Ultrasound is a useful tool for diagnostics and therapeutics in the medical field, and microbubbles can be used to improve diagnostics with ultrasonography. Recently, it was reported that the combination of nano- and micro-sized bubbles and ultrasound can enhance the effects of diagnostics and therapeutics. Therefore, this combination could be a new technology for ultrasound theranostics combined therapy and diagnostics. Especially, this theranostics is showing promise as drug delivery system and for tumor treatment. In this presentation, we will introduce our bubble preparation and feasibility studies of our bubbles for ultrasound theranostics.

In cancer diagnosis and therapy, radionuclide imaging and radionuclide therapy by using their radiation energy are informative and promising. Large tumor accumulation is needed for their success. Liposomes, one of the nanoparticles of drug delivery system, have a potential to deliver drugs to the tumor via the enhanced permeability and retention (EPR) effect. We have been studying application of radionuclide-encapsulated liposomes for tumor imaging and therapy. It is also attractive as "theranostic" agent, because both radionuclides for imaging and therapy can be encapsulated in the same liposomes. However, conventional radionuclide-encapsulated liposomes also accumulate in the normal tissues, such as the liver and spleen, hindering their clinical application. I herein present a new strategy focusing on the radionuclide-ligand complexes inside the liposomes that is able to escape from the liver after the accumulation and be rapidly excreted into urine.

Water is the most abundant substance in cells. Most intracellular reactions occur with the association of water molecules that surround the protein molecules. Application of pressure is a powerful method for modulating intermolecular interactions between protein and water molecules. This means that applied pressure is able to modulate the structure and function of protein molecules, without requiring the use of any chemical materials other than water molecules. We have developed a microscope that enables us to acquire high-resolution microscopic images at high-pressure conditions. The developed system allows us to visualize and manipulate the cellular architecture and activity.

Fluorescence imaging is one of the most powerful techniques for visualization of the temporal and spatial biological events in living cells, and fluorescent probes are also highly useful for fluorescence imaging. The light in near-infrared (NIR) region is recently paid much attention because of its high tissue penetration and low autofluorescence. In this presentation, we will report the development of small-molecule NIR fluorescent probes for hypoxia (Angew. Chem. Int. Ed., 52, 13028-13032 (2013)) and a small-molecule MRI-fluorescence dual imaging probe for atherosclerosis that specifically targets the atherosclerotic environment (Org. Biomol. Chem., 12, 8611-8618 (2014)).

The impact of development of ICT to medical and healthcare services has recently been discussed. In particular, the prevalence of intelligent wearable devices and embedded sensors in daily living environment enable to measure high-quality, multidimensional, and intensive longitudinal biomedical data (ILD) and also access large-scale health-related information. The utility of such data is thought to have a great potential to diagnosis and an early detection of diseases. Therefore, the establishment of a new framework to utilize it, especially a method to extract the useful information associated with diseases, has been focused. Indeed, Horizon2020 in EU incorporated such viewpoints into the projects called in the field of medicine and healthcare. Based on these situations, JST-CRDS also reported on the establishment of proactive health and medical systems for the control of health-related risks. In this talk, we briefly introduce this report and a new data mining framework for biomedical ILD.

In this talk, I will review bases of theory of DNB (Dynamical Network Biomarkers) analysis and its application to detection of predisease states. The DNB analysis is based on bifurcation theory for a complex biological network that triggers a disease, and can detect a predisease state bifurcating from a healthy-state attractor to a disease-state attractor. The DNB analysis can realize very early personalized diagnosis and preemptive medicine for various complex diseases.

We found the robust statistical laws of behavioral organization, specifically the laws of durations of resting and active periods in spontaneous physical activity (SPA), as well as their alterations in psychiatric disorders, including major depressive disorder. These strongly suggest the existence of the dynamical system organizing SPA and its dysfunctions in the disorders. In this talk, we introduce our recent studies on the reconstruction of the dynamical systems based on SPA in patients with psychiatric disorders, showing the alterations of their dynamical properties in the disorders. Further, using the intensive longitudinal data of SPA in patients with bipolar disorder, we demonstrate the concurrent changes of the reconstructed systems, associated with pathological states or clinical phases, along with the nontrivial changes around the vicinity of clinical phase transitions. These could lead to the objective monitoring of pathological states of psychiatric disorders and an early warning detection of pathological changes.

Normal heart contraction is initiated by electrical impulses from the sinoatrial (SA) node acting as the natural pacemaker of the heart. The heartbeat intervals fluctuate in a complex manner even for a healthy individual at rest. This fluctuation is caused by that of the pacing rate of the SA node modulated by the activity of sympathetic and/or parasympathetic nervous fibers via the autonomic nervous system. Therefore, through the analysis of heart rate fluctuations, called heart rate variability (HRV), it is possible to evaluate various aspects of ANS function. It has been reported that reduced and/or abnormal HRV in cardiac patients is associated with higher mortality risk. Hence, HRV are expected to serve as prognostic as well as diagnostic markers of various cardiovascular disorders. In this presentaion, we discuss characteristics of HRV and the key issues for evaluation of ANS functions thought to play an important role in the disease transition.

In this paper, pneumatically-driven surgical assist robots for minimally invasive surgery (MIS) are introduced. The smooth and continuous movement needed for highly precise control of surgical robots have realized by pneumatic servo control. We mainly introduce two robots. One is the endoscope holder for MIS where the camera is held by robot arm that follows the operator's head movement. The other is a novel hand-held robotic forceps for MIS. Intuitive operation is realized by an active transformation from the surgeon's wrist-rotation to the tip-rotation using an inertia measurement unit. The effectiveness of the robots is confirmed with in-vitro and in-vivo experiments.

If a novel concept machine is developed for many purpose at once, the machine can become overly complicated. Such complicated machine is not suitable for practical use because of its low reliability and low cost performance. Of course, cost performance can often be ignored in surgical robots development. However, expensive robots can be introduced only in large hospitals, which might limit the reach of its benefit to many people. Therefore, we are developing simple mechanisms by determining essential functions for each of the operations.

The mission of Japan Biodesign is to train the next generation of entrepreneurs and leaders in biomedical technology innovation for Japan and the global healthcare community.

The program is launched as a collaboration between Osaka University, Tohoku University, the University of Tokyo, the Japan Federation of Medical Devices Associations (JFMDA) and the Program in Biodesign at Stanford University. Training of the core faculty for Japan Biodesign started since 2014. Leaders from Stanford Biodesign did and will provide extensive mentoring for Japan Biodesign.

Faculties from these institutions work together to create new, interdisciplinary training structures and methodologies based on the Biodesign Process developed at Stanford. Japan Biodesign involves a novel ”All Japan” government-academia-industry partnership with support from Japan's Ministry of Education.

The presentation will provide the strategic planning of the program to contribute to creating ecosystem through development of entrepreneurs and innovative medical products and system from Japan.

Biodesign process consists from three phases; Identify, Invent & Implement. 7 months has passed since the 2015-2016 Japan Biodesign fellowship started. Currently, fellows are working on Invent and Implement phases. As Dr. Tomas J. Fogarty said in Biodesign textbook, “An idea, by itself, has no importance whatsoever; it is the implementation that idea and its acceptance by others that brings benefits to our patients.”

The purpose of the Implement phase is to create a multi-year plan for developing concepts into real product that improve patients' lives and is attractive to providers and payers to continue projects after finishing fellowship. We still have much to learn from Silicon Valley about combination of medicine, engineering & business because they have a lot of cases and roll models for young entrepreneurs.

I believe Japan Biodesign fellows will find ways to implement ideas of young entrepreneurs they identified and invented in Japan with utilizing the resources in Stanford & Silicon valley where medical device startups can develop technologies.

Japan Biodesign Fellowship Program was launched in October 2015, as a hands-on training program to develop talents who will lead medical device innovations in Japan. This 10-month, full-time program consists of a university-based program hosted by three partner universities, Osaka University, The University of Tokyo, and Tohoku University, and a tri-university joint program supported by Stanford University. This year, a total of 10 fellows with diverse background (medicine, engineering and business) joined the program to learn the Biodesign process, which covers need identification in clinical immersion (on-site observation), concept invention, and business planning for implementation. In this presentation, I will report the programs' current progress, including the clinical immersion with university-specific focus, the mentorship provided by Stanford University, and the lectures by real-world experts in specific areas (IP, regulation, reimbursement, and business planning). I will also discuss the remaining curricula such as specialist consultation for concept selection and business development.

Japan Biodesign was launched last October at Osaka University, The University of Tokyo, and Tohoku University in collaboration with Stanford University and JFMDA. Medical device industry is having a high expectation for this program that develops talents who will lead innovation and develop innovative devices based on needs. While the program is developed based on Stanford program, there are different environments between Japan and Stanford. The typical difference is Japan Biodesign plays the role of talent development of working people as well. Therefore we are developing the program which fosters not only entrepreneur but intrapreneur also, and will provide various courses, such as part-time and seminars. Japan Biodesign does not simply implement Stanford program as is. While utilizing the basic concept framework of Stanford program, we will develop a program to foster talents that is suitable for the Japanese environment, in order to respond to the expectation from the industry.

It is estimated that the global market size of ‘Digital Health' will increase drastically to more than $200B, and the market attracts a lot of companies all over the world. In such a setting, “How can Japan win the game by using our advantages?”

In most false cases of medical device development in Japan, it was found that the companies could not identify the appropriate needs while they had sets of very good high-techs. Namely, finding good needs is the critical factor for success in the development of medical device business, especially in Japan.

The Stanford Biodesign process, that is the need-pull process for medical device development, can be one of the best solutions to overcome this situation.

Therefore, we launched Japan Biodesign last year in collaboration with Stanford Biodesign in order to develop the global leaders that can perform the need-pull development process for medtech/healthcare innovation.

(Introduction) The biological fluid distribution have been tried to measure by the electrical impedance from 1960. Extracellular fluid including blood and intracellular fluid are consists of electrolytes solution, so these are resistance element. As for the cell wall is made of fat, so it is an insulator by a capacitance. (Purpose) At present the biological fluid measurement is the only method which is large-scale MRI. Therefore, we propose that easy and consecutive measurement method. So we tried whether subcutaneous fluid volume can be measured by bioimpedance. (Result) We found that the impedance from 500kHz to 1MHz is smaller than that of at 100Hz, and impedance is smaller within 1 minute after avascularization. (Conclusion) Because of the brachial cutaneous vein diameter expanded from 0 to 1 minute after avascularization. This phenomenon is approximately agrees with this result. We think that it is possible to measure subcutaneous fluid change by bioimpedance.

Study of the behavior of the cell by using micropattern is studied now, but it often target one kindof cell. Therefore the comparison of the cell of other kinds is difficult. It is insufficient only by control of the size same as an organization, and the control of the single cell's behavior is necessary for the application to regenerative medicine to make the cellular tissue which is near to the in vivo organization. Three types stripe micropatterns are made to control the extension direction of the cell in one direction by using Photolithography in this study. The manufactured micropatterns has mountain width, 1μm, 3μm, 5μm, height, 1μm, sulcular width, 3μm. The cell's behavior is observed by time lapse photography for 24 hours. About the extension, myoblast and fibroblast were similar results, but neuroblast was different results and confirmed the cell's behavior difference by the size of the groove width.

Oxygen plasma has been known as enhanced hydrophilic treatment techniques for surface modification.In this study, we investigated effect of oxygen plasma on characterize changes of PLLA fiber sheet and cell adhesion. The PLLA fiber sheet was fabricated by using CO2 gas laser supersonic drawing and the oxygen plasma treatment was performed by r.f. plasma CVD technique. After the plasma treatment, characterized changes of the surface was analyzed by X-ray photoelectron spectroscopy (XPS). The C=O bond ratio of the PLLA fiber sheet surface was increased. Additionally, NIH3T3 cells were spread on the plasma treated PLLA fiber sheet. The cell behavior was analyzed for 50 hours. In an early stage of cell culture, the cell adhesion and proliferation was accelerated by increased C=O bond of the PLLA fiber sheet. It was observed that the oxygen plasma treatment increased C=O bound and had enhancement of cell proliferation.

The effect of mechanical stimulation has been studied in vitro. Ultrasonic vibration has clinically applied to regenerative medicine and has treated bone or muscle. However, the effect of ultrasonic vibration on one kind of cell is unclear. In this study, effect of daily ultrasonic vibration (1 MHz, 30 min) on proliferation for some kind of cells was investigated. Cell was cultured on 6 well plate for 4 days. Piezo electric element was placed under well plate and was driven by function generator (16 V pp., sine wave). Vibration was attenuated gradually far from well on piezo electric element. To count number of cell, each of cell suspension absorbance were measured in day 4. Cultured cell in stronger vibrating well was exfoliated from culture surface. Proliferation of C2C12 cell was enhanced with mild vibration, and the optimum vibration depends on the kind of cells.

In vitro development of three-dimensional tissues is in high demand for regenerative medicine and drug screening. Here we present a novel inkjet head specialized for on-demand ejection of cell suspensions. Droplets are formed by membrane vibration, which is generated by a pulse actuation of the piezoelectric vibrator. During the non-ejecting period, the membrane is softly vibrated by a sinusoidal actuation to prevent the sedimentation of the cells inside the chamber.

We performed an initial feasibility study by ejecting a suspension of normal human dermal fibroblasts (NHDF) using this inkjet head. By combining the ejecting actuation and the stirring actuation, the number of cells per droplets remained stable for more than thirty minutes and cell viability was over 90%.

Next, we tried to construct three dimensional cardiac tissues by using cardiomyocytes derived from human iPS cells. Droplets with cardiomyocytes were ejected into the culture medium by repeating cycles of ejecting and stirring. After four days of incubation, the cells in the constructed cardiac tissue showed synchronous beating.

These results indicate that this inkjet head is suitable for the effective ejection of living cells.

Various techniques have been developed for studying cell response induced by mechanical stress such as modulating its structure or gene expression. However, conventional techniques and devices cannot load mechanical stress including high-frequency component of kHz to MHz expected to act greatly on cells because of their viscoelastic properties and induce unknown effects. Here we have developed an impulsive stimulation loading system which enables to push the cultured cells with a short duration. Requirements for the system are that loading time of stimulation is 1 μs to 100 μs and displacement imparted to cell is 1 nm to 1 μm. For generating high speed displacement, we drive a cantilever by irradiating nanosecond laser pulse. The displacement was measured by optical lever system with 25 nm and 2 ns resolution. In evaluation experiment, the cantilever was displaced over 1 μm with 4 μs, which meets the requirements.

The effects of mechanical properties of the culture substrate on the cellular behavior are intensively investigated. However, most of the studies adjusted the elastic modulus of culture substrates by changing the substrate component concentration. In this study, we take the advantage of the nonlinear mechanical properties of porcine amniotic membrane to realize the sole adjustment of substrate elastic modulus by stretching the membrane at different stresses in a lab-made device. Fibroblasts were able to attach and proliferate nearly to confluence on the membrane (~500 cells/mm2 ) under low stress (elastic modulus smaller than 30.0 kPa); whereas, the cells failed to attach on the membrane under high stress (elastic modulus ~ 6.0 MPa). It implicates that the dynamic characteristics of the amniotic membrane related with the device structure may also impact the cellular behavior because the elastic modulus of conventional culture dishes (~GPa) is much greater than 6.0 MPa.

The three-dimensional cell culture is the powerful tool for evaluate behavior of virus and medicine in vitro compared with two-dimensional dishes. In study we developed two lines perfusion culture systems with three-dimensional culture vessel in which one line was for culture cell and another one was for delivering virus or medicine. The three-dimensional culture vessel is composed of three-dimensional fibrous scaffold which is manufactured by laminating microfibers. This system constructed with closed circuit, silicone tube, roller pump, reservoir and three-dimensional scaffold. All devices except pump were set on CO2 incubator. For evaluating culture condition, we measured continuously pH and temperature change in 96 hours run. As a result, two system perfusion culture systems were able to maintain environment suitable for a cell culture at temperature and pH in 96 hours run.

In this study, a decellularized porcine aorta having long length was converted to a small-diameter vascular graft and then covered with electrospun segmented polyurethane (SPU) fibers in order to reinforce its mechanical property. The intima-media of aorta was decellularized using high hydrostatic pressure method. The decellularized intima-media was formed cylindrically and covered with SPU by using our original electrospinning apparatus. For SEM observation, two layers of inner decellularized intima-media and outer SPU fibers were observed. The thickness of SPU fibers was increased with increasing of electrospinning time. The extensibility of the hybrid blood vessel was inhibited by covering of SPU fibers. Also, the stiffness of them was similar to that of native blood vessels by controlling the thickness of SPU fibers. From these results, the compliance matching the hybrid blood vessel could be applicable as a novel small-diameter vascular graft.

Magnetic resonance imaging (MRI) is one of the most promising non-invasive methods to evaluate the organ functions. Especially, arterial spin labeling (ASL) method provides the information of the blood perfusion status without using contrast media. And diffusion weighted image (DWI) method, which can detect the diffusion of the water of tissue and organ, has a potential to reflect the perfusion status, too. However, we cannot distinguish perfusion from diffusion exactly by boxel size in vivo. Then, we tried MRI analysis by ASL and DWI, using the extracorporeal perfusion model of the pig kidney isolated after slaughtering. An electrolyte solution was perfused at the pressure of 30mmHg from the artery by drip infusion, and the perfusion study was carried out by ASL and DWI. As a result, although neither typical perfusion nor infarction clues were detected by ASL, a slight clue of perfusion could be detected by DWI.