Published papers

We present an experimental system for real-time monitoring of 3D constructed tissues at single-cell resolution to further understand cellular response against mechanical stimuli. The system enables us to continuously monitor the same cells in a 3D tissue at a subcellular level under uniaxial cyclic stretch. We confirmed our system's effectiveness by observing that 3D tissues cultured under cyclic stretch were oriented to the direction of stretch. Moreover, cells in a 3D tissue were successfully observed continuously at single-cell resolution even under cyclic stretch. We believe that the real-time observation of cellular response against mechanical stimuli with our demonstrated system could be an effective method for investigating the relationship between cellular response and mechanical stimuli in detail.

This paper describes a new fabrication method for the extracellular matrix (ECM)-based in vitro vascular model. The vascular model was fabricated with shape retaining mold and sacrificial mold (shape retaining and sacrificial molding, SRS-molding). We compared SRS-molding and sacrificial molding. In addition, complex mechanical stimuli such as stretching and flowing in the branches of the vascular model were analyzed by simulation software. Finally, we performed the perfusion culturing with our vascular model and stretching them. Our vascular model and mechanical stimuli analysis would elevate the vascular culturing to the next step.

This paper describes a shape-measurable sheet device using origami structures with single-walled carbon nanotubes (SWCNTs) strain sensors. Previous measurement systems tended to be unable to recognize the stretching and bending of the object surface as different deformation. Here, we propose a shape-measurable device based on origami structure that can distinguish the stretching and the bending appropriately using only strain sensors. We fabricated the strain sensors using SWCNTs that was formed a 5-7 nm thin film on a substrate. We experimented that our origami sheet device could recognize the bending and stretching information separately by attaching the device to cylinders. We are convinced that the origami sheet system could contribute to the observation of complex deformations in various fields.

This article describes a shape-recognizable sheet device using origami structures with single-walled carbon nanotubes (SWCNTs) strain sensors. Recently, a sheet-like measurement system that is directly attached to an object has been attracting attention for obtaining the shape, motion, and deformation of the object as alternative systems with external cameras. However, previous sheet-like measurement systems are difficult to distinguish between the stretch and the bend of the object appropriately. Here we propose a sheet-like measurement system that can distinguish the stretch and the bend individually by using origami structures. We formed a strain sensor using SWCNTs that was deposited on a substrate to form a 5-7 nm thin film. By patterning the SWCNTs strain sensors, origami-based sheet devices were fabricated. We confirmed that our origami sheet device obtained the bending and stretching information separately by attaching the device to cylinders. We believe that the origami system could contribute to the observation of complex deformations such as artificial skin, human interface, and biomedical applications. [2020-0324]

This paper reports a unique phase separation behavior, a simultaneous-crosslinking-driven phase separation in co-gelation (SPSiC) core–shell microgel that spontaneously forms from a homogeneous pre-gel solution of multiple polymers. The SPSiC microgel, composed of an alginate shell and an N-isopropylacrylamide (NIPAM) core, were synthesized by a single fabrication step wherein a mixed pre-gel solution of sodium alginate and NIPAM monomer was ejected by centrifugation with photo-polymerization and ion crosslinking instantaneously. Phase separation was modeled by varying the degree of polymerization and the size of the polymer chain. Moreover, an implantable, multi-functional drug delivery system combined with a transdermal glucose sensor was demonstrated with core–shell Janus SPSiC microgels. This work shows a macroscopic phase separation behavior, which occurs during the gelation process, and also provides a simple and unique methodology to create multifunctional bio-microprobes.

This paper describes a novel approach to magnify the shrink/swell degree of stimuli-responsive hydrogels with micro-scale mechanical metamaterials. The mechanical matematerial fabricated by two-photon stereolithography can be embedded in a structural-color stimuli-responsive hydrogels to amplify the sensitivity (the change in structural color) (Figure 1). To prove this concept, we here constructed micro-scale mesh-like structures with negative poisson ratio. By responding to an applied displacement of 'z = 50 μm, this structure expanded to 'x = 90 μm, showing its displacement amplification. The fabricated structures embedded in poly-N-isopropylacrylamide (PNIPAM) hydrogel showed that the shrinkage of the PNIPAM hydrogel successfully drive the embedded mechanical-metamaterial structures. We believe that this system would be an effective approach to increase the sensitivity of the structural color gel sensors for practical applications.

We present a pulsatile flow generator with an extracellular matrix (ECM)-based microfluidic device for mimicking venous blood flow in vivo. The pulsatile flow can be generated by directly stretching the ECM channel with stepping motors, imitating in vivo veins compressed by surrounding muscles. The flow velocity was estimated by the theoretical calculation based on finite element simulation. Moreover, vein endothelial cells were cultured in our device with fluidic shear stress and stretch stress simultaneously.

This paper describes surface tension driven swarm robots for emerging various coordinate motions. Swarm robots that can swim driven by Marangoni effect are self-assembled by surface tension at air-liquid interface and are loosely coupled, ensuring that the swarm robots have the robustness of total swarm system. Even if large external disturbance is applied, the swarm robots separate to protect the total system and continue swimming. Furthermore, the active robot can rescue a stopped robot by self-assembly, and combination task is also exhibited. We believe that our proposed surface tension driven swarm robots will be a powerful approach to the various biochemical application including highly robust swarm robots and models to mimic biological organisms.

We propose an ultrasound-triggered drug delivery system (DDS) with release promoting particles for long-term controlled drug release with low power ultrasound. By using a centrifugal fluidic device, we fabricated calcium alginate hydrogel microbeads containing fluorescent silica nano-particles as a drug model and tungsten micro-particles for promoting release. The silica nano-beads were efficiently released from the microbeads by the ultrasound because the tungsten micro-particles can receive the energy of the applied ultrasound. This ultrasound method will be a key technology of DDS for control of drug release with less burden on the patients.

This paper describes ultrasound-triggered drug release from hydrogel microspheres with release booster. As a drug carrier, calcium alginate hydrogel microspheres containing drug model and tungsten particles were fabricated by using a centrifugal microfluidic device. The tungsten particles with high acoustic impedance enable the hydrogel microspheres to have high sensitivity to ultrasound so that the release rate of the drug models improves. By applying ultrasound to the hydrogel microspheres, we confirmed the release of fluorescent silica nanoparticles and protein as a drug model. Importantly, the drug model was released from our hydrogel microspheres even in a cavitation-suppressed environment, indicating that this system could reduce the damage to tissues. Our proposed ultrasound-triggered drug release system using tungsten particles would be an effective on-demand drug delivery system (DDS).

Ultrasound-triggered drug delivery has been widely researched for its potential to improve the therapeutic efficacy of drugs. This paper presents drug release using hydrogel microbeads with release enhancer for efficient ultrasound-triggered drug delivery. By using a centrifuge-based microfluidic device, drug-model-encapsulating calcium alginate hydrogel microbeads containing tungsten particles with high acoustic impedance were fabricated. Because the tungsten particles work as release enhancer, the hydrogel microbeads become to have high sensitivity to ultrasound with localized variation in acoustic impedance so that the release rate of drug models improves. By applying ultrasound at 20 kHz to the hydrogel microbeads, the release of fluorescent silica nanoparticles that are a drug model for virus vectors, micelles, and proteins was tested. Importantly, the proposed hydrogel microbeads released the drug model even under a cavitation-suppressed environment. Furthermore, the additional coating on the hydrogel microbeads with poly-L-lysine enabled us to adjust the release rate of the drug model. The proposed ultrasound-triggered drug release system using release enhancer is expected to be an effective approach for expanding the varieties of applicable treatments using on-demand drug delivery systems.

We propose a wireless and battery-free digestible sensor for the detection of intestinal bacteria. This device has a dissolvable Mg planer coil that is covered with a coating layer composed of dietary fiber. This dietary fiber layer is selectively degraded by intestinal bacteria, resulting in the dissolution of the Mg coil that can be wirelessly monitored without any internal batteries. In this report, in vitro wireless detection on the degradation of our device was demonstrated as a proof-of-concept experiment. We believe that this device could be a new non-toxic easy-monitoring device for detecting biological substances without heavy burden to human.

© 2018 The Author(s). This paper describes a microfluidic-based flexible reflective display constructed using dyed water droplets and air gaps as pixel elements. Our display is composed of a flexible polydimethylsiloxane sheet with a connected pixel-patterned microchannel. Several types of dyed water droplets and air gaps are sequentially introduced to the microchannel through a suction process to display a multicolor image. The displayed image is stable and can be retained without an energy supply. To ensure that images are displayed correctly, the geometric parameters of the dot pixel design and minimum differential pressure necessary to drive the water droplets are evaluated. As a demonstration, we successfully display three-color dot-matrix reflective images and bitmap characters in the microchannel. Our proposed method can be applied to energy-less and color-changeable displays for use in future daily-life accessories, such as bags, shoes, and clothes, and can change the surface color and pattern of these accessories.

© 2017 IOP Publishing Ltd. We propose an inline pressure sensor composed of a polydimethylsiloxane (PDMS) microfluidic tube integrated with graphene sheets. The PDMS tube was fabricated through molding, and a multilayered graphene sheet was transferred on the surface of the PDMS tube. The pressure inside the tube was monitored using the changes in the electrical resistance of the transferred graphene. The proposed pressure sensor could be suitable for precise pressure measurement for a small amount of fluid in microfluidic systems including organ-on-a-chip devices.

© 2018 IOP Publishing Ltd. In vitro perfusable 3D tissue models mimic in vivo tissues and have several benefits in drug testing. However, processes used to fabricate these models often tend to be complicated. Here, we present a double-layer perfusable collagen tube device for multilayered in vitro 3D cell culture. The device is simply made by the repetition of a molding process. The thicknesses of the collagen layers in the tube device can be flexibly designed, and heterogeneous cell types can be co-cultured in/on each collagen layer. Moreover, while our collagen tube is directly attached to silicone tubes, the collagen tube can easily be connected to an external pump system for perfusion culture. We fabricated six different sizes of collagen devices (inner diameter approximately 300-1000 μm) using different molds, and successfully controlled the coefficients of variation to be below 5% for the diameters of each layer for all six device sizes. The device is strong enough to manipulate with tweezers, and can remain stable for more than 3 months in a medium. For the cell culture, we successfully and correctly encapsulated cells in the layer shape at the desired position, and confirmed cell migration. Using the perfusion culture, we demonstrated that the alignments of the HUVEC actin filaments become parallel to the flow direction. We believe that our device could advance the easy fabrication of various tissue models (that is, models mimicking in vivo tissues). In particular, the device could help fabricate vascularized tissue models, and contribute to the development of pharmacokinetic testing platforms and regenerative medicine.

© 2019 by the authors. We propose a wireless pressure sensor composed of a graphene sheet and a transmitter coil integrated with a polydimethylsiloxane (PDMS) tube. The pressure inside the tube was monitored wirelessly using an external receiver coil. We then monitored the typical blood pressure range, 12-20 kPa, using this fabricated sensor by changing the turn number of the receiver coil and the overlapping length of the coils. Furthermore, we demonstrated wireless blood pressure measurement by connecting our sensor to the blood vessel of a rat. Our results suggested that this sensor can be easily inserted between an implantable medical device and blood vessels for in vivo blood pressure monitoring. The proposed wireless pressure sensor could also be suitable for monitoring in vivo implanted medical systems, such as artificial organs and pump systems.

© 2019 by the authors. Engineering of the skeletal muscles has attracted attention for the restoration of damaged muscles from myopathy, injury, and extraction of malignant tumors. Reconstructing a three-dimensional muscle using living cells could be a promising approach. However, the regenerated tissue exhibits a weak construction force due to the insufficient tissue maturation. The purpose of this study is to establish the reconstruction system for the skeletal muscle. We used a cell-laden core-shell hydrogel microfiber as a three-dimensional culture to control the cellular orientation. Moreover, to mature the muscle tissue in the microfiber, we also developed a custom-made culture device for imposing cyclic stretch stimulation using a motorized stage and the fiber-grab system. As a result, the directions of the myotubes were oriented and the mature myotubes could be formed by cyclic stretch stimulation.

© 2019 Author(s). We describe a microfiber-shaped hepatic tissue for in vitro macroscopic tissue assembly, fabricated using a double coaxial microfluidic device and composed of cocultured Hep-G2 cells and human umbilical vein endothelial cells (HUVECs). The appropriate coculture conditions for Hep-G2 cells and HUVECs in the microfiber-shaped tissue were optimized by changing the thickness of the core and the cell ratio. The HUVEC networks were formed in the microfiber-shaped tissue following culture for 3 days. Using this microfiber-shaped tissue as a building block, two types of macroscopic assembled tissues were constructed - parallel and reeled tissues. In both tissue types, the connection of the HUVEC network across the adjacent microfiber-shaped tissues was established after 2 days, because the calcium alginate shell of the microfiber-shaped tissue was enzymatically removed. Our approach could facilitate the generation of complex and heterogeneous macroscopic tissues mimicking the major organs including the liver, kidney, and heart for the treatment of critically ill patients.

© 2019, The Author(s). This paper presents eye-recognizable and repeatable biochemical flexible sensors using low angle-dependent stimuli-responsive photonic colloidal crystal hydrogel (PCCG) microbeads. Thanks to the stimuli-responsive PCCG microbeads exhibiting structural color, users can obtain sensing information without depending on the viewing angle and the mechanical deformation of the flexible sensor. Temperature-responsive PCCG microbeads and ethanol-responsive PCCG microbeads were fabricated from a pre-gel solution of N-isopropylacrylamide (NIPAM) and N-methylolacrylamide (NMAM) by using a centrifuge-based droplet shooting device (CDSD). As a proof-of-concept of thin and flexible biochemical sensors, temperature- and ethanol-sensing devices were demonstrated. By comparing the structural color of the stimuli-responsive PCCG microbeads and the color chart of the device, sensing information, including skin temperature of the human body and ethanol concentration in alcoholic beverages, was obtained successively. We expect that our device design using low angle-dependent stimuli-responsive PCCG microbeads would contribute to the development of user-friendly biochemical sensor devices for monitoring environmental and healthcare targets.

© 2019 IEEE. This paper describes a DNA aptamer-linked structural-color hydrogel sensor that can quantitatively and repeatably detect biochemical substances through visual information without any specific equipment. The initial color of structural-color hydrogel could be adjusted by controlling the concentration of the colloidal silica particle. We co-polymerized a DNA aptamer that specifically binds to silver ions into acrylamide hydrogel and evaluated its quantitative shrinking response to silver acetate solution. In addition, we succeeded in initializing our DNA aptamer hydrogel sensor by heating, indicating that our chemical sensor could repeatably measure the target chemical substance for the long term. We believe that our structural-color biochemical sensor could be applied to various routine monitoring such as healthcare diagnosis and water safety.