Sentinel lymph node biopsy (SLNb) plays an important role in determining whether breast cancer has metastasized. The current standard method for SLNb is to use radioactive material and blue dye to detect sentinel lymph nodes (SLNs). However, this method has limitations such as radiation exposure, radioactive material disposal, and subjective evident interpretation of the blue dye. To overcome these limitations, we developed a non-radioactive detector, the photoacoustic finder (PAF), which utilizes the photoacoustic (PA) signal from the SLN's blue dye to identify SLNs instead of radioactive material. For evaluating the PAF, in this ex vivo clinical study, we compared the detection rate of standard SLN detection methods and PAF in resected SLNs from breast cancer patients. A total of 92 breast cancer patients were enrolled in the study, and 164 SLNs resected from the patients were analyzed. The detection rate was similar for gamma probe (85%, 139 of 164 SLNs) and PAF (85%, 139 of 164 SLNs), while the detection rate using blue dye visual inspection was 74% (122 of 164 SLNs), which was lower than gamma probe and PAF. These results affirm the validity of PAF as a non-radioactive alternative for detecting SLNs, indicating the potential feasibility of non-radioactive SLNb in future applications.
Photoacoustic Tomography (PAT) is a useful tool for fast 3D imaging that provides structural, molecular, and functional in vivo information. It is capable of producing 3D images using a multi-element hemispherical array transducer. PAT images can be enhanced a great number of ultrasonic transducer components with multiplexers, but this can result in high costs and slow temporal resolution because of using multiplexers. In this research, we present a deep learning solution to improve both the spatial and temporal resolution in PAT. We demonstrated that the trained neural network enhanced the image quality of a quarter-cluster-sampled data of static whole-body imaging. Our approach increased limited-view aperture and the spatial resolution by around three and two times, respectively. Additionally, it allowed to improve temporal resolution by four times without multiplexing. Our method also demonstrated excellent performance in contrast-enhanced PA imaging, enabling molecular imaging. Our strategy has the potential to enable high spatial and temporal resolution observation of biodynamics in 3D PAT without being limited by hardware constraints.
KEYWORDS: Image segmentation, In vivo imaging, Image restoration, Monte Carlo methods, Education and training, Network architectures, Gallium nitride, Photoacoustic imaging, Image quality, Tissues
Photoacoustic imaging (PAI), recognized as a promising biomedical imaging modality for preclinical and clinical studies, uniquely combines the advantages of optical and ultrasound imaging. Despite PAI’s great potential to provide valuable biological information, its wide application has been hindered by technical limitations, such as hardware restrictions or lack of the biometric information required for image reconstruction. We first analyze the limitations of PAI and categorize them by seven key challenges: limited detection, low-dosage light delivery, inaccurate quantification, limited numerical reconstruction, tissue heterogeneity, imperfect image segmentation/classification, and others. Then, because deep learning (DL) has increasingly demonstrated its ability to overcome the physical limitations of imaging modalities, we review DL studies from the past five years that address each of the seven challenges in PAI. Finally, we discuss the promise of future research directions in DL-enhanced PAI.
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.
Excessive bleaching can cause changes in the amino acid composition as well as the surface structure of the hair. Thus, proper hair bleaching and quantification is important to achieve cosmetic purposes while maintaining the healthy properties of the hair. Here, we propose a novel method to quantify the degree of hair bleaching at the nanoscale resolution using a photoactivated atomic force microscopy (pAFM). We demonstrated that acquiring and quantifying pAFM images of hair according to bleaching time can help determine the appropriate bleaching time. We believe that this result will help to prevent unwanted hair damage due to bleaching.
Peripheral vascular disease (PVD) is a narrowing of the arteries in the extremities that might result in amputation when left untreated. The conventional ways to diagnose PVD are vascular imaging techniques such as ultrasound (US) Doppler, computed tomography (CT) angiography, and magnetic resonance angiography, which generally can only visualize large vessels or require contrast agents. Photoacoustic (PA) imaging could be a promising agent-free, highresolution modality to visualize vessels and be applied in various clinical studies. We have previously demonstrated an agent-free multi-structural photoacoustic (PA) and US peripheral angiography technique using contour scanning. To reduce the effect of the optical fluence, we compensated the PA images using the background PA signals that represent optical attenuation in the tissue. To evaluate its capability to provide functional information of the vasculature, we demonstrated an intentional blood flow occlusion with a pressure cuff and observed the changes in the quantification metrics. From the experiments, we confirmed the potential of the technique for providing a diagnostic evaluation of the peripheral vasculature.
We present high-resolution and high-SNR in vivo vascular imaging of the mouse eye, brain, and ear with photoacoustic microscopy (PAM) integrated with a transparent ultrasound transducer. We observed microvessels in a chemically damaged mouse eye. Particularly, the performance of PAM as a comprehensive eye disease diagnosis tool was demonstrated by observing not only corneal neovascularization, but also iris blood vessels and hemorrhages in a cloudy state of the corneal. Second, we delineated in vivo mouse brain vascular imaging at high resolution with a depth encoding. Third, we monitored the ears of tumor-bearing mice to observe for angiogenesis over time.
We present a multimodal imaging system that seamlessly integrates ultrasound imaging, photoacoustic imaging, and optical coherence tomography using a transparent ultrasonic transducer. We demonstrate the system’s use in imaging responses to mouse body in vivo.
We developed a handheld photoacoustic signal detector for sentinel lymph node (SLN) localization. The detector consists of a solid-state dye laser and a transparent ultrasound transducer (TUT). The TUT was designed as a focused-type. The TUT had an 8 MHz center frequency with a 30% bandwidth. Using the detector, we confirmed photoacoustic signals in a tube filled with methylene blue (MB) below 10-mm thick chicken tissues. We successfully performed in vivo photoacoustic detection for MB injected SLN localization and subcutaneously injected melanoma assessments. We believe that our detector will play an effective role in SLN localization and biopsy.
We demonstrate an agent-free multi-structural peripheral angiography technique based on the volumetric photoacoustic (PA) and ultrasound (US) images. The volumetric images are obtained by stacking B-mode PA/US images along the elevational direction using a motorized scanner. Three structural features such as skin, bone, and vasculature are extracted from the volumetric US image and combined with the PA microvasculature image to provide a multi-structural vascular image of the foot. For quantitative PA imaging, we have tested the reliability of the PA images. The method can be used to provide a comprehensive anatomic and functional analysis of the extremity.
Multi-modal imaging technique has significantly spotlighted since it can provide a variety of information by combining the complementary merits of several single-modal imaging. In particular, in order to compensate for each shortcoming and improve image quality, an integrated optical and ultrasonic imaging system is being actively researched. However, the non-transparency of the ultrasound transducer made it difficult to integrate the optical and ultrasound imaging system. In previous study, we introduced the transparent ultrasound transducer (TUT) and dual-modal photoacoustic imaging (PAI)/ultrasound imaging (USI) system using the TUT. In this study, we present the multi-modal imaging system integrated with PA, US and optical coherence tomography (OCT). OCT has the advantage of acquiring anatomical information at optical resolution under subsurface and transparent media. To explore the usefulness of the multi-modal imaging system, we have successfully performed in vivo animal experiments: 1) eye imaging experiments and 2) subcutaneous melanoma imaging. In PAI, blood vessels and melanoma are clearly visualized. In OCT, the morphological information in shallow depth are observed in detail. In USI, the melanoma boundary and surrounding tissues are clearly confirmed. These results show that TUT based multi-modal imaging system can serve as a comprehensive in various applications.
We report a novel photoacoustic (PA) scoring method for the risk stratification of thyroid nodules, which is combination of the American Thyroid Association (ATA) and PA malignancy probability. We performed multi-spectral PA imaging and multi-parametric PA analysis for thyroid cancer patients (23 malignancy and 29 benign cases). Initial multi-parametric PA analysis showed that malignancy of the thyroid nodules can be diagnosed with a 78% sensitivity and 93% specificity. Moreover, our novel score called ATAP improved the sensitivity to 83% while maintaining the specificity. The results suggest that the ATAP may help physicians examine thyroid nodules, thus reducing unnecessary biopsies.
Extrinsic contrast agents with excellent light absorption properties in the second near-infrared (NIR-II, 1000-1350 nm) region can be a key to enhance the contrast of photoacoustic imaging (PAI) in deep tissues. Here, we demonstrated a photoacoustic (PA) contrast agent at 1064 nm optical wavelength for deep-tissue in vivo PAI. We successfully synthesized nickel(II) dithiolene-based polymeric nanoparticles (NNP) that have strong absorption at NIR-II light and generate improved PA signal with a 1064 nm pulse laser. To confirm the feasibility of the NNP, we have conducted both in vitro and in vivo PA experiments and acquired highly contrast-enhanced PA images. We successfully obtained contrast-enhanced PA images of a tube filled with NNP deeply located below several layers of chicken tissue. The maximum PAI penetration depth was about 5 cm. Next, we performed bladder, sentinel lymph node and gastrointestinal tract, which are clinically important, PAI in rats to confirm that NNP could be utilized as a PA agent in deep tissues in vivo. NNP was injected into each of the three cases, and we confirmed that PA contrast was significantly increased after the injections. These results demonstrate that the enhanced PA signals generated by irradiating 1064 nm laser to NNP in deep-tissue has sufficient contrast for PAI. Based on the excellent absorbability of NNP at 1064 nm and the translability of clinical PAI systems, this study is expected to provide a great opportunity for a variety of studies on non-invasive deep tissue in vivo.
Ultrasound transducers, one of the most widely used sensors in the era of the fourth Industrial Revolution, have been recognized and used in a variety of industries including medical, automotive, and robotics. In particular, recent research has focused on the development of multi-mode imaging systems that combine ultrasound and optical imaging to improve the accuracy of information acquisition. Unfortunately, its efficient combination has been severely limited due to the inherent opacity of conventional ultrasound transducers. These limitations cause off-axes between the ultrasound (US) and optical signal paths, resulting in low signal-to-ratio and bulky system. This is especially a critical problem for a photoacoustic (PA) imaging system that requires the ultrasonic transducer to detect the photoacoustic signal. Here, we introduce a newly developed optically transparent ultrasound transducer (TUT) to overcome the limitation. We combined the developed TUT with an optical resolution photoacoustic microscopy (OR-PAM). Using a mouse, we successfully acquired in vivo PA and US images and confirmed the feasibility of the TUT and TUT integrated OR-PAM system.
Cutaneous melanoma accounts for only 5% of skin cancer, but it is as dangerous as it is associated with 75% skincancer- related deaths. Clinical decision-making and prognosis is the thickness of melanoma into the tissue. Another feature is that the cancer that can occur anywhere on the body, including the face, chest, thigh, soles, and groin, and its size is also very diverse. Here, we developed a hand-held scanner and obtained 3D photoacoustic images of in vivo human melanoma by using multispectral real-time clinical photoacoustic and ultrasound imaging system with the scanner. The scanner allowed wide-field scanning of 3.8 cm (transducer aperture size) × 3 cm (scanning range). Four patients were recruited to obtain photoacoustic melanoma images of various sites (thigh, sole, etc.), types (in situ, invasive, etc.) and sizes (sub-mm to cm). Five wavelengths were used to perform spectral unmixing. The penetration depth of melanoma was successfully confirmed by the multispectral photoacoustic images. The melanoma depth measured by photoacoustic imaging was significantly similar to histopathologic results obtained after excision (mean absolute error = 0.6 mm). In this study, we acquired small-to-large size and various types of melanoma multispectral photoacoustic images in vivo. We hope that this study will be an additional criterion for histopathological results that may have a positive impact on the diagnosis, treatment, and prognosis of melanomas.
Thyroid cancer is one of the most commonly diagnosed cancers in the world. Ultrasonography and fine-needle aspiration biopsy are the typical standard-of-care method for diagnosing thyroid nodules. However, about 20% of fine-needle aspiration biopsies generate undeterminable results, which can lead to overdiagnosis and overtreatment. In this study, we propose photoacoustic imaging as an additional triaging tool for identifying cancerous nodules in vivo. We enrolled and photoacoustically imaged 28 patients (19 malignant and 9 benign) who have thyroid nodules. To perform multispectral analysis, we used a series of 5 different wavelengths (i.e., 700, 756, 796, 866, and 900 nm), which were selected based on the optical absorption property of oxy- and deoxy-hemoglobin. All the raw data were automatically stored for further off-line processing, while the corresponding images were visualized on the clinical ultrasound machine in real-time. By using the multispectral photoacoustic data, we calculated the oxygen saturation values of the nodule areas. The result showed that the oxygen saturation level of malignant nodules was lower than that of benign nodules (p < 0.005), which matched with the well-known property of cancerous nodules. Based on the oxygen saturation value, malignant and benign nodules were differentiable with a sensitivity of 80% and specificity of 89%. The result showed the great potential of multispectral photoacoustic analysis as a novel method to identify malignancy of thyroid nodules in vivo. We also verified the robustness of the result by testing reproducibility and comparing inter-physician interpretation.
A sub-wavelength convertible Bessel-beam (BB) and Gaussian-beam (GB) photoacoustic microscope (PAM) in reflection-mode has been developed. A miniature ultrasonic transducer was placed in front of the objective with a high numerical aperture and a working distance of a few millimeters to achieve the reflection-mode and sub-wavelength resolution. For BB-PAM system, a conical lens and an achromatic doublet lens were used to achieve extended depth of field (DoF). In particular, it was designed to easily convert the system from BB to GB by removing the two lenses described above, so that the DoF of BB- and GB-PAM can be compared accurately. The 532 nm pulsed laser used in this system was coupled to a single mode fiber. The sample was scanned using X-Y direction motors and the system was controlled using Labview software. The lateral resolution of the focus regions of BB- and GB-PAM obtained were 300 and 260 nm, respectively. As a result of measuring the DoF of BB-PAM, it was about 250 ~ 300 μm, which was about 7 ~ 8 times better than the DoF of GB-PAM. In-vivo vascular structure of a mouse ear was successfully visualized using BB- and GB-PAM to compare the DoF of the two systems. Thus, the system developed in this study confirmed that BBPAM enabled high-resolution imaging at extended DoF than GB-PAM, and further believed that this system could be useful for a variety of biomedical research.
The standard method to treat cutaneous melanoma, which is the most prevalent skin cancer, is surgical excision of visible boundary with an additional margin. The margin is typically decided by surgeons’ experience based on the color of the lesion. It is very important to determine appropriate excision area because the operation will continue until a histological evaluation is made the there is no cancerous cells in the excised margin. Here, we demonstrate the results from our initial pilot study for detection of melanoma boundary using photoacoustic (PA) imaging. We recruited a patient who had a cutaneous melanoma lesion on the left heel. We excised the lesion with surgical operation by adding ~1 cm margin to the visible boundary, and then immediately acquired multispectral PA images of the lesion. By scanning a linear array transducer using a motorized stage, we acquired volumetric PA images of the lesion. From the multispectral analysis of PA signals, we could tell cutaneous melanoma from surrounding normal tissue and marking pen. Although much more studies are required for clinical evaluation, the initial results demonstrate that the PA imaging can provide additional information to surgeons for better selection of excision area of cutaneous melanoma.
KEYWORDS: Imaging systems, Ultrasonography, Real time imaging, Photoacoustic spectroscopy, Control systems, Demodulation, Visualization, Biomedical optics, Blood vessels, Laser systems engineering
We had developed a real-time clinical photoacoustic (PA) and ultrasound (US) imaging system by combining a programmable ultrasound machine and a wavelength-tunable laser. The system was able to acquire real-time images of biological tissue, but the user had to restart the image acquisition software to modify parameters for optimizing the images. We have recently updated the system to adjust imaging parameters in real-time by implementing a real-time parameter control software, which is compatible with the programmable platform of the US machine. To adjust the parameters of both PA and US images, we also implemented custom functional blocks including beamforming, frequency demodulation, log compression, decimation, scan conversion, and image display. To acquire real-time images, we performed all the calculations by using parallel processing with a graphic processing unit in US machine. The updated system has the great potential to be widely applied to a variety of clinical and preclinical applications because it allows real-time optimization of imaging parameters as well as visualizing the images in real-time.
KEYWORDS: Near field, Super resolution, Light sources, Photoacoustic microscopy, Metals, Plasmonics, 3D photoacoustic microscopy, Near field scanning optical microscopy, Biomedical optics, Luminescence
Super-resolution microscopy has been increasingly important to delineate nanoscale biological structures or nanoparticles. With these increasing demands, several imaging modalities, including super-resolution fluorescence microscope (SRFM) and electron microscope (EM), have been developed and commercialized. These modalities achieve nanoscale resolution, however, SRFM cannot image without fluorescence, and sample preparation of EM is not suitable for biological specimens. To overcome those disadvantages, we have numerically studied the possibility of superresolution photoacoustic microscopy (SR-PAM) based on near-field localization of light. Photoacoustic (PA) signal is generally acquired based on optical absorption contrast; thus it requires no agents or pre-processing for the samples. The lateral resolution of the conventional photoacoustic microscopy is limited to ~200 nm by diffraction limit, therefore reducing the lateral resolution is a major research impetus. Our approach to breaking resolution limit is to use laser pulses of extremely small spot size as a light source. In this research, we simulated the PA signal by constructing the three dimensional SR-PAM system environment using the k-Wave toolbox. As the light source, we simulated ultrashort light pulses using geometrical nanoaperture with near-field localization of surface plasmons. Through the PA simulation, we have successfully distinguish cuboids spaced 3 nm apart. In the near future, we will develop the SR-PAM and it will contribute to biomedical and material sciences.
Access to the requested content is limited to institutions that have purchased or subscribe to SPIE eBooks.
You are receiving this notice because your organization may not have SPIE eBooks access.*
*Shibboleth/Open Athens users─please
sign in
to access your institution's subscriptions.
To obtain this item, you may purchase the complete book in print or electronic format on
SPIE.org.
INSTITUTIONAL Select your institution to access the SPIE Digital Library.
PERSONAL Sign in with your SPIE account to access your personal subscriptions or to use specific features such as save to my library, sign up for alerts, save searches, etc.