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IntroductionPhotoacoustic technology can be used for non-invasive imaging of blood vessels. In this paper, we report on our prototype photoacoustic imaging system with a newly designed ultrasound sensor and its visualization performance of microvascular in animal.MethodsWe fabricated an experimental system for animals using a high-frequency sensor. The system has two modes: still image mode by wide scanning and moving image mode by small rotation of sensor array. Optical test target, euthanized mice and rats, and live mice were used as objects.ResultsThe results of optical test target showed that the spatial resolution was about 2 times higher than that of our conventional prototype. The image performance in vivo was evaluated in euthanized healthy mice and rats, allowing visualization of detailed blood vessels in the liver and kidneys. In tumor-bearing mice, different results of vascular induction were shown depending on the type of tumor and the method of transplantation. By utilizing the video imaging function, we were able to observe the movement of blood vessels around the tumor.ConclusionWe have demonstrated the feasibility of the system as a less invasive animal experimental device, as it can acquire vascular images in animals in a non-contrast and non-invasive manner.

The photoacoustic imaging (PAI) system is an emerging imaging modality that can be useful in clinical diagnostic testing. Previous studies have shown utility of PAI in diagnosing breast cancer, visualizing vascular change in ageing, and planning flap reconstruction surgeries. In this study, we show that PAI can be used to non-invasively visualize microvascular injuries in smokers, and in a vasculitis patient.We used two prototype PAI systems, PAI-03, and PAI-04 in this study. These systems were equipped with hemisphere-detector arrays, and used lasers at wavelengths of 795 nm (PAI-03), 756 and 797nm (PAI-04). Healthy volunteers and a patient diagnosed with vasculitis were enrolled upon obtaining written informed consent. The whole hand of the volunteers was scanned.We noted there were unique circular structures that we coined “minute signals”. There were higher number of minute signals in smokers than in non-smokers. Enhanced minute signals were noted in the patient with vasculitis. In this patient, minute signals were suggested to have lower oxygenated hemoglobin content, likely suggesting blood clots or hemorrhage. Our study shows PAI systems can visualize unappreciated abnormalities in fine vasculatures non-invasively. Use of PAI can extend to other clinical entities with suspected vascular involvement.

This study aimed to identify the characteristics of the vascular network in the superficial subcutaneous layer of the breast and to analyze differences between breasts with cancer and contralateral unaffected breasts using vessel branching points (VBPs) detected by three-dimensional photoacoustic imaging with a hemispherical detector array. In 22 patients with unilateral breast cancer, the average VBP counts to a depth of 7 mm below the skin surface were significantly greater in breasts with cancer than in the contralateral unaffected breasts (p

Photoacoustic lymphangiography, which is based on photoacoustic technology, is an optical imaging that visualizes the distribution of light absorbing tissue components like hemoglobin or melanin, as well as optical absorption contrast imaging agents like indocyanine green (ICG) in the lymphatic channels, with high spatial resolution. In this report, we introduce the three-dimensional (3D) images of human lymphatic vessels obtained with photoacoustic lymphangiography.We used the 3D photoacoustic visualization system (PAI-05). Some healthy subjects and lymphedema patients were recruited. To image the lymphatic structures of the limbs ICG was administered subcutaneously as in fluorescence lymphangiography. Photoacoustic images were acquired by irradiating the tissue using a laser at wavelengths of near-infrared region. On the same occasion, fluorescence images were also recorded.The lymphatic vessels up to the diameter of 0.2 mm could be observed three-dimensionally with the venules around them. In the patient-group, dermal backflow patterns were often observed as dense interconnecting 3D structures of lymphatic vessels. Collecting vessels passing below the dermis were also observed, which were not observed by fluorescence lymphography.Photoacoustic lymphangiography provided the detailed observation of each lymphatic vessel, leading to deeper understanding of 3D structures and physiological state of the vessel.

To practically apply photoacoustic (PA) imaging technology in medicine, we have developed prototypes of a photoacoustic mammography (PAM) device to acquire images for diagnosing breast cancer in the Kyoto University/Canon joint research project (CK project supported by MEXT, Japan). First, the basic ability of the PAM system to visualize the network of blood vessels and the Hb saturation index was evaluated using a prototype of PAM that has a flat scanning detector and is capable of simultaneously acquiring photoacoustic (PA) and ultrasound images. Next, another prototype of a PAM device with hemispherical sensors was developed to improve the visibility of the 3D structure of vessels by reducing the limited view effect. In clinical examination of breast cancer cases, the PAM system allowed 3D visualization of fine vessel networks with a spatial resolution of a half-millimeter and enabled us to determine the features of tumor-related vascular structures in human breast cancer. In addition, the oxygen saturation status of Hb was visualized using two different wavelengths, enabling more precise characterization of the tumor microenvironment. Results of clinical evaluation using our developed prototype of a PAM device confirmed that PA imaging technology has the potential to promote early detection of breast cancer, and realization of its practical use is expected in the near future.

Photoacoustic (PA) imaging (PAI) has been shown to be a promising tool for non-invasive blood vessel imaging. A PAI system comprising a hemispherical detector array (HDA) has been reported previously as a method providing high morphological reproducibility. However, further improvements in diagnostic capability will require improving the image quality of PAI and fusing functional and morphological imaging. Our newly developed PAI system prototype not only enhances the PA image resolution but also acquires ultrasonic (US) B-mode images at continuous positions in the same coordinate axes. In addition, the pulse-to-pulse alternating laser irradiation shortens the measurement time difference between two wavelengths. We scanned extremities and breasts in an imaging region 140 mm in diameter and obtained 3D-PA images of fine blood vessels, including arterioles and venules. We could estimate whether a vessel was an artery or a vein by using the S-factor obtained from the PA images at two wavelengths, which corresponds approximately to the haemoglobin oxygen saturation. Furthermore, we observed tumour-related blood vessels around breast tumours with unprecedented resolution. In the future, clinical studies with our new PAI system will help to elucidate various mechanisms of vascular-associated diseases and events., 光超音波イメージングで人体の精細な動静脈像を得ることに成功 --腫瘍血管の解析や再建手術への応用に期待--. 京都大学プレスリリース. 2018-10-25.

Photoacoustic tomography (PAT) is a novel modality that can visualize blood vessels without contrast agents. It clearly shows blood vessels near the body surface. However, these vessels obstruct the observation of deep blood vessels. As the existence range of each vessel is determined by the distance from the body surface, they can be separated if the position of the skin is known. However, skin tissue, which does not contain hemoglobin, does not appear in PAT results, therefore, manual estimation is required. As this task is very labor-intensive, its automation is highly desirable. Therefore, we developed a method to estimate the body surface using the cloth-simulation technique, which is a commonly used method to create computer graphics (CG) animations; however, it has not yet been employed for medical image processing. In cloth simulations, the virtual cloth is represented by a two-dimensional array of mass nodes. The nodes are connected with each other by springs. Once the cloth is released from a position away from the body, each node begins to move downwards under the effect of gravity, spring, and other forces; some of the nodes hit the superficial vessels and stop. The cloth position in the stationary state represents the body surface. The body surface estimation, which required approximately 1 h with the manual method, is automated and it takes only approximately 10 s with the proposed method. The proposed method could facilitate the practical use of PAT.

We analysed the vascular morphology of the palm using a photoacoustic tomography (PAT) instrument with a hemispherical detector array. The three-dimensional (3D) morphology of blood vessels was determined noninvasively. Overall, 12 females and 11 males were recruited as healthy volunteers. Their ages were distributed almost evenly from 22 to 59 years. In all cases, many vascular networks were observed just beneath the skin and were determined to be veins anatomically. To analyse the major arteries, the layer containing the subcutaneous venous network was removed from the image. The analysis focused on the common and proper palmar digital arteries. We used the curvature of these arteries as a parameter to analyse their morphologies. There was no significant difference in the curvature between genders when comparing the subjects as a whole. The blood vessel curvature increased with age. Good agreement was found between the 3D numerical analysis results and the subjective evaluation of the two-dimensional (2D) projection image. The PAT system enabled visualization of the 3D features of blood vessels in the palm and noninvasive analysis of arterial tortuousness., 非造影・非侵襲の「光超音波イメージング技術」によって手掌動脈の可視化と血管形状の定量解析に成功. 京都大学プレスリリース. 2018-02-02.

Introduction Breast cancer induces angiogenesis, one of the primary factors responsible for tumor progression. Therefore, the ability to visualize angiogenesis at a higher resolution is crucial. Photoacoustic tomography is a noninvasive method of visualizing angiogenesis involving light absorption and ultrasonic wave emission. If the irradiation light wavelength is adjusted for hemoglobin, vascular imaging is possible. Furthermore, using two wavelengths for oxidized and reduced hemoglobin, “S-factor,” can be calculated, which nearly corresponds to oxygen saturation. Therefore, photoacoustic imaging allows the assessment of breast lesions from vascular structural and functional viewpoints. Objectives This study aimed to demonstrate the possible utility of photoacoustic tomography for clinical application focusing on the morphologic features and oxygen saturation status of breast tumor-related vessels. Methods For the morphological analysis, we applied a machine learning-based method for automatic vessel extraction, and for the functional analysis we evaluated hemoglobin oxygen saturation calculating signals obtained at two wavelengths. In our system, a 3D ultrasound image was simultaneously acquired as a volume image of a tumor, which helped analyze the positional relationship between the vessels and the tumor. Results On morphological analysis, the fine structure of tumor-related vessels was rendered in high resolution. In our system, the blood vessels branched toward the tumor 2-3 more times more frequently than observed on contrast-enhanced MRI, illustrating a finer level of blood vessels near the tumor on our system than on MRI. Next, we analyzed the six morphologic features of vessels (radius, volume, curvature, contraction, maximum angle and vessel branch number) that are associated with the pathologic condition in neuroscience. We determined that the feature distribution of vessels located close to the tumor differed from that located away from the tumor. For example, vessels near the tumor had higher curvature, which means they are more tortuous than healthy vessels. The difference in the distribution of all six features was statistically significant on the Kolmogorov-Smirnov test. On functional analysis, S-factor measurement of the healthy human breast demonstrated clearly demarcated arteries and veins. The S-factor of any artery was nearly 100%, while that of the veins inside the breast cancer tended to be a little higher (approximately 5%) compared to that in the healthy part. This tendency of veins was not recognized in benign tumors. This could show arteriovenous shunt in cancer microenvironment. We found low saturation signals emerging in the tumor tissue following bevacizumab-containing chemotherapy, indicating the possibility that our system reveals microenvironment changes. Discussion If our system can identify the structure or oxygen saturation characteristics unique to tumor-associated vasculature, it could contribute to the improved accuracy of breast cancer diagnosis and allow the observation of tumor vessel normalization because of the drug treatment. An earlier grasp of the therapeutic effect could lead to the provision of individualized medicine. Citation Format: Matsumoto Y, Gu L, Bise R, Asao Y, Sekiguchi H, Yoshikawa A, Ishii T, Takada M, Kataoka M, Sakurai T, Yagi T, Sato I, Togashi K, Shiina T, Toi M. Machine learning-based structural analysis and oxygen saturation measurement of tumor-associated vessels in breast cancer using a photoacoustic tomography system [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-01-02.

Background: A breast-specific photoacoustic imaging (PAI) system prototype equipped with a hemispherical detector array (HDA) has been reported as a promising system configuration for providing high morphological reproducibility for vascular structures in living bodies. Methods: To image the vasculature of human limbs, a newly designed PAI system prototype (PAI-05) with an HDA with a higher density sensor arrangement was developed. The basic device configuration mimicked that of a previously reported breast-specific PAI system. A new imaging table and a holding tray for imaging a subject's limb were adopted. Results: The device’s performance was verified using a phantom. Contrast of 8.5 was obtained at a depth of 2 cm, and the viewing angle reached up to 70 degrees, showing sufficient performance for limb imaging. An arbitrary wavelength was set, and a reasonable PA signal intensity dependent on the wavelength was obtained. To prove the concept of imaging human limbs, various parts of the subject were scanned. High-quality still images of a living human with a wider size than that previously reported were obtained by scanning within the horizontal plane and averaging the images. The maximum field of view (FOV) was 270 mm × 180 mm. Even in movie mode, one-shot 3D volumetric data were obtained in an FOV range of 20 mm in diameter, which is larger than values in previous reports. By continuously acquiring these images, we were able to produce motion pictures. Conclusion: We developed a PAI prototype system equipped with an HDA suitable for imaging limbs. As a result, the subject could be scanned over a wide range while in a more comfortable position, and high-quality still images and motion pictures could be obtained.

道路橋の伸縮装置は，軸重の影響を直接受けるが，その疲労耐久性の評価手法は明確になっていない．本研究では，伸縮装置の疲労耐久性評価の考え方を整理し，耐久性評価に用いる軸重や応力範囲の計算方法，繰返し数の与え方，S-N線図を決定する方法などの考え方を示した．また，この結果を，モジュラー式伸縮装置に適用した例を示す．モジュラー式伸縮装置は，橋軸直角方向に横ビームを並べ，それを橋軸方向のサポートビームで支える形で，長大スパンにも適用できるシステムである．また，BWIMにより実測された軸重データを用い，疲労耐久性を評価した．

A lens array of 20 × 20 three element electrostatic lenses (einzel lenses) for multiple electron beam direct write (MEBDW) systems is presented.

Background: Tumor angiogenesis and hypoxia are associated with breast cancer growth and metastasis. Photoacoustic (PA) tomography is an optical imaging technology that visualizes distribution and oxygenation status of hemoglobin with high spatial resolution. Initially we developed a photoacoustic mammography (PAM) having a flat-shaped scanning detector that could detect breast tumors. Nevertheless, the flat-shaped detector array has the drawback of a limited view. Here we developed a novel PAM system with a hemispherical-shaped detector array (HDA), which enables us to identify microvasculatures non-invasively and allow the collection of nearly spatially isotropic three-dimensional reconstructed image of blood vessels. This non-invasive vascular imaging system may be able to characterize tumor angiogenesis and analyze the status of microcirculation. The aim of this study was to analyze the imaging findings of tumor-related vasculature in breast cancer patients. Patients and method: A PAM system with HDA has been generated in a cooperation project between Canon Inc., Japan, and Kyoto University. Twenty-two primary breast cancer patients, including 5 patients with non-invasive cancer and 17 patients with invasive cancer, diagnosed between December 2014 and December 2015 underwent the PAM imaging analysis. We also applied the breast deformation algorithm from the breast shape in a MRI image to that in a PA image in order to create a fusion image of the two modalities for the analysis. Features of peri- and intra-tumoral vasculature, and their oxygenation status were evaluated. The study protocol was approved by the institutional review board at Kyoto University Hospital (UMIN000012251). All patients provided informed consent to participate in this study. Results: The abnormal peri-tumoral vasculature was detected in 86% of all non-invasive and invasive disease cases. In invasive cancer cases, most tumor-related blood vessels were centripetally directed toward the tumor, and 93% of centripetal blood vessels appeared to be disrupted or rapidly narrowed at the tumor boundary. The centripetal blood vessel structure was frequently observed in invasive cancer compared with non-invasive cancer (61% vs 35%). PA images before and after preoperative chemotherapy were obtained in one case, where intra-tumoral blood vessels became finer after chemotherapy, reflecting normalization of intra-tumoral microcirculation induced by chemotherapy. Conclusions: A PAM system with HDA has provided a high-resolution vascular images of primary breast cancers. The morphological differences of peri-tumoral vasculature were observed between invasive disease and non-invasive disease. These results suggest the potential of PA imaging as a non-invasive tool to analyze tumor vasculature of human breast cancers and maybe be helpful for breast cancer diagnosis. (Acknowledgements) This work was partially supported by the Innovative Techno-Hub for Integrated Medical Bio-imaging Project of the Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. Citation Format: Toi M, Asao Y, Takada M, Kataoka M, Endo T, Kawashima M, Yamaga I, Nakayama Y, Tokiwa M, Fakhrejahani E, Torii M, Kawaguchi-Sakita N, Kanao S, Matsumoto Y, Yagi T, Sakurai T, Togashi K, Shiina T. Development of photoacoustic vascular imaging system for breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-01-10.

We present a new method to fabricate sharp metal tips on cantilevers for a SPM. The metal tip, which is deposited and patterned as a film on a silicon mold with pyramidal etch pits, is attached by metal-to-metal bonding to a metal pad on a substrate. Then the tip on the substrate is peeled off the mold at room temperature. The tip surface is very smooth without grain boundaries associated with deposited thin films. A platinum tip with a radius curvature of less than 15nm was successfully fabricated. In addition, the mold can be reused because the mold is not dissolved during the tip fabrication. By applying this method in which the tip fabrication process is independent of the cantilever process, we succeeded to form a tip on a piezoresistive cantilevers. Moreover, we used the cantilever with the tip in a piezoresistive AFM and an AFM/STM apparatus and obtained high resolution topography and surface conductance images, respectively.

In 2014, the Japanese Government created the new innovation funding program, called “ImPACT; Impulsing PAradigm Change through disruptive Technologies” and established in the Council for Science, Technology and Innovation (CSTI), the Cabinet Office. ImPACT consists of 16 programs and its period is for 5 years (JFY2014-2018). One of ImPACT is this program; Innovative Visualization Technology to Lead to Creation of a New Growth Industry. The goal of this program is to develop the technologies for real-time 3D photoacoustic imaging of blood vessels in the human body and the physical properties of substances, and then demonstrate the value of applications in medical, healthcare, and cosmetic fields. The configuration of the program consists of six projects: “Visualization and measurement technology,” “Tunable laser technology,” “Ultrasound sensor technology,” “Wide-field visualization system” and “Micro-visualization system” for the achievement of real-time 3D visualization, and “Demonstration of value”for demonstrating the value of applications. Six research institutions and six companies will work together for a common goal. I will present the targets and strategies of the program and show recent research results.

In this study, we propose an advanced model-based reconstruction algorithm for three-dimensional photoacoustic imaging. The algorithm is based on accurate forward photoacoustic models and an optimization algorithm which minimizes the square of the error between the measured acoustic signals and the signals predicted by the forward models. The forward photoacoustic models incorporate system-configuration and detector-dependent factors such as frequency response and finite size effect. A conjugate gradient-based optimization algorithm is used for reconstructing images. In addition, we make use of the symmetry and locality of the photoacoustic waves in the computations of the forward photoacoustic models in order to reduce the memory requirements and computation time in three-dimensional image reconstruction. The results show that the proposed algorithm provides high-resolution and high-quality photoacoustic images.

In this study, we characterized a newly developed imaging system, "dual illumination mode photoacoustic tomography (PAT) system". The PAT system can simultaneously or separately illuminate biological tissues from a forward and backward direction toward an array transducer. The shape of the custom-made transducer is rectangular, which allows direct illumination of tissue surfaces in front of the array transducer through a holding plate from the backward direction. The transducer frequency was designed at 1 MHz by considering the trade-off relationship between ultrasound attenuation and image resolution. A Ti:Sa laser optically pumped with a Q-switched Nd:YAG laser, having a tunable wavelength of 700 to 900 nm, was chosen for deep light penetration in tissues. The laser light was sufficiently expanded and homogenized to keep the level of laser-pulse fluence on the sample surface under the ANSI safety limit. System performance was tested with phantoms. The results of our study showed that the system visualized all the absorbers embedded in a 50-mm-thick tissue-mimicking phantom with a lateral resolution of 2~3 mm.

This study presents an algorithm to estimate the background optical properties for quantitative imaging, based on the initial pressure distribution obtained from photoacoustic tomography (PAT). The algorithm utilizes an alternative illumination mode of our original PAT system, which separately illuminates tissue from forward and backward directions toward an array transducer. The optical properties are determined by minimizing the difference between the following two ratios: one is the ratio of initial pressure distribution obtained from the illumination modes, the other is the ratio of the calculated light fluence distribution. We show that the algorithm estimates the background optical properties even if the initial pressure distribution is reconstructed under the limited-view conditions.

We have developed a sensitive method for the measurement of rhodanese activity in human serum which is based on the colorimetric method for the determination of thiocyanate produced from methanethiosulfonate and cyanide as substrates. Thiocyanate gives a red complex with ferric ion in an acidic condition. The present method is about 70-fold more sensitive than the conventional method using cyanide and thiosulfate as substrates and correlates well (r = 0.997) with the conventional method in bovine liver rhodanese. Within-run precision of the method is 0.91% for 420 units/l serum and the calibration curve is linear up to 1850 units/l. The normal value for human serum, determined by the present method on 31 healthy persons, was 20.9 +/- 20.0 units/l (mean +/- 2S.D.). Rhodanese activity was clearly elevated in some serum samples which were observed at abnormal values in some biochemical diagnostic tests and showed significant positive correlations with guanase activity (r = 0.728, p less than 0.01) and glutamic-oxalacetic transaminase activity (r = 0.625, p less than 0.01).

In this paper we present a novel sample injection chip. Microvalves and microchannels are integrated on the chip. The valve is a passive lowpass valve that allows a liquid flow at a low flow rate and prohibits it when the flow rate exceeds a threshold. We can control the injection volume by changing the channel design. The chip consists of a channel substrate, an upper valve substrate and an under valve substrate. These substrates are separately fabricated and bonded by using MEMS techniques. The chip, not to leak at a pressure difference of 5.0 MPa, was successfully applied to high performance liquid chromatography (HPLC). A specific volume of sample (100 nl) was injected to the HPLC column. The results show that the sample injection chip has the possibility of being used in the micro-HPLC systems.

The development of a MEMS torsional mirror with X-shaped cross-sectional torsional beam is presented in this paper. The torsional resonant mode of the torsional mirror was designed to be the lowest resonant mode. Therefore, vertical and horizontal movements of the mirror were reduced. This torsional mirror has been fabricated using anisotropic etching from both sides of Si (100) wafer.

A new method to fabricate sharp metal tips on cantilevers for a scanning probe microscope (SPM) is presented in this paper. The metal tip film, which is and patterned on a silicon mold with etch pits, is attached by metal-to-metal bonding to a metal pad on a cantilever. Then a tip is fabricated on the cantilever by peeling the metal tip film off the mold at room temperature. Because the back side of the metal tip film becomes the tip surface, the tip surface is very smooth without grain boundaries associated with deposited thin films. A platinum tip with a radius curvature of less than 15 nm was successfully fabricated. In addition, the mold can be reused because the silicon mold is not dissolved during the tip fabrication. By applying this method in which the tip fabrication process is independent of the cantilever process, we succeeded to form a tip on various cantilevers. Moreover, we used the cantilever with the tip in a piezoresistive atomic force microscope and an atomic force microscope combined with a scanning tunneling microscope (AFM/STM) apparatus and obtained simultaneously high resolution topography and surface conductance images of a sample surface.

A 1500-nm-band laser signal is upconverted to the mid-visible part of the spectrum by quasi-phase matched, sum-frequency generation with an 800-nm-band laser pump in a periodically poled KTiOPO4. For an appropriate combination of the two fundamental wavelengths, an acceptance bandwidth of 40-60 nm cm for the pump wavelength is attainable simultaneously with a temperature acceptance bandwidth of 60-70 degrees C cm in an angularly noncritical condition. Using a distributed feedback laser at 1590 nm and a Fabry-Perot laser at 807 nm, we demonstrate a temperature tolerance as large as 60 degrees C with a 10-mm-long crystal.

In a sum-frequency generation system based on periodically poled nonlinear optical crystal, a new approach to the expansion of acceptance widths of temperature and wavelength has been demonstrated. By using periodically poled KTiOPO4 (PPKTP), the condition is found theoretically so that the tolerances of temperature and wavelength are enlarged. A temperature acceptance width of 60°C is obtained experimentally by mixing the light of two diode lasers (1590 nm and 808 nm) in a 10-mm-long PPKTP crystal.

Diagnostic investigation has been made of a-Si image devices by the transient photocurrent (TP) measurements. The states at the interface of the blocking electrodes play an important role in determining the gain and the response speed of a-Si:H devices. By the aid of the top layer of a-SiN x , satisfactory performance has been obtained in a-Si:H photoreceptor of electrophotography.