Details of a Researcher - Onoe, Hiroaki

Papers - Onoe, Hiroaki

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Morphological Control of Endothelial Tube Formation by Three-Dimensional Lane-Shaped Patterns

Ikezawa Y., Onoe H.

Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems (MEMS) (Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems (MEMS)) 2019-January 594 - 596 2019.01

ISSN 9781728116105

© 2019 IEEE. This paper describes an analytical platform to control endothelial tube formation by patterning cells and extracellular matrix (ECM) within 3D lane-shaped pattern. By using PDMS groove patterns (50-250\ \mu \mathrm{m} in width and height, several millimeters in length), human umbilical vein endothelial cells (HUVECs) were patterned three-dimensionally in collagen gel. The patterned HUVECs spontaneously form endothelial vascular tissues, but their morphologies can be controlled by the dimensions of patterns, cell densities, ECMs, etc. We succeeded in forming vascular tube tissues, and found that a number of branches of the vascular tissues depends on the dimensions of 3D-patterns. We believe that our culture system could be a useful tool for understanding the tube formation behavior of endothelial cells and for creating 3D-shape-controlled vascular tissues as a quantitative model in vitro.

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Hierarchical Hydrogel Drug Delivery System Enables Controlled Release of Adeno-Associated Viruses for Gene Therapy

Miyahara H., Kurashina Y., Ogawa Y., Kurihara A., Yoshida T., Okano H.J., Fujioka M., Onoe H.

ISSN 9781728116105

© 2019 IEEE. This paper describes a drug delivery system (DDS) to release Adeno-associated viruses (AAVs) for gene therapy. Our system has two-level hierarchical structures made of different hydrogel materials: (i) Calcium alginate hydrogel microparticles (\sim 100\ \mu \mathrm{m} in diameter) that can properly immobilize AAVs inside and release them for gene transfection triggered by enzymatic degradation, and (ii) a millimeter-scale collagen sheet that encapsulates those alginate microparticles with AAVs for stable fixation to even a tiny and complicated diseased site in our body, such as an inner ear for the treatment of hereditary hearing loss (Figure 1). We fabricated the AAVs-immobilized hydrogel microparticles and evaluated their AAV releasing functions by measured the gene transfection ratio to cultured HeLa cells. In addition, we also demonstrated that the controlled release of AAVs immobilized in the alginate microparticles embedded in the millimeter-scale collagen sheet can be externally triggered from the outside. We envision that our developed composite hydrogel DDS could be an essential and general tool for gene therapy in practical medical scenes, especially in the treatment at complicated internal sites.

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Eye-recognizable and repeatable biochemical flexible sensors using low angle-dependent photonic colloidal crystal hydrogel microbeads

Mio Tsuchiya, Yuta Kurashina, Hiroaki Onoe

Scientific Reports (Scientific Reports) 9 ( 1 ) 17059 2019

Research paper (scientific journal), Joint Work, Accepted

© 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.

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Microfiber-shaped building-block tissues with endothelial networks for constructing macroscopic tissue assembly

Yuta Kurashina, Ryo Sato, Hiroaki Onoe

APL Bioengineering (APL Bioengineering) 3 ( 4 ) 046101 2019

Research paper (scientific journal), Joint Work, Accepted

© 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.

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4D printing of multi-hydrogels using direct ink writing in a supporting viscous liquid

Takuya Uchida, Hiroaki Onoe

Micromachines (Micromachines) 10 ( 7 ) 433 2019

Research paper (scientific journal), Joint Work, Accepted

© 2019 by the authors. We propose a method to print four-dimensional (4D) stimuli-responsive hydrogel structures with internal gaps. Our 4D structures are fabricated by printing an N-isopropylacrylamide-based stimuli-responsive pre-gel solution (NIPAM-based ink) and an acrylamide-based non-responsive pre-gel solution (AAM-based ink) in a supporting viscous liquid (carboxymethyl cellulose solution) and by polymerizing the printed structures using ultraviolet (UV) light irradiation. First, the printed ink position and width were investigated by varying various parameters. The position of the printed ink changed according to physical characteristics of the ink and supporting liquid and printing conditions including the flow rates of the ink and the nozzle diameter, position, and speed. The width of the printed ink was mainly influenced by the ink flow rate and the nozzle speed. Next, we confirmed the polymerization of the printed ink in the supporting viscous liquid, as well as its responsivity to thermal stimulation. The degree of polymerization became smaller, as the interval time was longer after printing. The polymerized ink shrunk or swelled repeatedly according to thermal stimulation. In addition, printing multi-hydrogels was demonstrated by using a nozzle attached to a Y shape connector, and the responsivity of the multi-hydrogels to thermal-stimulation was investigated. The pattern of the multi-hydrogels structure and its responsivity to thermal-stimulation were controlled by the flow ratio of the inks. Finally, various 4D structures including a rounded pattern, a spiral shape pattern, a cross point, and a multi-hydrogel pattern were fabricated, and their deformations in response to the stimuli were demonstrated.

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Effect of Cyclic Stretch on Tissue Maturation in Myoblast-Laden Hydrogel Fibers

Shinako Bansai, Takashi Morikura, Hiroaki Onoe, Shogo Miyata

Micromachines (Micromachines) 10 ( 6 ) 399 2019

Research paper (scientific journal), Joint Work, Accepted

© 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.

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Spatially-targeted laser fabrication of multi-metal microstructures inside a hydrogel

Manan Machida, Takuro Niidome, Hiroaki Onoe, Alexander Heisterkamp, Mitsuhiro Terakawa

Optics Express (Optics Express) 27 ( 10 ) 14657 - 14666 2019

Research paper (scientific journal), Joint Work, Accepted

© 2019 Optical Society of America under the terms of the OSA Open Access Publishing Agreement The spatially-targeted fabrication of bimetallic microstructures coexisting in the supporting hydrogel is demonstrated by multi-photon photoreduction. Microstructures composed of gold and silver were fabricated along a predefined trajectory by taking advantages of the hydrogel's ionic permeability. Different resonant wavelengths of optical absorption were obtained for gold, silver, and their bimetallic structures. Transmission electron microscopy and energy dispersive X-ray analysis revealed that the optical properties are attributable to the formation of bimetallic structure consisted of core-shell nanoparticles. The fabrication of dissimilar metal structures within hydrogel is a promising technique for optically driven actuators in soft robotics and sensing applications by allowing for site-selective optical properties.

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Graphene-Based Wireless Tube-Shaped Pressure Sensor for In Vivo Blood Pressure Monitoring

Nagisa Inoue, Yoshihiko Koya, Norihisa Miki, Hiroaki Onoe

Micromachines (Micromachines) 10 ( 2 ) 139 2019

Research paper (scientific journal), Joint Work, Accepted

© 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.

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Biohybrid device with antagonistic skeletal muscle tissue for measurement of contractile force

Yuya Morimoto, Hiroaki Onoe, Shoji Takeuchi

Advanced Robotics (Advanced Robotics) 33 ( 5 ) 208 - 218 2019

Research paper (scientific journal), Joint Work, Accepted, ISSN 01691864

© 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group and The Robotics Society of Japan. This paper describes a fabrication method and driving property of a biohybrid device with an antagonistic pair of skeletal muscle tissues and a flexible substrate. Since two skeletal muscle tissues are symmetrically arranged with the flexible substrate as the central axis, the flexible substrate deforms according to differences in their tension. In the formation of the antagonistic pair of skeletal muscle tissues, we assembled myoblast-laden hydrogel sheets and cultured them to construct a single skeletal muscle tissue on each side of the flexible substrate. We confirmed that the skeletal muscle tissue on the flexible substrate had the fundamental morphology and function of skeletal muscle. Furthermore, we made the biohybrid device actuate with deformation of the flexible substrate by selective contractions of the skeletal muscle tissues. From the deformation of the flexible substrate, we estimated the contractile force of each skeletal muscle tissue in the biohybrid device using finite element analysis. This biohybrid device, composed of an antagonistic pair of skeletal muscle tissues and a flexible substrate, can potentially be used in biological studies and pharmacokinetic assays involving the antagonistic pair of skeletal muscles.

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Double-layer perfusable collagen microtube device for heterogeneous cell culture

Shun Itai, Hisatsugu Tajima, Hiroaki Onoe

Biofabrication (Biofabrication) 11 ( 1 ) 0150110 2019

Research paper (scientific journal), Joint Work, Accepted, ISSN 17585082

© 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.

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Multipoint bending and shape retention of a pneumatic bending actuator by a variable stiffness endoskeleton

Shotaro Yoshida, Yuya Morimoto, Lanying Zheng, Hiroaki Onoe, Shoji Takeuchi

Soft Robotics 5 718 - 7252 2019

Research paper (scientific journal), Joint Work, Accepted

Phase-separated core-shell hydrogel microbeads from homogeneous mixed polymer solution by simultaneous gelation

Kurashina Y., Tsuchiya M., Kasahara K., Onoe H.

23rd International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2019 (23rd International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2019) 910 - 911 2019

ISSN 9781733419000

© 2019 CBMS-0001. We propose a generation method of the hydrogel microbeads with the core-shell structure based on phase separation of homogeneous polymer solution mixed with sodium alginate and N-isopropylacrylamide (NIPAM). Without using oil phase and tubing/pumping apparatus, centrifugally generated microdroplets of photocrosslinkable monomer solution can be polymerized by UV irradiation with the assistant of ionic gelation of alginate hydrogel. By using the centrifugal microfluidic device with UV LEDs, the homogeneous mixed polymer solution was successfully turned into hydrogel microbeads with the phase-separated core-shell structure with simultaneous photo-polymerization and ionic crosslink. We envision that our proposed core-shell hydrogel microbeads would be useful tools for functional drug delivery systems and health monitoring biochemical sensors for in vivo applications.

Fabrication of metal microstructures in elastic hydrogel by multiphoton photoreduction

Terakawa M., Machida M., Onoe H., Niidome T., Heisterkamp A.

Optics InfoBase Conference Papers (Optics InfoBase Conference Papers) Part F140-CLEO_Europe 2019 2019

ISSN 9781557528209

© 2019 IEEE Soft materials, including elastic polymers and hydrogels, are promising materials for soft robots, implantable devices, and wearable devices owing to their flexibility and biocompatibility. In recent years, the scope of use of such soft materials is expanding further because of their integration with metal micro- and nanostructures, which exhibit attractive optical and electrical properties. In this study, we demonstrate the formation of metal microstructures inside a hydrogel by photoreduction of metal ion by using femtosecond laser. Because the hydrogels have permeability to fluids, metal ions are able to be added by simply immersing the hydrogel into the metal ion solution. Femtosecond laser pulses were focused and scanned in the hydrogel to fabricate metal microstructures [1, 2]. The optical diffraction pattern obtained with the silver grating inside the hydrogel showed spaced diffraction spots, which indicated that a regular, periodic silver grating was formed. Notably, the distance between the diffraction spots changed when the water content in the hydrogel was reduced. The grating period decreased when the hydrogel shrank owing to the loss of water (Fig. 1(a)), but the straight shapes of the line structures were preserved, which demonstrated the optical tunability of the fabricated structure.

Assembly of actomyosin bundles in microfluidic channel

Kawara S., Hiratsuka Y., Onoe H.

ISSN 9781733419000

Artificial reconstruction of a highly aligned actomyosin bundle utilizing a laminar-flow microfluidic device enables the fabrication of a bio-actuator mimicking skeletal muscle. At the boundary of two fluid streams involving fibrous myosinⅡ and actin macromolecules respectively, actomyosin bundles are spontaneously assembled and aligned along with the flow direction. We successfully obtained several millimeter-scale actomyosin bundles from the microfluidic devices and also revealed that the actin filament was highly aligned in the bundle, which could enhance the mechanical force produced by contraction. We conceive that our methodology for the assembly of actomyosin bundle would contribute to the development of bio-actuators and furthermore to the understanding of the self-organization mechanism and the mechanical characteristics.

Ultrasound-triggered controlled release of nanoparticles from hydrogel microbeads by release-promoting particles

Kubota T., Kurashina Y., Onoe H.

ISSN 9781733419000

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.

Surface tension driven swarm robots for emerging coordinating motions

Yoshida K., Hayashi T., Onoe H.

ISSN 9781733419000

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.

Stretching motion-driven ECM-based pulsatile flow generator for mimicking venous blood flow in vivo

Shimizu A., Goh W.H., Itai S., Hashimoto M., Miura S., Onoe H.

ISSN 9781733419000

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.

Rapid stimuli-responsivity of hydrogel microfiber actuator with surface porous structure

Karube M., Onoe H.

ISSN 9781733419000

This paper describes a stimuli-responsive microfiber-shaped hydrogel actuator with a porous surface layer. By using cellulose nanofibers as a sacrificial template material, we formed nanoscale pores on the surface of the microfiber in gentle condition, enabling the rapid response to external stimuli because the formed nanopores can work as pathways of fluid between inside and outside of the microfiber. We analyzed the formed nanopores by scanning electron microscope (SEM) and confirmed that the nanoporous hydrogel micro-actuator responded faster than the non-porous one. Our cellulose nanofiber-based nanoporous forming approach could be widely applied to polymer-based soft robotics and biomedical soft actuators because of its gentle and biocompatible processes.

Metal wiring on flexible origami structure for stable resistance value against deformation

Uchida T., Yasuga H., Iwase E., Onoe H.

ISSN 9781733419000

This paper describes a new approach to fabricate a flexible circuit that has stable electric resistance value against deformation. The flexible circuit is fabricated by depositing metal wiring on a folded flexible origami structure. We confirmed that the resistance value of the metal wiring on the origami structure was stable against stretching and bending compared to that of the wiring formed on a simple elastic flexible sheet. Using this origami structure, we demonstrated a simple wearable device that fits a wrist. We believe that this origami-based flexible device could be a one possible route to robust and stable wearable devices that can be freely and largely expanded.

Detection of swell/shrink behavior of stimuli-responsive hydrogel by single walled carbon nanotube strain sensor

Iyama E., Kiriya D., Onoe H.

ISSN 9781733419000

In this research, we propose a method to detect the swell/shrink behavior of stimuli-responsive hydrogel by a strain sensor. The strain sensor is composed of single walled carbon nanotubes (SWCNTs) and a flexible sheet. By integrating the SWCNT strain sensor with a stimuli-responsible hydrogel, the swell/shrink behavior of the hydrogel can be simply sensed as an electrical resistance change of the SWCNT strain sensor. Our approach could contribute to simplify the stimulus detection and could be effective for the integration of high-sensitive chemical sensors with electrical devices.

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