Research Projects

Research Outline

Our group is devising multi-scale “soft” robots and devices from nano to macro scale based on micro/nano engineering such as MEMS and machining and mechanical dynamics using ultrasound. Utilizing these technologies, our research goals are to construct novel platforms that contribute to cutting-edge medical fields such as drug delivery systems (DDS), tissue engineering, and regenerative medicine. Specifically, the following topics are being researched.

  • Development of intelligent hydrogel microdevices
  • Minimally invasive administration of nano-drugs by ultrasound irradiation
  • Construction of cellular tissue using hydrogel scaffolds
  • Development of non-contact cellular actuation systems using ultrasound
  • Construction of cellular tissue maturation systems by soft robotics and AI

Our group is working with medical and biological researchers to address various medical and life issues, which will be solved with mechanical engineering knowledge and technology. In addition to the above themes, new platforms are being developed day and night. We are always looking for new ideas, devising products on a multi-scale, contributing to medical research, and presenting our research results at international conferences…etc. Let’s work together to deliver research projects that will surprise the world!

Development of intelligent hydrogel microdevices

Hydrogels are composed of a polymer network containing water, and exhibit extremely various functions and characteristics depending on their molecules. In particular, hydrogel microbeads, which are microprocessed hydrogels, are characterized by their microscopic size and huge specific surface area, which enable faster material diffusion and homogeneity of materials unlike those of bulk hydrogels. Because of these characteristics, the research of drug delivery (DDS), biosensors, and other biomedical applications has been attracting attention. Especially, since hydrogels change their properties in response to the surrounding environment, combining them can devise intelligent devices with multiple functions. Our research goal is to construct drug carriers and intelligent robots that work in vivo seances.

Simultaneous crosslinking induces macroscopically phase-separated microgel from a homogeneous mixture of multiple polymers
This paper reports a unique phase separation behavior, a simultaneous-crosslinking-driven phase sep- aration 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 de- livery 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.

Minimally invasive administration of nano-drugs by ultrasound irradiation

The stratum corneum in the skin blocks the permeation of substances with a molecular weight of 500 (approximately 1–2 nm) or larger, thereby protecting our bodies from external enemies. However, this also prevents the transdermal administration of nano-sized drugs. In addition to conventional low-molecular-weight drugs, macromolecular drugs have recently risen in prominence due to their high specificity, safety, and drug efficacy. Macromolecular drugs include nucleic acid drugs, which have been the focus of attention in COVID-19, and antibody drugs, which are specially effective drugs for cancer. The development of an efficient administration method for these systems is expected. Therefore, our research goal is to devise a needle-less and safe method of drug administration by developing an ultrasound irradiation device and hydrogel nanocarriers for transdermal drug administration. In addition to drug administration, this research is also potential for applications in cosmetology and gene delivery.

Quantitative Analysis of Acoustic Pressure for Sonophoresis and Its Effect on Transdermal Penetration
Ultrasound facilitates the penetration of macromolecular compounds through the skin and offers a promising non-invasive technique for transdermal delivery. However, technical difficulties in quantifying ultrasound-related parameters have restricted further analysis of the sonophoresis mechanism. In this study, we devise a bolt-clamped Langevin transducer-based sonophoresis device that enables us to measure with a thin lead zirconate titanate (PZT) sensor. One-dimensional acoustic theory accounting for wave interaction at the skin interface indicates that the acoustic pressure and cavitation onset on the skin during sonophoresis are sensitive to the subcutaneous support, meaning that there is a strong need to perform the pressure measurement in an experimental environment replacing the human body. From a series of the experiments with our new device, the transdermal penetration of polystyrene, silica and gold nanoparticles is found to depend on the size and material of the particles, as well as the hardness of the subcutaneous support material. We speculate from the acoustic pressure measurement that the particles’ penetration results from the mechanical action of cavitation.

Construction of cellular tissue using hydrogel scaffolds

The cells adhere to each other and to their surroundings to form cell aggregates, which come together to form tissues. However, cells alone do not form 3D tissues, as they only layered on the culture surface. Therefore, micro-scale cellular tissues can be formed by assembling cells using hydrogel. Therefore, micro-scale cellular tissues can be formed by constructing cell scaffolds with hydrogel. By stacking and assembling these small tissues, it is possible to form a huge three-dimensional tissue. In this process, cellular tissues similar to organs can be formed by co-culturing multiple types of cells and by providing a vascular network. Such techniques can be applied to cellular tissues for use in regenerative medicine and drug discovery research.

Microfiber-shaped building-block tissues with endothelial networks for constructing macroscopic tissue assembly
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 2days, because the calcium alginate shell of the microfiber-shaped tissue was enzymatically removed. Our approach could facilitate the generation of complex and heterogeneous macro- scopic tissues mimicking the major organs including the liver, kidney, and heart for the treatment of critically ill patients.

Development of non-contact cellular actuation systems using ultrasound

Ultrasound has traditionally been used as a non-contact method for in vivo sensing and cell and tissue disruption. In addition to these techniques utilizing weak/strong ultrasound, it is also possible to employ ultrasound as an actuator. This allows for gentle, non-contact manipulation of cells, thus allowing manipulation without contaminating the cells. We have taken advantage of this characteristic of ultrasound to establish methods to detach cells without damaging them and to aggregate methods to cellular tissues. Thereby, we are developing novel technologies to innovate cell manipulation methods.

Enzyme-free release of adhered cells from standard culture dishes using intermittent ultrasonic traveling waves
Cell detachment is essential in culturing adherent cells. Trypsinization is the most popular detachment technique, even though it reduces viability due to the damage to the membrane and extracellular matrix. Avoiding such damage would improve cell culture efficiency. Here we propose an enzyme-free cell detachment method that employs the acoustic pressure, sloshing in serum-free medium from intermittent traveling wave. This method detaches 96.2% of the cells, and increases its transfer yield to 130% of conventional methods for 48 h, compared to the number of cells detached by trypsinization. We show the elimination of trypsinization reduces cell damage, improving the survival of the detached cells. Acoustic pressure applied to the cells and media sloshing from the intermittent traveling wave were identified as the most important factors leading to cell detachment. This proposed method will improve biopharmaceutical production by expediting the amplification of tissue-cultured cells through a more efficient transfer process.

Cell agglomeration in the wells of a 24-well plate using acoustic streaming
Cell agglomeration is essential both to the success of drug testing and to the development of tissue engineering. Here, a MHz-order acoustic wave is used to generate acoustic streaming in the wells of a 24-well plate to drive particle and cell agglomeration. Acoustic streaming is known to manipulate particles in microfluidic devices, and even provide concentration in sessile droplets, but concentration of particles or cells in individual wells has never been shown, principally due to the drag present along the periphery of the fluid in such a well. The agglomeration time for a range of particle sizes suggests that shear-induced migration plays an important role in the agglomeration process. Particles with a diameter of 45 mum agglomerated into a suspended pellet under exposure to 2.134 MHz acoustic waves at 1.5 W in 30 s. Additionally, BT-474 cells also agglomerated as adherent masses at the center bottom of the wells of tissue-culture treated 24-well plates. By switching to low cell binding 24-well plates, the BT-474 cells formed suspended agglomerations that appeared to be spheroids, fully fifteen times larger than any cell agglomerates without the acoustic streaming. In either case, the viability and proliferation of the cells were maintained despite acoustic irradiation and streaming. Intermittent excitation was effective in avoiding temperature excursions, consuming only 75 mW per well on average, presenting a convenient means to form fully three-dimensional cellular masses potentially useful for tissue, cancer, and drug research.

Construction of cellular tissue maturation systems by soft robotics and AI

Cellular tissues are given mechanical stimulation, which causes young cellular tissues to mature in a similar way as muscles are exercised. However, since cells have no voice, researchers are left to their own experience to select what kind of stimulation is most appropriate for the cellular tissue. To overcome this limitation, we are conducting research to seek the conditions for applying the most suitable mechanical stimuli to cells by using AI.

The paper is coming soon…