In order to encourage publications of research achievements in English, Japanese Society for Medical and Biological Engineering (JSMBE) launched a new English journal of Advanced Biomedical Engineering (ABE; abe-journal.org) two years ago, and more than 50 articles have been published. Based on the experience of the editorship, this symposium aims at providing manuscript preparation, how to write a scientific manuscript, and how to reply to review comments. Some examples will be presented. Most contents are common to Japanese and English, and we will touch the issues specific to English writing. In addition, the same contents will be published in Transaction of JSMBE, and the reprint will be distributed at the site.

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Submitting a manuscript and publishing a paper is one of the most powerful methods to publicize one's research achievements worldwide. The authors, however, should meticulously conform to some guidelines / regulations. These rules arise primarily in association with the manuscript requirements for its scientific nature, such as novelty, importance and validity. In this talk, we would like to provide information on citations, copyrights, multiple submissions, research / publication misconduct, ethics for studies using animals and humans, and disclosure of conflict of interests, to enhance members' better submission and response to reviews.

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High temporal resolution is a big advantage of ultrasonography for measurement of tissue dynamics. High frame rate (HFR) ultrasound can increase the imaging frame rate from several tens of Hertz of conventional ultrasonography up to several thousand Hertz and, thus, significantly enhances the advantage of ultrasonography. We realized HFR B-mode and blood flow imaging of the carotid artery at a very HFR of over 3 kHz using a linear-array probe. Also, we have also realized HFR echocardiography using spherically diverging beams (Fig. (a), 316 Hz), whose image quality is very similar to conventional beamforming (Fig. (b), 39 Hz). Such methods would be useful for measurement of tissue dynamics.

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High-intensity focused ultrasound (HIFU) causes selective tissue necrosis through heating and is used for a noninvasive treatment of cancer therapy. However, HIFU thermal treatment has a problem of long treatment time because cooling time is needed between two consecutive shots of focused ultrasound exposure to avoid near-field heating owing to heat accumulation. It is known that acoustic cavitation generated in the focal region of HIFU enhances tissue heating. The objective of this study is to develop a method to accelerate HIFU thermal treatment by using cavitation bubbles. Cavitation bubbles were generated at six positions in the direction perpendicular to ultrasound propagation and they were observed by high-speed ultrasound imaging in real time. The coagulation volumes of chicken breast with and without cavitation bubbles were compared. The results show the high efficiency of the proposed HIFU exposure sequence using cavitation-enhanced heating for HIFU thermal treatment.

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Scanning acoustic microscope (SAM) is useful for tissue characterization because it is possible to obtain two-dimensional information of acoustic properties, viz., velocity and attenuation coefficient, in the microscopic region. We have studied development of SAM and its application to quantitative evaluation of biological tissue and a single cell. We developed a SAM system using a pulse signal and analytical procedure to obtain acoustic properties. Recently, we also developed an acoustic and optic hybrid system to obtain both optical and elastic images and acoustic properties for a single cell in real time. We applied the system to a 3T3-L1 mouse fibroblast cell using an acoustic lens with center frequency of 250MHz. Measurements were conducted immediately and enough later after takeoff from the culture apparatus. Sound velocities were 1602 m/s and 1558 m/s, and thicknesses were 7.9 μm and 16 μm, respectively. Properties changes of the cell were successfully detected quantitatively.

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Many of tissue characterization methods to estimate the size and/or the number of scatterers in the local regions of the living tissues based on the attenuation factor and the power spectrum of the echo signal have been proposed. Furthermore, statistical analysis method of echo signals for estimating the scatterer density and uniformity of the scattering structure was already applied clinically. The determination of cancer metastasis in the lymph nodes and tissue structure estimation of the liver became possible by use of the complex of these technologies.

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The tissue elasticity and viscosity are important information in diagnosis. A method which estimates tissue viscoelastic modulus using shear wave by acoustic radiation force was proposed. However, since the signal to noise ration of this shear wave is low, it is difficult for this method to estimate tissue viscoelastic modulus distribution. Therefore, we propose a method which can estimate tissue viscoelastic modulus distribution. Our method uses the coupler with which the viscoelastic modulus is already known and the vibration by ultrasonic probe. We measure the strain distributions of coupler and tissue, and we estimate the viscoelastic modulus (storage elastic modulus and loss elastic modulus) distribution from the strain ratio and the time delay between coupler strain and tissue strain. Moreover, we verified the validity of our method by phantom experiment and experiment which used the pig tissue. As a result, using our method, we can estimate the viscoelastic modulus distribution quantitatively.

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Recently, Photoacoustic imaging (PAI) technique has been developed to achieve volumetric imaging of blood vessel in biological tissue. Comparing with Optical Coherence Technique or Near Infra-Red Spectroscopy, PAI is expected as more deep part measurement technique due to only one way propagation of light in tissue. In PAI technique, conventional UT probe which needs to contact with tissue surface is generally used for detecting ultrasonic induced by Photoacoustic effects. The author developed laser-ultrasonics which performs remote and non-contacting ultrasonic measurement by laser interferometer. Using this technique, the author has achieved non-contacting measurement of ultrasonic signal induced by photoacoustic effects. In my presentation, we will show a result of three-dimensional imaging of artificial blood vessel with 0.1 mm diameter in simulated biological tissue by aqueous suspensions of Intralipid.

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The ICT system to collect and manage the personal health information is a low cost efficient medical system indispensable to the coming aging society. The wristband-shaped wearable health monitoring tools are attracting attention, and are already going to form the steadfast market. In order to realize "unconscious health sensing" by minimizing the presence of sensor devices, novel device technologies for super-miniaturization with improving biocompatibility are necessary to be developed. In this talk, I will briefly overview the present conditions of sensor devices used for e-health care and a trend of the device development towards "unconscious health sensing" at first. Then I will explain wet device technologies we recently developed. The techniques for patterning electrodes on hydrogel and power generation with enzymes will combined to develop a patch-type, totally organic sensing tool.

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Super aging society such as Japan would need tele-healthcare systems for home medical care to suppress medical cost inflation. In this situation, we have developed a tele-healthcare system for end-of life decision at home using a wireless electrocardiograph combined with a smartphone and a sphygmogram signal extracted from an ordinary video camera. The experimental results have indicated that long term monitoring through the smartphone and a server will provide rich information on the patient's terminal status for doctors in remote locations. However, it is necessary to collect many clinical data to predict the timing of end-of-life more precisely.

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This presentation introduces NTT e-Health-related activities and standardization trends.

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We use big data in sleep research. One is genome-wide association study, which analyze hundreds of thousands of single nucleotide polymorphisms from hundreds to thousands of participants. Another is annual medical check data from hospitals or workplaces. We hope to elucidate unexpected underlying mechanisms for sleep-control or for complications of sleep disorders.

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According to the progress of genome sequencing technology, the cost of genome analyses is rapidly decreasing, and the feasibility of genome-based personalized healthcare is dramatically increasing. Actually, a lot of large-scale genome cohort studies are established to realize personalized healthcare. Tohoku University is also constructing a new genome cohort in the process of constructive recoveries from the Great East Japan Earthquake on March 11, 2011. On the other hands, the cost of information analyses of genome data is not decreased, mainly due to the increase of the amount of data produced by new generation sequencers and high sensitivity of the data. In this talk, I will introduce our approaches to build a basis of in-silico analyses though the setup of a new computer system in Tohoku Medical Megabank, and discuss some issues in information analyses to realize the genome-based personalized healthcare.

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The aim of this study is to develop the estimation model that provides the level of mental stress using physiological response. Physiological indices were recorded during psychological load such as watching slideshow including uncomfortable images or tiny "Sudoku" task in participants. Multiple regression model in which target variable was subjective stress index STAI was obtained using the measured physiological responses. The figure shows the result of STAI score and the correlation coefficient was 0.80. The results indicated the possibility of the objective evaluation for mental stress though it is necessary to investigate the optimal psychological load for the evaluation.

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The pupil dilates in response to emotion such as anger, anxiety, or fear, and constricts under fatigue or sleepiness. Such psycho-sensual pupillary responses, i.e., pupillary constriction together with oscillation (fatigue wave), have been applied in a commercial setting as an objective index of sleepiness due to fatigue. We continuously measured the pupillary response and recorded the electrocardiogram simultaneously, and demonstrated the clinical significance of the autonomic nerve system by a heart rate variability analysis and a fast Fourier transformation analysis of the pupillary oscillation. We then investigated whether the pupillary oscillation can be an index of stress in work with Visual Display Terminals (VDT) by examining the relationship between the pupillary oscillation and the General Health Questionnaire-28. We report an attempt of clinical application of the pupillary response.

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Keeping ubiquitous stress evaluation approach in mind, we propose a rating of perceived stress by integration of psychological and physiological responses with the multivariate analysis and model. Questionnaires with GHQ28 (mental health survey) and STAI (state - trait anxiety test) were used at viewing loathing pictures and temporal demanded puzzle as task stressors or stimuli. As physiological indices from heart rate, blood pressure, respiration, and fingertip pulse waves, SDNN (standard deviation of RR intervals) and frequency components ratio LF/HF of heart rate variability were estimated to evaluate the autonomic nervous regulation. By a principal component analysis, the anxieties of STAI and the temporal behavior of SDNN and LF/HF were selected to estimate and predict the stress levels. Cooping with the individual differences, clustering samples into three clusters in the space of STAI, then fuzzy inference was designed to propose the perceived stress level for the risk avoidance.

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Stress is an important factor when we consider responses in the cardiovascular and the autonomic nervous systems. After ethical committee allowance, responses in the cardiovascular system and autonomic nerve were evaluated with the individual characteristics. We investigated relationship between responses to the stress and individual characteristics. Healthy adult participants were assessed with type A scale, Beck depression scale, Hostility scale and Japanese Coronary-prone Behavior Scale (JCBS). Participants were showed hateful images and performed a mathematical task (Sudoku). Heart rate (HR), systolic blood pressure (SBP), LF/HF and pulse wave transmission time (PTT) were measured. The maximum value of the cross-correlation coefficients between BP and HR (ρmax BH), BP and PTT (ρmax BT) were analyzed. In both tasks, higher type A scored groups had larger LF/HF, suggesting that the individual characteristics were correlated with the autonomic nervous system. Significant correlation between the Beck depression score and the decrease in PTT and the increase in BP during hateful images were observed. High type A scored or high depression level had the relationship with the stress.

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Pupillary responses may have potentials to evaluate a person's state of mind. Subjects (n= 17) viewed pictures, which could produce emotions (pleasant, neutral and unpleasant feeling), serially presented on an LCD with gray color images as ISI. We compared the pupil diameters on viewing gray images after emotional picture presentation. The pupil diameter after having pleasant feeling was significantly smaller than the diameter after viewing neutral pictures. On the contrary, pupil was significantly dilating after when the subjects had unpleasant feeling from the stimulus pictures. Those findings could be useful for evaluation of human state of mind.

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July in 2011, Ministry of Health, Labor and Welfare (MHLW) decided on the policy that the psychiatric disorder was included among 5 biggest diseases in Japan and immediately studied how to cope with them because they involved national health significantly. Other diseases contain cancer, stroke, myocardial infarction, and diabetes mellitus, which were called as 4 biggest diseases in 2006 by MHLW. In this social condition in Japan, among psychiatric disorders depression represents stress diseases and influences a dysfunction of autonomic nervous system (ANS), showing insomnia, appetite loss, constipation, diarrhea, sweat, and palpitation. Consequently, objective measuring some dysregulation of ANS before and at onset of depression using medical engineering techniques advantages to prevent and to detect early of depressive state and depression. From the above, it is very important to accelerate the development of measurement of psychological stress using medical engineering techniques for national mental health in Japan.

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To stabilize mental stress assessment, we are studying quantitative measurements based on the bio-signal fluctuation triggered by a task stressor. Unfortunately, the loads imposed by most task stressors are highly user dependent. We investigate the task stressors of uncomfortable images, annoying sounds, Sudoku puzzles, and visual search tasks. Task stressor loads are quantified by subjective rating scores or by operation times. In the experiments, we extract two quantitative indices from bio-signals; LF/HF ratio from ECG/respiration and pupil diameter fluctuation. We use the correlation between the bio-signals indices and the subjective scores of mental stress (GHQ28, STAI) to evaluate task stressor repeatability. The results show that visual search tasks are the most reliable (uniform across subjects). The other tasks demand some form of user-specific adjustment. The results confirm the effectiveness of a compound index consisting of LF/HF and pupil index.

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There has been a continuous attention for molecular imaging, a technique for in situ analysis of molecules in the body. Especially, NMR (Nuclear magnetic Resonance)-based technique is one of the most promising approaches because it could give various information of target molecule, e.g., molecular structure or surrounding chemical/biophysical environment. However, the NMR-based technique has a shortcoming of low sensitivity and thus the target molecules (measuring objects) are typically restricted to biomolecules highly abundant in our body. In order to overcome this shortcoming and to realize NMR-based in-situ analysis of molecules (molecular activities), many efforts have been made in this research field. In this talk, I will introduce one of our recent efforts to develop highly sensitive and selective NMR or MRI contrast agents (molecular probes).

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Several kinds of imaging tools are used both in basic sciences and clinical diagnoses, such as positron emission tomography (PET), single photon emission computed tomography (SPECT), optical imaging, magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound imaging (US). Among these, CT, MRI and US are categorized as morphological imaging technologies, although some molecular imaging trials are undertaken these days. PET, SPECT and optical imaging are mainly used for molecular imaging. Molecular imaging probes are composed of signal molecules and targeting molecules, and nano-particles can be used as a targeting molecule. Especially, nano-particles have great advantages in making multimodal imaging probes, since multiple kinds and/or amount of signal molecules can be combined to them.Herein, we discuss the advances and disadvantages of each imaging technique, and in vivo molecular imaging with nano-particles would be discussed by showing our practical examples.

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Protein assemblies are a class of highly organized biomaterials, which hold promise as novel materials for (bio)nanotechnological applications. Especially, hierarchical assemblies formed with protein monomers as building blocks have been recently designed and developed as supramolecular platforms with several applications such as catalysis of biochemical reactions, bio-electronics, medical imaging, drug delivery and tissue engineering. These protein frameworks have emerged attractive due to the two-dimensional and three-dimensional organization to form supramolecular architectures such as sheets, rings, cages and tubes or wires. They are promising in terms of innate biocompatibility, easy bio-conjugation to incorporate multiple functionalities and well-defined nano-scale lengths for manomedicinal applications.

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We developed a method to detect intracellular cytoskeletal proteins using antibody-functionalized nanoneedle. The nanoneedles are ultra-thin cylindrical-shaped AFM probes sharpened to 200 nm in diameter. Following insertion, the nanoneedle was retracted from the live cell and the mechanical force needed to unbind the antibody-target protein complex was measured, we named the peak force “fishing force”. Using this method, intermediate filament proteins, actin filaments and microtubules were successfully detected. The intermediate filament proteins, nestin and neurofilament, which are well-known marker proteins of neural cells could be detected in single living cells, mouse embryonic carcinoma P19, within a minute.

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Theranostics refers to be the combination of disease diagnosis and therapy. Microbubbles, nanobubbles and bubble liposomes (BL) hold significant potential for theranostics applications, given their propensity to be visualized in vivo with extremely high sensitivity, their ability to improve drug delivery across biologic barriers, and the possible of loading therapeutic molecules into or onto their shell. The combination of ultrasound exposure and bubbles can be utilized to enhance drug delivery efficiency in ultrasound-mediated delivery systems. Ultrasound-induced microstreams/microjets in fluid surrounding the bubbles form transient pores in the plasma membrane through which exogenous materials such as plasmid DNA, siRNA, proteins and/or drugs in the fluid can then enter the cell. The combination of ultrasound exposure and bubbles is also a novel strategy for antigen delivery in dendritic cell (DC)-based cancer immunotherapy, thus making the prevention of metastasis in therapeutic models of antigen delivery into DCs possible. Arg-Gly-Asp (RGD)-BL represent a novel echo contrast agent, and may be useful for noninvasively diagnosing acute thrombotic vessel occlusion. Furthermore, the induced cavitation of RGD-BL by low-frequency ultrasound, showed great potential to accelerate the thrombolytic effect in thrombotic vessel occlusion model of rabbit.

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It is known that bone remodeling process advances under the control of mechanical stress in the body. Synthetic biomaterials, such as hydroxyapatite, are widely used to repair various bone defects. Octacalcium phosphate (OCP) and the related materials are bioactive and bioresorbable materials (Suzuki O. Jpn Dent Sci Rev 49: 58, 2013). The OCP materials show an osteoconductivity if implanted in various bone tissues. However, the resorption of the materials is enhanced under load bearing conditions, which is restored again if the assumed mechanical stress is alleviated. The effect of the mechanical stress on the biomaterial implantation condition was simulated using a culture device, which utilizes deformation of PDMS membrane deformation (Masuda T et al. J Biotechnol 133: 231, 2008), by analyzing bone tissue related cells, including osteoblasts. It is likely that the bone regeneration with the biomaterials could be controlled depending on the extent of the mechanical stress.

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Myocardium contracts against ventricular wall stretch that comes along with ventricular filling. Mitochondria generate required ATP for myocardial contraction. It is well known that mitochondrial ATP production process is one of the sources of reactive oxygen species (ROS). ROS are known as toxic molecules, but also important physiological regulators of intracellular signaling pathways. In the present study, we investigate the relation between myocardial stretch and mitochondrial ROS production, and discuss the role of mitochondria on myocardial response to stretch. Isolated mouse ventricular myocytes were exposed to 10% axial stretch using carbon fiber technique. ROS production was studied using DCF-loaded cells. Axial stretch significantly increased ROS production. Applying 5 μM mitochondrial metabolic uncoupler FCCP blunted the response, indicating mitochondrial ROS production is stretch-sensitive. The present results suggest that stretch enhances electron transport chain to prepare for the more ATP production for the more preloaded, namely, the more energy-consuming contraction.

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Adhesion of cells flowing in microvessels to the vessel wall is an important process in hemostasis and immune system, and it also relates to malaria and metastasis. This process may depend on the mechanical property of cells, the size and geometry of vessels, the volume fraction of red blood cells, the shear rate, and the biochemical property of ligand-receptor interactions. We have developed a numerical model of cellular flow in microvessels to clarify the effects of these parameters. A cell is modeled as a liquid drop enclosed by a thin membrane. The finite element method for membrane mechanics is coupled with the lattice Boltzmann method for fluid mechanics. A ligand-receptor interaction model is also coupled with those methods. All the procedures are implemented in GPU computing for accelerating simulations. We simulate flow of leukocytes and circulating tumor cells, and rolling motion of malaria-infected red blood cells in microvessels.

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Mechanical forces play crucial roles in a variety of cell functions, including growth, survival, ploriferation, and migration. Cells may use cytoskeletal structures to sense externally applied forces. Actually, the dynamics of actin stress fibers (SFs) are greatly affected by the tension increases in SFs induced by intrinsic contractile force or extrinsic forces. Here, we propose a novel cencept, "mechano-sensing" by actin filaments. To test this hypothesis, we examined the effect of actin-modulating protein cofilin on a single actin filaments with or without tension in the filaments. When the filament was tensed, it was hard to be severed by cofilin. Single molecular imaging showed that binding rate of cofilin was decreased when the filament was tensed. This suggests that tension in the filament is sensed by the filament itself and modulate the cofilin binding. Actin filaments/stress fibers may act as "negative tension senor" in cells.

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Endothelial cells (ECs) sense shear stress and transduce its information into functional responses that play important roles in vascular homeostasis. A unique feature of shear-stress-sensing is the involvement of many membrane-bound-molecules, but the mechanisms remain unknown. Because cell membrane-bound properties affect the activities of membrane-bound proteins, shear stress may activate various membrane-bound molecules by altering the physical properties of EC membranes. To determine how shear stress influences the cell membrane, cultured ECs were exposed to shear stress and examined for changes in membrane lipid order by Laurdan two-photon imaging. Upon shear stress stimulation, the lipid order of membranes rapidly decreased, and caveolar membrane changed from the liquid-ordered state to the liquid-disordered state. A similar decrease in lipid order occurred when the artificial membranes were exposed to shear stress, suggesting that this is a physical phenomenon. These findings indicate that ECs identify shear stress through changes in their membrane lipid order.

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Mammalian cells utilize glucose as an essential fuel, taking it up in a stereoselective manner through GLUTs, whereby only D- and not L-, glucose is recognized. Cellular uptake of D-glucose through GLUTs can be monitored by 2-NBDG, a widely used D-glucose analogue emitting green fluorescence. For evaluating stereoselectivity of the uptake more precisely, we have developed 2-NBDLG, the first commercially available fluorescent L-glucose analogue (f-LG), as a negative control substrate for 2-NBDG. In the present talk, I introduce some critical features of 2-NBDLG when applied to mammalian cells as well as its unexpected turn.

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Diffuse optical tomography (DOT) has potential to provide clinically important functional information which is cannot measured by X-ray CT and MRI. The light is scattered by tissue and an adequate mathematical model is essential for DOT. In this project, we establish the forward model and image reconstruction algorithm based on the radiative transfer equation (RTE), which is more accurate but complicated than the conventionally used diffusion equation (DE), and a time-resolved system to measure the optical properties of tissue. A hybrid RTE-DE algorithm is developed to reduce the computational cost however keeping the high accuracy. The image reconstruction based on the RTE is evaluated by simulation and the results are clearly improved compared with that based on the DE. The feasibility study has been started to assess the applicability of RTE-based DOT to the brain and thyroid gland in which light propagation is affected by low- or non-scattering regions.

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Raman scatting realizes non-staining molecular imaging because of high selectivity of molecular species with molecular vibrations. However, conventional spontaneous Raman imaging requires long measurement time due to the low cross-section of Raman scattering. Coherent nonlinear Raman imaging overcomes the problem. In the presentation, our developed coherent nonlinear Raman microscopy system using a high-speed tunable and synchronized picosecond mode-locked laser is described. The combination of coherent nonlinear Raman and second harmonic generation visualizes lipid and collagen, respectively. Simultaneous imaging of lipid and collagen applies to observation of arteriosclerotic lesion of artery. A prototype of lock-in image sensor for stimulated Raman imaging, which is one of the coherent Raman imaging, is also described, and the fundamental properties of the sensor and imaging results will be shown. The lock-in image sensor enables parallel excitation and detection of stimulated Raman. At the last, the concept of coherent nonlinear Raman endoscopy will be described.

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Innovative photoacoustic imaging system with transparent piezo-electronic material was developed. High quality ZnO thin film was processed in a certain condition. VZO layer was acted as the electrode. Optical fiber for transmission of the high power laser was assessed. The imaging system successfully visualized normal and osteoarthritis knee joints of rats. The study was conducted with the collaboration of academia and industry.

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The oxygen level of the interior of living cells and tissues is one of the central parameters in many physiological, pathological, and therapeutic processes. Oxygen deprivation is connected with various diseases and occurs in tumor microenvironments. Quantification of the oxygen levels in biological cells and tissues is, therefore, of essential importance in cell biology and cancer therapy.We have reported that a red-emitting iridium complex BTP serves as a hypoxia-sensing probe for tumor imaging in living mice. BTP exhibits oxygen-sensitive phosphorescence that can be utilized to visualize the oxygen levels in living cells and tissues. In this study we made chemical modifications of BTP to improve its optical and physicochemical properties as biological oxygen sensor, and measured the phosphorescence lifetimes of the BTP derivatives in cultured cells and tissues of tumor-bearing mice to evaluate the oxygen levels in cells and tissues.

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Vulnerable plaques in atherosclerotic lesions cause acute myocardial infarction and stroke. Therefore, detection of high-risk, vulnerable plaque is important for risk stratification and to provide early treatment. Plaque vulnerability is characterized by the large size of the lipid-rich atheromatous core, the thin fibrous cap, and the infiltration of inflammatory cells such as macrophages, although intimal thickening is observed in both vulnerable and stable plaques. Several imaging approaches have been applied to detect vulnerable plaques; however, quantification of plaque inflammation is necessary to predict the risk of plaque rupture. Recently, clinical trials to detect atherosclerotic lesions with molecular imaging technologies have been settled out. Furthermore, optical imaging probes are receiving much attention as a promising candidate for vulnerable plaque detection due to its easy-to-use properties.Herein, several examples of the atherosclerotic plaque imaging methods would be introduced, and the capability of optical imaging for vulnerable plaque detection would be discussed.

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Fluorescence imaging technique is a powerful technique for medical diagnosis. Some imaging techniques, such as Indocyanine green (ICG) lymphangiography and fluorescence-guided surgery with protoporphyrin IX in brain tumor, are known to be very promising in clinical trials. However, once the fluorescence object is buried into the tissue more than a few millimeters deep, it is difficult to visualize the object due to the strong scattering and absorption properties of tissue. To recover the lost spatial information, we have studied on a 3-dimensional (3D) reconstruction using data from time-domain measurements of the fluorescence and excitation. Particularly, we have employed a method, fluorescence-assisted diffuse optical tomography (FA-DOT), to quantify the absorption of the fluorescence object. We also have developed a simple targeting method for the practical way in clinical application. In this talk, we will present results by some phantom measurements to clarify the experimental artifact and analyze the effect on the reconstruction to establish the robust 3D reconstruction method. Then, we will discuss the future prospects.

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Introduction
A precise preoperative staging is necessary to determine the appropriate treatment strategy for digestive organ cancer. However, the accurate diagnosis is difficult. 5-Aminolevulinic acid (5-ALA) has metabolized protoporphyrinIX (PpIX) in a cancer cell. Lanthanide nanoparticles (LNPs) by the near-infrared (NIR) irradiation emits the light can excite PpIX. We investigated whether can be observed in the deeply-placed cancer be used in 5-ALA and LNPs combination.
Methods
We administered LNPs to tumor-bearing mouse model, and examine its pharmacokinetics. Mouse model incorporating gastric cancer cells were studied after administration only LNPs and administration of mixture of 5-ALA and LNPs by NIR irradiation.
Results
LNPs were accumulated in the cancer lesion. LNPs emission was observed in the tumor lesion. The cancer lesions were detectable on PpIX fluorescence imaging was by near NIR excitation.
Conclusions
These results suggested that fluorescence diagnosis of deeply-placed cancer may be possible by using the mixture 5-ALA and LNPs.

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In order to establish deeply penetrating photoacoustic cancer imaging technology, we are designing and synthesizing photoacoustic probes and developing imaging technology of the probes. Both small organic molecule- and plasmonic gold nanoparticle-based probes are studied as photoacoustic probes. As photoacoustic imaging provides a spatial distribution of photon absorber, intrinsic photon absorber such as hemoglobin becomes a strong background in the case of visualizing the probe signal selectively. Thus, a method to extract the probe signal from the background signal has been required. We applied multispectral unmixing method to the photoacoustic data to identify the probe of distinct optical absorption spectrum. The multispectral photoacoustic measurements of activatable rhodamine probes as small organic molecules, and various plasmonic gold nanoparticles were performed using a tunable laser. Accordingly, there is high probability that the multispectral unmixing method enables us to visualize accurate distribution of the photoacoustic probe.

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To unravel the dynamics of the neuronal circuit, multicellular neuronal activities should be analyzed. Optical imaging from neuronal populations in vivo is feasible for analyzing the dynamics of the neuronal circuit. A multiphoton microscope can observe deeper brain regions, but cannot observe deeper than the cortical region. We designed and developed the fluorescent imaging system equipped with the micro-endoscope for deep brain imaging. This endoscope was consisted with a GRIN lens and an image fiber, and has a smaller diameter and a higher special resolution than traditional endoscopes. We have also developed the special optical system for the endoscope. The main component of the optical system has a size within 40 cm square. Using this optical system, the fluorescence images were captured from neurons expressing green fluorescent protein in a mouse brain preparation. Our portable imaging system would facilitate the in vivo imaging studies with less invasive manners.

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The application of intracellular electrode has been limited for basic researches, because the electrode insertion causes cell death to the target. We found a unique cell membrane penetration technique by local photo-oxidative reaction with photosensitizer, and the survival ratio of the processed cell is more than 80%. In this study, we extended the research to electrophysiology, with the capillary coated with photosensitizer hematoporphyrin. We evaluated the perforation function by microinjection, and the success rate of membrane impermeable fluorescence dye Lucifer Yellow CH into rat PC12 cells was 70%. With this evidence, we applied the capillary as the glass microelectrode. When the electrode touched cell membrane under the irradiation, the recorded potential by the electrode dropped gradually, and we could measure the resting potential under the dark condition without causing cell death at least a several minutes. We will develop this method to establish novel intracellular electrode array for neural interfaces.

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Understanding and control of functional roles in the central nervous systems are important themes in the field of neuroscience and neuroengineering. In particular, development of recording and analysis methods for neuronal networks which consist of enormous numbers of neurons has been major challenge. We have carried out recording and regulation of networks of cortical neurons reconstructed in vitro using microfabrication techniques, in order to figure out the developmental changes in neuronal networks. Here, we attempt to introduce our recent experiments and results: 1) Characterization of self-organization processes in cultured cortical networks during development, 2) Evaluation and control of stem cell-derived neuronal networks and 3) Development of artificial cultured neuronal networks in structures and functions using microfabrication and microfluidics techniques.

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Information processing in the brain is formed by the interaction of multiple neurons. The simultaneous intracellular recording from multiple neurons in vivo is an essential techniques, because the intracellular recording enables us to observe not only action potentials but also postsynaptic potentials. However, multiple in vivo intracellular recording is formidable tasks for researchers. To overcome this difficulty, we developed an automated intracellular recording (AIR) system. The AIR system can automatically move an electrode in the brain, find a neuron and record its intracellular potential. We evaluated the performance of the AIR system in anesthetized mice. The success rate for one electrode was 63 % (n=11 electrodes). The average stable recording time was 56 min, and a maximum time was 193 min. Additionally, we run 6 AIR systems in parallel and succeeded in simultaneous recording from 4 neurons; 2 neurons from the primary somatosensory and 2 neurons from the secondary motor area.

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Instability of neural recordings from the brain is a big problem to develop invasive brain-machine interfaces (BMIs) including our vehicular system for a rat "RatCar". Its ability to estimate actual locomotions from motor cortical activities has strictly depended on local functionality around the electrodes. It has been almost impossible to select specific neurons to record, and to keep the selection after the implant surgery. Meanwhile, neurons are known to be functionally plastic to change their own behaviour according to synaptic inputs. We have recently started a challenge to induce plastic changes of the motor cortex by applying micro-current stimuli to forcibly correlate their activities with voluntary locomotion. In this work, our methodology and preliminary results are described towards a more persistent controller for BMI systems.

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To realize a low-invasive and high accuracy BMI (Brain-machine interface) system, we have already developed a fully-implantable wireless BMI system which consists of ECoG neural electrode arrays, neural recording LSIs, a Wi-Fi based wireless data transmitter and a wireless power receiver with a rechargeable battery. For accurate estimation of movement intentions, it is important for a BMI system to have a large number of recording channels. In this paper, we report a new multi-channel BMI system which is able to record up to 4096ch ECoG data by multiple connections of 64-ch LSIs and time division multiplexing of recorded data. This system has an ultra-wide-band (UWB) wireless unit for transmitting the recorded neural signals to outside the body. By preliminary experiments with a human body equivalent liquid phantom, we confirmed 4096ch UWB wireless data transmission at 128Mbps mode below 25mm distance.

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Recently, experimental studies for activities of multi-neurons have been significantly increased because of advanced technologies of extracellular recordings with multi channel linear-probe or calcium imaging with two-photon microscopy. Therefore the sizes of experimental data have been also increased with the development of the experimental technique. However, the method that extracts the spike trains of multiple neurons from raw data have not yet established. In this study, we introduce an improved spike-sorting framework using a novel signal detection and a clustering method. We also introduce a cell-sorting framework using the sparseness of cell sizes and spike firing.

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Continuous-flow left ventricular assist devices (LVADs) are becoming the standard therapy for patients with end-stage heart failure in Japan since 2011. The number of centers approved for implantable LVADs therapy becomes more than 30; however, there are still only two LVAD centers in Tohoku region. We have had 17 outpatients in 6 prefectures in Tohoku region. To prepare for the emergency, before discharge, we met and educated the local emergency department staff, medical services providers, and patients' co-worker. Three patients underwent heart-transplantation and 14 patients are still outpatient. A patient died 28 days after discharge because of wrong manipulation of battery exchange. Re admission rate was 1.09 times/patient/per year. Its main causes were driveline infection and neurologic complications. QOL for patients with LVADs significantly improved; however, we should make on effort to diminish the re-admission rate.

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1. BackgroundEVAHEART LVAS is used as a bridge-to-transplant for patient with severe heart failure. Most patients perform normal daily activities at their home after implantation. A smaller controller was introduced in 2013. In the course of development, risk analysis for home care had been conducted. 2. Design to enhance safetyConsiderable fears were incorrect operations on power source management and on troubleshooting. A human factor test for these procedures was carried out with 15 participants. They performed actual procedures and some problems were reported through interviews. Based on the results some designs were modified, for instance the battery connector was changed because of possible insufficient connection. New controller has an internal memory which stores operation history, so incorrect operation during home care can be detected when patients visit the hospital.3. ConclusionNo critical adverse event has been reported with new controller because of incorrect operation during home care.

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【Backgrounds】Treatment for end-stage heart failure has been shifting from inpatient care to domiciliary treatment according to the commence of health insurance reimbursement for implantable left ventricular assist device (LVAD). Majority of patients with LVAD treatment are able to enjoy better quality of life and rehabilitation in society, which was not achievable with conventional medical treatment.【Current status and management】We established the ventricular assist device center at Tohoku University Hospital in April, 2013, and have dedicated ourselves to manage domiciliary treatment for patients with LVAD. There have been currently three so-called LVAD nurses belonging to the VAD center, and all are qualified with a certificate for LVAD specialist. The LVAD nurses play a role as a contact person and a coordinator for outpatient clinic for patients and their family including emergent occasion. They are also in charge of home anti-coagulant management utilizing a coagucheck XS○R personal. Infection control of drive-line exit site is another area of important management by them. When infection is suspected, the patients are required to send them some photographs of the exit site which are then meticulously assessed along with the updated information on each patient obtained over the phone. Selected surgical dressings and instruction on sterilization technique for patients are also provided by the LVAD nurses.【Summary】The number of patients requiring LVAD treatment has been increasing and the number of available devices has also been expanding over the last three years. Accordingly, medical professionals are requested to provide individualized care and management for each patient. The VAD center has undoubtedly played a central role to enable the patients with LVAD to live their lives at home by a team effort with integrated knowledge and expertise shared among LVAD specialists.

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Data handling of medical devices are one of the most important things under home medical care. We examined data handling of total artificial heart (TAH) under home medical care based on animal experiments of the TAH.A system that collecting and storing all data of total artificial heart and experimental animal and notifying only emergency data as alarm was developed. The datum was stored almost in real-time and can be accessed through the Internet. We could handle the data from remote by the developed system.The most important and difficult point on the data dealing with under home medical care is notifying of the data. The data must be layered according to the priority and collected almost in real-time. On development of the TAH, data handling under home medical care must be concerned.

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