (e.g., malignant from benign) with a high sensitivity and specificity.

Three-dimensional (3D) photoacoustic tomography is a method of choice for imaging round organs such as brain and breast. Many research groups have used a fully populated hemispherical transducer array with 256, 512, 1028, or 2048 elements and used that for 3D imaging. These transducer arrays are expensive and require a sophisticated data acquisition unit. Other groups have used much smaller number of transducers with a rotating mechanism which eventually filled out the entire hemisphere. We have built a 3D hemispherical array with 28 transducers which are placed on a 3D printed dome-like unit. The location of transducers however may be off-placed by a few millimeters (due to human error and errors in 3D printing). This may be to defocus the reconstructed image if the acceptable positions of transducers are not selected. In this work, we developed a compensation algorithm for misplacement of these transducers using Cuckoo search (CS) algorithm. The CS algorithm finds the optimum location for the transducers using levy flight which relies on levy distribution. The optimum location of each of these transducers is found within -4 mm to 4 mm of their locations. Universal back projection algorithm was used for image reconstruction and the sharpness of 3D image was used as the cost function; additionally, two more objective functions, the Brenner gradient, and the Tenenbaum gradient was investigated.

We developed a deep learning algorithm, called enhancement Unet (E-Unet), to improve the signal-to-noise ratio (SNR) of signals acquired in a photoacoustic computed microscopy (PAM) system. We tried various combination of custom loss functions which included peak-amplitude, peak-position and mean-squared signal value with Adam optimizer for training purposes. For the testing purposes, we acquired PAM data with complicated phantoms in biological tissue. The performance of the improved signals is evaluated in terms of SNR, structural similarity index (SSIM), root mean square error (RMSE) and Pearson correlation.

To understand various phenomena that occur in living tissue, high-speed volume imaging technology that visualizes the dynamics of cells and molecules in living tissue is desired. For this purpose, we have developed a reflective MS-PAI with high excitation wavelength flexibility using a supercontinuum light source and bandpass filters, and a fast B-scan rate of over 100 fps. The ability of the MS-PAM for cell dynamics imaging was demonstrated by performing time-lapse volume imaging of contrast agent-stained cells flowing through blood vessels. We plan to combine the MS-PAM technology with functionalized contrast agents (imaging probes) to analyze dynamic phenomena.

Optical resolution photoacoustic microscopy enables label-free imaging of structures containing a variety of endogenous chromophores. For fast image acquisition, we combine a galvo scanner with a fixed, acoustically focused detector, where the sample to be imaged is located slightly outside the acoustic focal plane at a distance where the whole field of view lies within the sensitive area of the acoustic detector. Errors arising due to the uneven sensitivity and the varying relation between arrival time and axial position are avoided by applying a model-based reconstruction to the received signals, using a calculated or measured three-dimensional point spread function.

Photoacoustic imaging has recently demonstrated strong viability for tool tip visualization in surgical guidance. The rigidity of conventional transducers requires applied pressure for complete tissue contact when placed on curved organs while flexible arrays are able to conform to different geometries. This work presents photoacoustic images acquired with a rigid laparoscopic transducer and a flexible array transducer on different curved surfaces and provides quantitative comparisons on image quality and transducer characterization. The wider field-of-view and correct target depth in images make the flexible array advantageous for tool tip identification in photoacoustic-guided surgery over the laparoscopic transducer.

High Power Diode Laser (HPDLs) can potentially be more suitable laser sources for commercial implementation of short pulse application such as optoacoustic biomedical imaging, compared to the commonly used solid state lasers due to their lower cost, compact size and higher repetition rate. However, the commercially available HPDLs are designed and characterized to operate with much longer pulse durations and lower peak powers compared to what usually is required in optoacoustics applications. In this paper, we study the operation of the HPDL devices, out of the manufacturer datasheet ratings at high current (< 40A) and short pulses (< 100ns). Two short pulse, high current drivers have been used to control the HPLDs. We have obtained optical peak powers of 257 W and energies per pulse of 5.2 µJ at 20 ns optical pulse duration with a single HPDL chip and using a four HPDL chips array, we have achieved optical peak powers of 750 W and energies per pulse of 31.2 µJ at 40 ns optical pulse duration. This new operating regimen improves the performance of HPDL for optoacoustic biomedical imaging techniques.

Medical ultrasound is an imaging technique that utilizes ultrasonic signals as information carriers and has wide applications such as seeing internal body structures and finding the sources of an internal diseases. The most used ultrasonic transducer today is based on piezoelectricity. The piezoelectric transducer, however, may have a limited bandwidth and insufficient sensitivity for reduced element size. In this work we demonstrate the generation of wideband ultrasound pulses using high power diode lasers (HPDLS), short pulsed current sources and composite absorbers. We design and implement the pulsed current sources optimized for the HPDLs. We fabricate candle soot PDMS composite targets. We have achieved peak pressure of 323 kPa and bandwidths at -6 dB of 34 MHz using a diode laser with an optoacoustics conversion efficiency of 5.3 *10^-3 Pa/(W/m² ). Finally, we present a compact low-cost tunable ultra-wideband laser ultrasound emitter.

Photoacoustic (PA) wavefront shaping (WS; PAWS) could allow focusing light deep in biological tissue. This could enable increasing the penetration depth of biomedical optical techniques including PA imaging. However, focussing at depth requires a light source of long coherence length (CL), presenting a challenge because the CLs of typical PA excitation lasers are short. To address this challenge, we developed a PAWS system based on an externally modulated external cavity laser with a long CL. The system was demonstrated by focussing light through rigid scattering media using both PAWS and optical WS. PAWS enabled focussing through diffusers with 8 × enhancements, while all-optical WS enabled focussing through various scattering media including a 5.8 mm thick tissue phantom. By enabling PAWS with increased coherence, the system could facilitate exploring the practical depth limits of PAWS, paving the way to focussing light deep in tissue.

In the inverse problem of photoacoustic tomography (PAT), initial pressure distribution induced by the photoa-coustic effect is estimated from a set of measured ultrasound data. In the recent decade, utilization of various deep learning approaches for the inverse problem of PAT have been proposed. However, many of these approaches do not provide information of the uncertainties of the reconstructed images. In this work, we propose a deep learning based approach for the Bayesian inverse problem of PAT based on variational autoencoders. The approach is evaluated using numerical simulations and compared against posterior distribution obtained using a conventional Bayesian image reconstruction approach. The approach is shown to provide rapid and accurate reconstructions with reliability estimates.

Transabdominal imaging using photoacoustics (PA) is limited by optical attenuation of tissue due to high scattering and absorption in the near infrared (NIR) window. Tissue attenuation is lowered when imaging with longer wavelengths in the NIR window (> 950 nm). However, intrinsic optical contrast is limited in this range and exogenous agents such as gold nanorods (AuNRs) prove popular alternatives. AuNRs have unique optical absorption peaks, due to localized surface plasmon resonance (LSPR), which allow tuning to wavelengths with minimal tissue attenuation. However, AuNRs tend to be bulky (> 50 nm) when adjusting peak LSPR to deep NIR wavelengths leading to poor clearance. In this study, we explored PA signal generation of a biodegradable and biocompatible semiconductor contrast agent – Cu-Fe (bornite) nanocrystals. The semiconductor nature of the nanocrystals allows for particles to be small (3-8 nm) facilitating excretion through kidneys. Here, PA signal generation of bornite was compared to two conventional photoacoustic contrast agents – AuNRs and indocyanine green dye. We found that at similar mass concentrations, bornite generated PA signal 5× greater than AuNRs. In-vivo imaging of bornite showed a 2x increase in sensitivity compared to AuNRs at similar volume concentrations.

In quantitative photoacoustic tomography (QPAT), distributions of optical parameters inside the target are reconstructed from photoacoustic images. In this work, we utilize the Monte Carlo (MC) method for light transport in the image reconstruction of QPAT. Modeling light transport accurately with the MC requires simulating a large number of photon packets, which can be computationally expensive. On the other hand, too low number of photon packets results in a high level of stochastic noise, which can lead to significant errors in reconstructed images. In this work, we use an adaptive approach, where the number of simulated photon packets is adjusted during an iterative image reconstruction. It is based on a norm test where the expected relative error of the minimization direction is controlled. The adaptive approach automatically determines the number of simulated photon packets to provide sufficiently accurate light transport modeling without unnecessary computational burden. The presented approach is studied with two-dimensional simulations.

We have developed fluorescent dye-encapsulating nanoparticle reagents that can be administered to animal model, enabling both photoacoustic and fluorescence imaging. Two types of in vivo photoacoustic imaging systems were developed to visualize the imaging reagents administrated to tumor model mouse. Of the two imaging systems, one used a high frequency linear array ultrasound transducer and the other used a low frequency concave array ultrasound transducer. We also used an IVIS system for fluorescence imaging of the reagents administered to tumor model mouse. IVIS allows us to easily obtain the fluorescence distribution of the reagent on a two-dimensional plane of the whole body of mouse. We successfully obtained photoacoustic images of the distribution of reagents after intravenous administration. The photoacoustic image, as well as the fluorescence image, was able to visualize the tumor accumulation of the reagents due to the EPR (Enhanced Permeation and Retention) effect. Our fluorescent dye-encapsulated nanoparticle reagents can be used for the evaluation in vivo localization and accumulation over time. The reason for this success is that we took advantage of the ability of the reagents to simultaneously generate photoacoustic and fluorescence signals. This means that the measuring conditions for photoacoustic imaging could be determined based on the fluorescence data acquired with IVIS. In the case of in vivo photoacoustic imaging of the administered reagents such as the nanoparticle reagents developed in this study, whose distribution changes over time and has not previously been used as imaging targets, the simultaneous fluorescence signals must be effective in detecting photoacoustic signals of the reagents.

Optical-resolution photoacoustic microscopy (OR-PAM) is a label-free and non-invasive technique for imaging blood vessel and hemoglobin oxygen saturation (sO₂) of living animals in vivo, providing functional information for disease diagnosis. However, most state-of-the-art OR-PAM systems require bulky and costly pulsed lasers, which hinders their wide applications in clinical settings. Here, a reflection-mode low-cost photoacoustic microscopy system using two laser diodes (LDs) was developed for in-vivo microvasculature and sO₂ imaging with a high resolution of ~6 μm. The sO2 measurement is validated in both blood phantom and in vivo animal experiments. The phantom study shows that our system has a strong linear relationship with the preset sO₂ (R ² = 0.96). The in-vivo experiment of mouse ear imaging demonstrated that our system can achieve high-resolution and high-quality imaging of microvasculature and sO₂. This technical advancement in cost reduction and superior imaging performance promotes the fast and wide applications of PAM in biomedical fields.

Photoacoutisc (PA) imaging can not only depict the geometrical features of a target like ultrasound but also allow to decompose of the contribution from different material sources based on their own specific optical absorption characteristics. With the potential of PA imaging, how to utilize the extracted information beyond diagnosis and monitoring is an open research question. Despite this interest in the field, the PA-based automation of regulating conditions of contrast sources such as position and concentration has not been actively studied. This regulation has the potential to be used for several applications including precise/long-term dose control of exogenous contrast agents in the context of drug delivery. In addition, material decomposition allows for the selective regulation of specific contrast agents. This would be advantageous in clinical situations where it is necessary to use multiple types of contrast agents simultaneously and independently. In this report, we propose a system architecture to realize closed-loop source regulation through real-time spectroscopic PA imaging and develop an experimental setup to demonstrate the feasibility of this approach. The system autonomously terminated the ICG flow within the target performance range which is defined considering the specifications of the system.

Generating an image of acceptable quality will take several minutes in circular scanning geometry-based Photoacoustic tomographic (PAT) imaging systems. Although, the imaging speed can be improved by employing multiple single-element ultrasound transducers (UST) and faster scanning. The low signal-to-noise ratio at higher and the artifacts arising from sparse signal acquisition hamper the imaging speed. Thus, there exists a need to improve the speed of the PAT imaging system without compromising the image quality. To improve the frame rate of the PAT system, we propose a convolutional neural network (CNN) based deep learning architecture for reconstructing the artifact-free PAT images from the fast-scanning data. The proposed model is trained with the simulated dataset and its performance was evaluated using experimental phantom and in-vivo imaging. The efficiency to improve the frame rate was evaluated on both the single-UST and multi-UST PAT systems. Our results suggest that the proposed deep learning architecture improves the frame rate by six-fold in a single UST PAT system and by two-fold in a multi-UST PAT system. The fastest frame rate of ~ 3Hz was achieved without compromising the quality of the PAT image.

Tumor hypoxia causes resistance to radiotherapy. A non-invasive imaging method is needed to quantitatively measure tumor hypoxia to predict radiotherapy response before starting treatment. Furthermore, radiotherapy can damage blood vessels, which can reduce vascular perfusion and oxygen delivery. We have developed Oxygen Enhanced – Dynamic Contrast Enhanced Multispectral Optoacoustic Tomography (OE-DCE MSOT) that can evaluate hypoxia and vascular perfusion in a single scan session. OE MSOT measures oxygen saturation with medical grade air (%sO₂ ^air using 21% O₂) breathing gas and 100% breathing gas (%sO₂ ^O2), and the “available oxygen capacity” (ΔsO2) that is the difference between %sO₂ ^air and %sO^{2 air} . DCE MSOT uses the normalized pharmacokinetics profile of an exogenous contrast agent in a tumor to calculate NKtrans and kep, which indicate the wash-in and wash-out vascular perfusion rates, respectively. We have shown that our DCE MSOT methodology avoids the problem of variable fluence within in vivo tissues. We applied OE-DCE MSOT to study the effect of radiotherapy on three tumor models that have different levels of vascular perfusion and hypoxia. Our results showed that %sO2 ^air , %sO₂ ^O2 , ΔsO₂ identified normoxic, mildly hypoxic, and hypoxic models, which was related to the high-to-low status of vascular perfusing as measured with NKtrans . A change in ΔsO₂ and NKtrans indicated early response to radiotherapy. These results demonstrate the advantages of OE-DCE MSOT for simultaneously evaluating tumor hypoxia and vascular perfusion before and soon after treatment.

Corticosteroids are commonly used medications for dermatological diseases. The main mechanisms of corticosteroids are vasoconstriction and anti-inflammatory. In medical field, its effectiveness is determined based on the degree of skin whitening caused by vasoconstriction. In this study, we first quantitatively evaluate the vasoconstriction induced by corticosteroids using photoacoustic microscopy (PAM). We longitudinally monitor vascular density and observe vasoconstriction by corticosteroids. Further, the changes in vascular density are quantified in each skin layer. From these results, we believe that PAM could potentially be a useful evaluation tool to predict the effectiveness of the corticosteroids in dermatology.

Sharing the same acoustic imaging principle, photoacoustic (PA) imaging is available to be done simultaneously with ultrasound (US) imaging, while still discrepancy between two modalities exists as PA imaging relatively suffers with higher depth attenuation and low signal contrast compared to the US imaging. In order to balance the PA to the level of US, we designed an application-specific integrated circuit (ASIC) preamplifier built in with selective switching protocol to amplify only the PA signal. The preamplifier accepts two distinct triggers: synchronized to the Q-switch trigger given with actual beam emission, preamplifier switches and amplifies the PA signal with customized gain. On the other hand, within the flashlamp trigger given before the Q-switch trigger (approx. 300 μs), the preamp is switched off and the US acquisition bypasses amplification. The preamp affords single channel, and we implemented the designed preamplifier to the acoustic-resolution 3D PAUS scanner installed with 5-MHz single-element focused transducer. The signal-to-noise ratio (SNR) and according penetration depth enhancement was well validated by imaging both carbon leads and wire phantoms under optically turbid media (5% diluted milk), measured to be ~ 16.8 dB at 25 mm and 10.6 dB at 33.7 mm, respectively. To fully demonstrate the improvement of PA images under practical circumstance, the bimodal whole-body image of a healthy anesthetized nude Balb/c mouse was acquired with and without the preamplifier. As a result, the organs (spleen, liver, cecum) and vasculatures lying down in the deeper region were unveiled from preamplifier-applied PA images. Above all, our proposed switchable preamplifier well preserved PA signal of weak level against sequentially acquired with high intensity US signals, extending the penetration depth and increasing the PA image contrast. Further extension toward multichannel application would be helpful to translate array US transducer-based simultaneous PA/US imaging toward clinical practice.

This paper reports a new optically transparent focused P(VDF-TrFE) (poly(vinylidene fluoride-co-trifluoroethylene)) transducer for photoacoustic microscopy (PAM), which is fabricated by a new process based on pre-cutting and direct-lamination. Compared with the previous fabrication process, it is simpler, and makes it possible to achieve a high numerical aperture (NA) without stretching the (brittle) piezoelectric film. For demonstration, a prototype transducer has been fabricated with a 10-μm-thick 70/30 P(VDF-TrFE) film laminated onto a plano-concave glass lens with an NA of 0.64. Experimental characterization shows that the transducer has an optical transmittance of 88.6% (@ 532 nm), an acoustic center frequency and -3 dB bandwidth of 24 MHz and 29 MHz, respectively. Using the new optically transparent focused P(VDF-TrFE) transducer, an optical-resolution PAM (OR-PAM) imaging setup has been built and imaging experiments have been conducted on different targets. The experimental results show the optically transparent focused P(VDF-TrFE) transducer could be useful for the development of new PAM systems for different imaging applications.

Photoacoustic imaging has begun to be widely used to observe drug delivery and accumulation in the body. Theranostic, which includes both diagnosis and therapy, is an attractive approach for treating cancer. In this study, we synthesized nanomaterials and verified the theranostic effect through fluorescence and photoacoustic imaging. Selectively transporting a drug to the tumor site is essential to increase the therapeutic effect while reducing side effects. BODIPY has the advantages of being able to change its structure more easily, good photostability, good biocompatibility and high absorption coefficient than cyanine or porphyrin dyes, however they are limited to in vivo experiment due to their poor water solubility. We overcome the limitations of BODIPY-based materials by encapsulating in micellar nanoparticles with Hexa BODIPY cyclophosphazene (HBCP) and DSPE-PEG2000 polymer. HBCP NPs also have a property of selectively accumulating in tumors with enhanced permeability and retention effect due to their bulky nano-size molecular structure. We checked the tumor targeting and retention time of HBCP NPs by monitoring them with fluorescence imaging. In addition, the high heat conversion efficiency of HBCP NPs enables photoacoustic imaging and Photothermal therapy. We also conducted whole body scanning of tail-vein injected tumor-bearing mice with acoustic resolution photoacoustic microscopy system to provide tumor accumulation information of HBCP NP with vascular structure. The result suggests that HBCP NP has a potential to be used as a material for image guided phototherapy.

Fusion sensors, including photoplethysmograms, cameras, microphones, ultrasound sensors, and accelerometers, are commonly used in mobile and wearable healthcare electronics to measure bio-signals. However, small size is in high demand, but integrating multiple sensors into small mobile or wearable devices is challenging. This study presents two new opto-ultrasound sensors: (1) a wearable device with both photoplethysmography (PPG) and ultrasound (US) capabilities, and (2) a PPG sensor built-in mobile smartphone with an integrated US sensor using a transparent ultrasound transducer (TUT). The TUT has a center frequency of 6 MHz, a 50% bandwidth, and is 82% transparent in the visible and near-infrared ranges. To demonstrate its potential, we developed a wearable device combining photoplethysmography and ultrasound capabilities and fused the TUT to the smartphone. We used this setup to measure heart rates optically and acoustically in human subjects and to calculate oxygen saturation optically through the TUT. This proof-of-concept represents a unique fusion of sensors for small mobile and wearable devices that aim to improve digital healthcare. The results of this research can serve as a basis for innovative development of sensor-based high-tech industrial applications such as healthcare, automobiles, robots, and drones.

Optical resolution photoacoustic microscopy (OR-PAM) provides high optical contrast and lateral resolution. However, the resolution of a typical OR-PAM using an objective lens is limited to not exceeding Abbe's optical diffraction limit. In this study, a lensless shear force scanning PAM is presented. Instead of a lens, the system uses an imaging probe that combines a non-coated tapered fiber with a quartz tuning fork (QTF). A shear force feedback mechanism is used to maintain a tens of nm (near-field) distance between the fiber tip and the sample. With the system, PA signals generated in the near field of a gold sputtered glass sample were successfully acquired. We also performed 2D PA scanning experiments and obtained PA images of gold cube samples with high lateral resolution. This study demonstrates the existence of a near field PA signal and shows its potential for super-resolution scanning PAM.

Photoacoustic tomography (PAT) is a non-invasive imaging modality showing great potential in medical diagnosis and research due to its high optical contrast and high-resolution deep imaging. After laser irradiation on the tissue surface, energy absorption leads to the generation of acoustic waves (also known as PA waves), which can be collected by ultrasound detectors such as single-element ultrasound transducers (SUTs). A variety of image reconstruction algorithms can be employed to obtain the initial pressure distribution map. Previously, desktops or workstations are widely used for performing image-forming processes owing to their high computation power. But with the upgrade of mobile phones, they possess more and more powerful CPU or GPU, sometimes comparable to desktop computers. The capability of PAT can be further enhanced with the use of the mobile platform. In this work, we explored the usage of mobile platforms to reconstruct PAT images without sacrificing image quality. A mobile application was developed based on Python, implementing a simple delay-and-sum (DAS) beamformer for generating PAT images. HUAWEI P20 was employed to test the application performance, which spent less than 30 seconds to form a well-reconstructed PAT image with the SNR value more than 40 dB. Downsampling process can be performed, leading to much less reconstruction time while the photoacoustic target structure was still reconstructed properly, especially for two-fold downsampling operation. These results indicated that mobile platforms could support fast PAT image reconstruction and at the same time support good image quality.

Photoacoustic imaging is a new imaging technique that can measure optical absorbers with high resolution. Lasers are commonly used as light sources for photoacoustic imaging, but there are many safety restrictions. Therefore, devices in which the light source is replaced by LEDs, which have fewer safety restrictions, are attracting attention. However, LED light sources have very low energy, and the photoacoustic signal generated is correspondingly small. Therefore, the photoacoustic signal is buried in noise, resulting in a low signal-to-noise ratio (SNR). Averaging can also improve SNR, but it is difficult to maintain a high frame rate. M-sequence signal processing can improve SNR while maintaining a high repetition rate, and its effectiveness has been demonstrated in photoacoustic measurements of laser light sources. However, LED power supplies have time delays in emission and circuit jitter, which affect decoding. Therefore, we propose a new decoding algorithm that compensates for LED jitter. We then experimentally verified the SNR improvement using this signal processing in practice.

This paper reports a new photoacoustic (PA) excitation method for evaluating the shear viscoelasticity of soft tissues. By illuminating the target surface with an annular pulsed laser beam, circularly converging surface acoustic waves (SAWs) are generated and detected at the center of the annular beam. The shear elasticity and viscosity of the target are extracted from the dispersive phase velocity of the SAWs based on the Kelvin-Voigt model and non-linear regression fitting. Agar phantoms with different concentrations and animal liver and fat tissue samples have successfully been characterized. Different from previous methods, the self-focusing effect of converging SAWs allows sufficient signal-to-noise ratio (SNR) to be obtained even with low laser energy density, which makes this approach well compatible with soft tissues.

Photoacoustic microscopy (PAM) is a non-invasive, label-free functional imaging technique that provides high absorption contrast with high spatial resolution. Spatial sampling density and data size are important determinants of the imaging speed of PAM. Therefore, undersampling methods that reduce the number of scanning points are typically adopted to enhance the imaging speed of PAM by increasing the scanning step size. For the reason that undersampling methods sacrifice spatial sampling density, deep learning-based reconstruction methods have been considered as an alternative; however, these methods have been applied to reconstruct the two-dimensional PAM images, which is related to the spatial sampling density. Therefore, by considering the number of data points, data size, and the characteristics of PAM that provides three-dimensional (3D) volume data, in this study, we newly reported deep learning-based fully reconstructing the undersampled 3D PAM data, which is obtained at the actual experiment (i.e., not manually generated). The results of quantitative analyses demonstrate that the proposed method exhibits robustness and outperforms interpolation-based reconstruction methods at various undersampling ratios, enhancing the PAM system performance with 80-times faster-imaging speed and 800-times lower data size. Moreover, the applicability of this method is experimentally verified by upscaling the sparsely sampled test dataset. The proposed deep learning-based PAM data reconstructing is demonstrated to be the closest model that can be used under experimental conditions, effectively shortening the imaging time with significantly reduced data size for processing.

Photothermal therapy (PTT) is a type of noninvasive, topical cancer treatment technique with photosensitive reagent that thermally reacts to a local laser irradiation over malignant tumor site. While phthalocyanine (Pc) variates are promising photosensitizer candidate having an excellent optical property tuned to deep penetrating near-infrared (NIR)-I window and generates high yield of reactive oxygen series, the hydrophobic characteristic of Pc does not withstand to general intravenous administration, which greatly limits the dye to penetrate into tumor tissue and ultimately lowers the treatment efficacy. The noncovalent conjugation with electron-rich transferrin (TF) not only increase the solubility of the dye, and but also quench the fluorescence and incapacitate strong photoinduced electron transfer required for reactive oxygen generation, which feeds back the dye to transform into interconvertible photothermal theragnostic contrast agent both for photoacoustic (PA) imaging and PTT. Moreover, the TF receptor-rich tumor cells are actively targetable and mediate high accumulation to the tumor site. The in vitro experiment demonstrated the feasible PA absorption spectra of ZnPcN4-TF, and extended aggregation test revealed the homogeneous superiority of ZnPcN4-TF compared to ZnPcN4 lumps. Lastly, the 72-hour in vivo whole-body photoacoustic imaging of MCF-7 tumor bearing mice was sequentially taken under two nominal wavelengths (710 nm as peak PA signal level, 800 nm as noise-equivalent level). From the result, the increased liver uptake verified the enhanced solubility, and active targetability toward MCF-7 tumor cell appeared in 54% PA signal level increase at maximum in after 8-hour postinjection.

Focusing Ultrasound (FUS) can be used to modulate diffusing light in tissue. In this method, diffused photons are modulated in the ultrasound focus area. Detecting these FUS modulated (or tagged) photons can provide spatially accurate information from the focus area. However, probably the biggest challenge in this method is to enable sufficient tagging photons since most of the illuminated and detected photons do not propagate thru the FUS target area resulting in a low number of tagged photons when compared to the background unmodulated light. Therefore, current applications utilizing such hybrid technique are still limited. Our study aims to optimize illumination and detection of photons that propagate through a FUS target area by adjusting the relative position and angle of a light source-detector pair. For the simulations, the K-wave toolbox was utilized to calculate the nonlinear acoustic pressure field in the discretized numerical model from the FUS source. Furthermore, light propagation in the model is simulated using an open-source Monte Carlo algorithm. The model design is a backward detection mode which is suitable for direct application to the human body.

Nerve imaging in radical prostatectomy would facilitate nerve-sparing surgery. Nerve imaging can be performed with photoacoustic (PA) imaging and voltage-sensitive dyes (VSD), as demonstrated in [Kang, 2019] for brain neural activity. Continuous-wave (CW) PA was used to image dynamic targets, e.g., flow [Zhao, 2021], by firing multiple modulated exciters at the same time. However, CWPA has not been investigated with clinical transducers for prostate applications. We report here the development of such a dual-wavelength laser diode-based system and experimental results. We differentiate the acoustic signals resulting from each laser to provide fast and simultaneous spectral image.

An on-chip photoacoustic transducer is proposed by monolithically integrating piezoelectric micromachined ultrasonic transducers (PMUTs) on metasurface lenses for applications such as single-cell metabolic photoacoustic microscopy (SCM-PAM)1 . As shown in Figure 1a, every PMUT cell has a ring-shaped top electrode, and the membrane center is transparent without piezoelectric and electrode materials. The laser beam, therefore, can travel through a PMUT cell after being focused by a metasurface lens bonded on the backside of the PMUT (see Figure.3). The on-chip photoacoustic transducer fully leverages current PMUT and metasurface technologies and does not rely on transparent piezoelectric and electrode materials like typical transparent ultrasonic transducers2 . Moreover, the on-chip photoacoustic transducer has a monolithic integrated achromatic metasurface lens (see Figure 3), which can easily and efficiently focus the visible light (wavelength range: 400-700 nm) at the same focus point. Design and process this and preliminarily test the performance of PMUT and metasurface.

In the past two decades, High-Intensity Focused Ultrasound (HIFU) has been actively investigated for inducing tissue ablation for tumours, healing arteries and even skin tightening for inducing facelifts. Being a non-contact and non-invasive procedure, HIFU is an attractive alternative over other procedures like radio-frequency ablations and microwave ablations as these are semi-invasive methods. Computer simulations in this domain can provide us with a fast-track way to test and deduce results virtually before conducting related experiments. In this study, we simulated the properties of bovine liver tissue virtually in a MATLAB-based k-Wave toolbox to track lesion variations with varying HIFU on-time and with a constant amount of heat deposition. Photoacoustic reconstructions were also carried out with a linear and circular array of transducers using the simple Delay-And-Sum (DAS) algorithm to access the real-time imaging capability of this technique for HIFU therapy. All the results obtained are discussed and validated. This study will, in general, aid in deciding the HIFU configuration and operational parameters with respect to the tissue type, lesion size, and lesion location within the tissue.

The eyes function through the cooperation of different ocular components, and complications with any components would lead to ocular diseases that deteriorate vision. Hence early and precise detection and monitoring of ocular diseases, along with the improved understanding of pathological mechanisms, becomes essential for successful treatment. Photoacoustic Imaging (PAI) is a non-invasive and non-destructive imaging modality based on the photoacoustic effect, which gives high spatial resolution, sensitivity, contrast and penetration depth. Since PAI can provide anatomic and functional ocular characterizations, it can be a potential tool for medical screening/diagnosis of ocular diseases, staging, treatment, and continuous post-treatment monitoring. Here, we perform deep-tissue imaging of the Goldfish (Carassius auratus) eye using a home-built Photoacoustic microscope to identify various ocular components like iris, crystalline lens, retina, optic nerve and blood vessels. The study can be extended to observe changes in these structures under different ophthalmic disease conditions.

Photoacoustic imaging (PAI) is now a very promising imaging technique that provides image with sufficient depth, good resolution, and optical contrast. A conventional PAI system is relatively expensive and mechanically bulky. The study demonstrated that MEMS PMUT achieves miniaturized ultrasound (US) sensor element (either single element or an array of elements) with superior performance in terms of power consumption, flexibility, broader bandwidth, and sensitivity. This implies that these technologically novel qualities hold promise for the use of PMUT as an acoustic sensor in PAI systems in place of the conventional piezoelectric bulk element-based spherical ultrasound (US) transducer. We report our study on the design and development of MEMS PMUT−(central frequency ~ 1MHz) based PAM−that integrates MEMS technology and imaging technology (specifically, photoacoustic imaging (PAI)). In this work, we present a temporal integration of the signals over a certain number (~20) of pulsed light-induced PA waves against the conventional technique to acquire a single 1D PA signals/data corresponding to one individual optical pulse−induced PA waves. This means to say that the enhancement of imaging performance with the use of PMUT acoustic sensor is associated with a reduction of obtainable temporal resolution, i.e., a trade-off exists. With the applied temporal integration method SNR has been improved ~ 20dB. The preliminary study demonstrates that the integration of PMUT in PA imaging modality holds promise as a future (imaging) technology both for biological studies and their applications.