Tokushima University / Educator and Researcher Directory --- Koshiyama, Kenichiro

Personal Web Page

https://sites.google.com/view/pbpekoshiyama

https://researchmap.jp/kkmd (researchmap)

https://orcid.org/0000-0003-2023-6742 (ORCID)

Field of Study

○	Engineering, Biomedical Engineering, Biomechanics

Subject of Study

○	Nonequilibrium Biomolecular Dynamics, Pulmonary acinar biomechanics, Molecular Basis of Drug Delivery Systems

Book / Paper

(See https://researchmap.jp/kkmd (researchmap) for Published Book / Papers / Presentations.)

Book:

1.	Kenichiro Koshiyama : 生命科学で使える初めての数理モデルとシミュレーション, YODOSHA CO., LTD., Mar. 2017.
2.	Kenichiro Koshiyama : マイクロ/ナノカプセルの調製，徐放性制御と応用事例, Technical Information Institute Co., Ltd., Oct. 2014.

Academic Paper (Judged Full Paper):

1.	Kensuke Fujita and Kenichiro Koshiyama : Polyhedron-based pulmonary acinus structure modeling considering alveolar distribution along airways for including respiratory bronchioles, International Journal for Computational Methods in Engineering Science and Mechanics, 26, 3, 231-240, 2025. (Keyword) alveolarization / computational modeling / gas exchange / lung biomechanics / lung development / Optimization (Link to Publication Site) ● Publication site (DOI): 10.1080/15502287.2025.2463673 (Link to Search Site for Scientific Articles) ● Summary page in Scopus @ Elsevier: 2-s2.0-85217734109 (DOI: 10.1080/15502287.2025.2463673, Elsevier: Scopus)
2.	Kenichiro Koshiyama and Kazuki Nakata : Effects of lipid saturation on bicelle to vesicle transition of a binary phospholipid mixture: a molecular dynamics simulation study, Soft Matter, 19, 39, 7655-7662, 2023. (Summary) Controlling the transition from lipid bicelles to vesicles is essential for producing engineered vesicles. We perform coarse-grained molecular dynamics (CGMD) simulations of unsaturated/saturated lipid mixtures to clarify the effects of lipid unsaturation on vesiculation at the molecular scale. The results demonstrate that vesiculation depends on the concentration of unsaturated lipids and the degree of unsaturation. The probability of vesiculation increases linearly with the apparent unsaturated lipid concentration at a low degree of unsaturation. Higher degrees of unsaturation lead to phase segregation within the binary bicelles, reducing the probability of vesiculation. A comparison between CGMD simulations and the conventional theory of vesiculation shows that the theoretical predictions of binary lipid systems must explicitly include phase segregation effects. Furthermore, simulations with biased lipid distributions reveal that vesiculation is facilitated by the preconcentration of unsaturated lipids in the core region of the bicelle but is then temporally limited as the unsaturated lipids move to the bicelle edges. These findings advance theoretical and experimental studies on binary lipid systems and promote the development of tailor-made vesicles. (Link to Publication Site) ● Publication site (DOI): 10.1039/D3SM00904A (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37782209 ● Search Scopus @ Elsevier (PMID): 37782209 ● Search Scopus @ Elsevier (DOI): 10.1039/D3SM00904A (DOI: 10.1039/D3SM00904A, PubMed: 37782209)
3.	Shigematsu Taiki and Kenichiro Koshiyama : Changes in free energy barrier for water permeation by stretch-induced phase transitions in phospholipid/cholesterol bilayers, Journal of Biomolecular Structure & Dynamics, 1-8, 2023. (Summary) Water permeation through phospholipid/cholesterol bilayers is the key to understanding tension-induced rupture of biological cell membranes. We performed molecular dynamics simulations of stretched phospholipid/cholesterol bilayers to investigate changes in the free energy profile of water molecules across the bilayer and the lipid structure responsible for water permeation. We modeled stretching of the bilayer by applying areal strain. In stretched phospholipid/cholesterol bilayers, the hydrophobic tail of the phospholipids became disordered and the free energy barrier to water permeation decreased. Upon exceeding the critical areal strain, a phase transition to an interdigitated gel phase occurred before rupture, and the hydrophobic tail ordering as well as the free energy barrier were restored. In pure phospholipid bilayers, we did not observe such recoveries. These transient recoveries in the phospholipid/cholesterol bilayer suppressed water permeation and membrane rupture, followed by an increase in the critical areal strain at which the bilayer ruptured. This result agrees with experimental results and provides a reasonable molecular mechanism for the toughness of phospholipid/cholesterol bilayers under tension.Communicated by Ramaswamy H. Sarma. (Link to Publication Site) ● Publication site (DOI): 10.1080/07391102.2023.2250447 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37656194 ● Search Scopus @ Elsevier (PMID): 37656194 ● Search Scopus @ Elsevier (DOI): 10.1080/07391102.2023.2250447 (DOI: 10.1080/07391102.2023.2250447, PubMed: 37656194)
4.	Taiki Shigematsu and Kenichiro Koshiyama : Shear-flow-induced negative tension of phospholipid bilayer: Molecular dynamics simulation, The Journal of Chemical Physics, 159, 1, 014901, 2023. (Summary) Shear flow has been theoretically predicted to suppress the undulation of surfactant bilayers and generate negative tension, which is considered to be a driving force of the transition from the lamellar phase to the multilamellar vesicle phase in surfactant/water suspensions, the so-called onion transition. We performed coarse-grained molecular dynamics simulations of a single phospholipid bilayer under shear flow to clarify the relationship between the shear rate, bilayer undulation, and negative tension, providing molecular-level insight into the undulation suppression. An increasing shear rate suppressed bilayer undulation and increased negative tension; these results are consistent with theoretical predictions. The non-bonded forces between the hydrophobic tails facilitated negative tension, whereas the bonded forces within the tails suppressed it. The force components of the negative tension were anisotropic in the bilayer plane and prominently changed in the flow direction, although the resultant tension was isotropic. Our findings regarding a single bilayer will underlie further simulation studies of multilamellar bilayers, including inter-bilayer interactions and topological changes of bilayers under shear flow, which are essential for the onion transition and are unresolved in the theoretical and experimental studies. (Link to Publication Site) ● Publication site (DOI): 10.1063/5.0153167 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37403852 ● Search Scopus @ Elsevier (PMID): 37403852 ● Search Scopus @ Elsevier (DOI): 10.1063/5.0153167 (DOI: 10.1063/5.0153167, PubMed: 37403852)
5.	Atsuki Ishikawa and Kenichiro Koshiyama : Mathematical modeling of pulmonary acinus structure: Verification of acinar shape effects on pathway structure using rat lungs., Respiratory Physiology & Neurobiology, 302, 2022. (Summary) The pulmonary acinus is the gas exchange unit in the lung and has a very complex microstructure. The structure model is essential to understand the relationship between structural heterogeneity and mechanical phenomena at the acinus level with computational approaches. We propose an acinus structure model represented by a cluster of truncated octahedra in conical, double-conical, inverted conical, or chestnut-like conical confinement to accommodate recent experimental information of rodent acinar shapes. The basis of the model is the combined use of Voronoi and Delaunay tessellations and the optimization of the ductal tree assuming the number of alveoli and the mean path length as quantities related to gas exchange. Before applying the Voronoi tessellation, controlling the seed coordinates enables us to model acinus with arbitrary shapes. Depending on the acinar shape, the distribution of path length varies. The lengths are more widely spread for the cone acinus, with a bias toward higher values, while most of the lengths for the inverted cone acinus primarily take a similar value. Longer pathways have smaller tortuosity and more generations, and duct length per generation is almost constant irrespective of generation, which agrees well with available experimental data. The pathway structure of cone and chestnut-like cone acini is similar to the surface acini's features reported in experiments. According to space-filling requirements in the lung, other conical acini may also be acceptable. The mathematical acinus structure model with various conical shapes can be a platform for computational studies on regional differences in lung functions along the lung surface, underlying respiratory physiology and pathophysiology. (Keyword) Acinar Cells / Animals / lung disease / Models, Biological / Pulmonary Alveoli / Rats (Link to Publication Site) ● Publication site (DOI): 10.1016/j.resp.2022.103900 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 35367411 ● Search Scopus @ Elsevier (PMID): 35367411 ● Search Scopus @ Elsevier (DOI): 10.1016/j.resp.2022.103900 (DOI: 10.1016/j.resp.2022.103900, PubMed: 35367411)
6.	Zhao Jianan, Feng Yu, Kenichiro Koshiyama and Wu Huimin : Prediction of airway deformation effect on pulmonary air-particle dynamics: A numerical study, Physics of Fluids, 33, 101906, 2021. (Link to Publication Site) ● Publication site (DOI): 10.1063/5.0065309 (Link to Search Site for Scientific Articles) ● Summary page in Scopus @ Elsevier: 2-s2.0-85118247278 (DOI: 10.1063/5.0065309, Elsevier: Scopus)
7.	Taiki Shigematsu, Kenichiro Koshiyama and Shigeo Wada : Kelvin-Helmholtz-like instability of phospholipid bilayers under shear flow: System-size dependence., Physical Review E, 102, 2-1, 022408, 2020. (Summary) We performed a series of molecular dynamics (MD) simulations of phospholipid bilayers under shear flow to estimate the effect of the system size on Kelvin-Helmholtz (KH)-like instability of the bilayer at the molecular scale. To extend the estimation by the MD simulations to the microscale, we introduced linear stability analysis for the fluid-fluid interface consisting of a thin membrane. For both the MD simulations and theoretical model, the critical velocity difference across the bilayer, where instability occurs, decreased with increasing wavelength of the bilayer undulation λ, which corresponds to the system size. When λ was more than about ten times larger than the bilayer thickness, the critical velocity difference in the MD simulations was in quantitative agreement with that obtained by the theoretical model. This means that the theoretical model is applicable for the shear-induced KH-like instability of the bilayer for large λ. The theoretical model showed that the critical velocity difference for the KH-like instability was proportional to λ^{-3/2}. Based on these results, we discuss the implications of the shear-induced bilayer instability in the shear-induced cell damage observed in experiments. (Link to Publication Site) ● Publication site (DOI): 10.1103/PhysRevE.102.022408 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32942508 ● Search Scopus @ Elsevier (PMID): 32942508 ● Search Scopus @ Elsevier (DOI): 10.1103/PhysRevE.102.022408 (DOI: 10.1103/PhysRevE.102.022408, PubMed: 32942508)
8.	Lihi Shachar-Berman, Yan Ostrovski, Kenichiro Koshiyama, Shigeo Wada, Stavros C. Kassinos and Josué Sznitman : Targeting inhaled fibers to the pulmonary acinus: Opportunities for augmented delivery from in silico simulations, European Journal of Pharmaceutical Sciences, 137, 105003, 2019. (Summary) Non-spherical particles, and fibers in particular, are potentially attractive airborne carriers for pulmonary drug delivery. Not only do they exhibit a high surface-to-volume ratio relative to spherical aerosols, but their aerodynamic properties also enable them to reach deep into the lungs. Until present, however, our understanding of the deposition characteristics of inhaled aerosols in the distal acinar lung regions has been mostly limited to spheres. To shed light on the fate of elongated aerosols in the pulmonary depths, we explore through in silico numerical simulations the deposition and dispersion characteristics of ellipsoid-shaped fibers in a physiologically-realistic acinar geometry under oscillatory breathing flow conditions mimicking various inhalation maneuvers. The transient translation and rotational movement of micron-sized elongated particles under drag, lift, and gravitational forces are simulated as a function of size (d) and aspect ratio (AR). Our findings underscore how acinar deposition characteristics are intimately linked to the geometrical combination of d and AR under oscillatory flow conditions. Surprisingly, the elongation of the traditionally recommended size range of spherical particles (i.e., 2-3 μm) for acinar deposition may lead to a decrease in deposition efficiency and dispersion. Instead, our findings advocate how elongating particles (i.e., high AR) in the larger size range of 4-6 μm might be leveraged for improved targeted deposition to the acinar regions. Together, these results point to new windows of opportunities in selecting the shape and size of micron-sized fibers for targeted pulmonary deposition. Such in silico efforts represent an essential stepping stone in further exploring aerosol drug carrier designs for inhalation therapy to the deep lungs. (Keyword) Administration, Inhalation / Aerosols / Computer Simulation / Drug Carriers / Models, Biological / Pulmonary Alveoli (Link to Publication Site) ● Publication site (DOI): 10.1016/j.ejps.2019.105003 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31302212 ● Summary page in Scopus @ Elsevier: 2-s2.0-85069054081 (DOI: 10.1016/j.ejps.2019.105003, PubMed: 31302212, Elsevier: Scopus)
9.	Kenichiro Koshiyama, Masaki Taneo, Taiki Shigematsu and Shigeo Wada : Bicelle-to-Vesicle Transition of a Binary Phospholipid Mixture Guided by Controlled Local Lipid Compositions: A Molecular Dynamics Simulation Study., The Journal of Physical Chemistry B, 123, 14, 3118-3123, 2019. (Summary) An essential step of nanoliposome formation in an aqueous lipid solution is the transition from discoidal lipid aggregate (bicelle) to vesicle. We investigate here the bicelle-to-vesicle transition of a binary lipid mixture of saturated and unsaturated phosphatidylcholine by performing nonequilibrium molecular dynamics simulations with the coarse-grained representation of di-palmitoyl-phosphatidyl-choline (DPPC) and di-linoleoyl-phosphatidyl-choline (DLiPC). When the DPPC molecules of a stable DPPC bicelle are randomly replaced with the DLiPC molecules, the transition occurs for higher apparent DLiPC concentrations. On the other hand, when the DPPC molecules only in the core region of the bicelle are replaced, the transition occurs even for lower apparent DLiPC concentrations. For the bicelle where the head and tail layers are pure DPPC and DLiPC monolayers, respectively, the side of the DLiPC monolayer becomes the concave surface of bending bicelle. Controlling the local lipid compositions in a binary lipid bicelle has the potential to determine the success of vesicle formation and the direction of bicelle bending. Our findings help explain nanoliposome formation with sonication and give useful information for controlling encapsulation efficiencies of nanoliposomes. (Tokushima University Institutional Repository) ● Metadata: 2006354 (Link to Publication Site) ● Publication site (DOI): 10.1021/acs.jpcb.8b10682 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30888822 ● Summary page in Scopus @ Elsevier: 2-s2.0-85064178810 (Tokushima University Institutional Repository: 2006354, DOI: 10.1021/acs.jpcb.8b10682, PubMed: 30888822, Elsevier: Scopus)
10.	Taiki Shigematsu, Kenichiro Koshiyama and Shigeo Wada : Stretch-Induced Interdigitation of a Phospholipid/Cholesterol Bilayer., The Journal of Physical Chemistry B, 122, 9, 2556-2563, 2018. (Summary) I phase under stretching. However, there is still no conclusive experimental evidence for this process, so its existence remains controversial. In this study, to explain the transition from energy balance, we propose a free-energy model. The model consists of three energy components: the elastic deformation energy, surface energy at the bilayer-water interface, and interphase boundary energy. To determine the parameters of the model, we perform MD simulations of a stretched 1,2-dipalmitoyl- sn-glycero-3-phosphocholine/cholesterol bilayer. The phase diagrams from our model are in good agreement with those obtained from MD simulations. The energy balance among the components in the stretched bilayer quantitatively explains the stretch-induced transition. In the model, increasing the system size to that used in experiments shows that interdigitation is favorable for rigid bilayers under stretching or in alcohol solutions. These results suggest that the stretch-induced interdigitation might be observed in microscopic experiments. (Keyword) 1,2-Dipalmitoylphosphatidylcholine / Cholesterol / Lipid Bilayers / Molecular Dynamics Simulation (Link to Publication Site) ● Publication site (DOI): 10.1021/acs.jpcb.7b10633 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29419298 ● Summary page in Scopus @ Elsevier: 2-s2.0-85043517116 (DOI: 10.1021/acs.jpcb.7b10633, PubMed: 29419298, Elsevier: Scopus)
11.	Kenichiro Koshiyama, Keisuke Nishimoto, Satoshi Ii, Toshihiro Sera and Shigeo Wada : Heterogeneous structure and surface tension effects on mechanical response in pulmonary acinus: A finite element analysis., Clinical Biomechanics, 2018. (Summary) In the lungs, the heterogeneous acinar structure and surface tension induce anisotropic deformation at the acinar and alveolar scales. Further research is needed on structural variation of acini, inter-acini connectivity, or dynamic behavior to understand multiscale lung mechanics. (Link to Publication Site) ● Publication site (DOI): 10.1016/j.clinbiomech.2018.01.001 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29370949 ● Search Scopus @ Elsevier (PMID): 29370949 ● Search Scopus @ Elsevier (DOI): 10.1016/j.clinbiomech.2018.01.001 (DOI: 10.1016/j.clinbiomech.2018.01.001, PubMed: 29370949)
12.	Philipp Hofemeier, Kenichiro Koshiyama, Shigeo Wada and Josué Sznitman : One (sub-)acinus for all: Fate of inhaled aerosols in heterogeneous pulmonary acinar structures., European Journal of Pharmaceutical Sciences, 113, 53-63, 2017. (Summary) Computational Fluid Dynamics (CFD) have offered an attractive gateway to investigate in silico respiratory flows and aerosol transport in the depths of the lungs. Yet, not only do existing models lack sufficient anatomical realism in capturing the heterogeneity and morphometry of the acinar environment, numerical simulations have been widely restricted to domains capturing a mere few percent of a single acinus. Here, we present to the best of our knowledge the most detailed and comprehensive in silico simulations to date on the fate of aerosols in the acinar depths. Our heterogeneous acinar domains represent complete sub-acinar models (i.e. 1/8th of a full acinus) based on the recent algorithm of Koshiyama & Wada (2015), capturing statistics of human acinar morphometry (Ochs et al. 2004). Our simulations deliver high-resolution, 3D spatial-temporal data on aerosol transport and deposition, emphasizing how variances in acinar heterogeneity only play a minor role in determining general deposition outcomes. With such tools at hand, we revisit whole-lung deposition predictions (i.e. ICRP) based on past 1D lung models. While our findings under quiet breathing substantiate general deposition trends obtained with past predictions in the alveolar regions, we underscore how deposition fractions are anticipated to increase, in particular during deep inhalation. For such inhalation maneuver, our simulations support the notion of significantly augmented deposition for all aerosol sizes (0.005-5.0m). Overall, our efforts not only help consolidate our mechanistic understanding of inhaled aerosol transport in the acinar depths but also continue to bridge the gap between "bottom-up" in silico models and regional deposition predictions from whole-lung models. Such quantifications provide what is deemed more accurate deposition predictions in morphometrically-faithful models and are particularly useful in assessing inhalation strategies for deep airway deposition (e.g. systemic delivery). (Link to Publication Site) ● Publication site (DOI): 10.1016/j.ejps.2017.09.033 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28954217 ● Summary page in Scopus @ Elsevier: 2-s2.0-85030169754 (DOI: 10.1016/j.ejps.2017.09.033, PubMed: 28954217, Elsevier: Scopus)
13.	Luosha Xiao, Toshihiro Sera, Kenichiro Koshiyama and Shigeo Wada : Morphological Characterization of Acinar Cluster in Mouse Lung Using a Multiscale-based Segmentation Algorithm on Synchrotron Micro-CT Images., The Anatomical Record, 299, 10, 1424-1434, 2016. (Summary) Understanding the three-dimensional morphology of pulmonary acini is essential when exploring the biomechanics of respiratory function. In this study, we characterized the morphology of individual acini and a cluster of acini stemming from the same terminal conducting airway using a quantitative approach based on the semi-automatic segmentation of synchrotron micro-CT images of mouse lung. The volume and surface area of five clusters of mouse acini including 50 individual acini were estimated based on the voxel and surface mesh of segmented acini at FRC. The pathway length and width were estimated for one cluster including 15 acini based on the skeleton of segmented acini. The acinar volume was 0.09 ± 0.07 mm(3) (mean ± SD), and the surface area was 6.82 ± 4.49 mm(2) , in agreement with previous studies. The volume of the acinar clusters was 0.89 ± 0.34 mm(3) , and the surface area was 68.18 ± 17.66 mm(2) . The largest volume acinus per cluster was found in the distal region of the terminal conducting airway, and apparent respiratory bronchioles were observed only in large-volume acini. The generation number of pathways per acinus was 8 ± 2 (range: 6-12). The pathway length at lower generations (generations 2-6) increased with the generation number in a single cluster, while did not significantly change at lower generations in some acinar groups. The pathway width increased with increasing generation numbers. Our approach characterized the quantitative morphology of pulmonary acinar clusters in mouse lung, and the results can be used in further biomechanical simulation studies. Anat Rec, 299:1424-1434, 2016. © 2016 Wiley Periodicals, Inc. (Keyword) Acinar Cells / Algorithms / Animals / Image Processing, Computer-Assisted / Lung / Mice / Synchrotrons / X-Ray Microtomography (Link to Publication Site) ● Publication site (DOI): 10.1002/ar.23452 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27488590 ● Search Scopus @ Elsevier (PMID): 27488590 ● Search Scopus @ Elsevier (DOI): 10.1002/ar.23452 (DOI: 10.1002/ar.23452, PubMed: 27488590)
14.	Kenichiro Koshiyama and Shigeo Wada : Collapse of a lipid-coated nanobubble and subsequent liposome formation., Scientific Reports, 6, 2016. (Summary) We investigate the collapse of a lipid-coated nanobubble and subsequent formation of a lipid vesicle by coarse grained molecular dynamics simulations. A spherical nanobubble coated with a phospholipid monolayer in water is a model of an aqueous dispersion of phospholipids under negative pressure during sonication. When subjected to a positive pressure, the bubble shape deforms into an irregular spherical shape and the monolayer starts to buckle and fold locally. The local folds grow rapidly in multiple directions and forming a discoidal membrane with folds of various amplitudes. Folds of small amplitude disappear in due course and the membrane develops into a unilamellar vesicle via a bowl shape. Folds with large amplitude develop into a bowl shape and a multivesicular shape forms. The membrane shape due to bubble collapse can be an important factor governing the vesicular shape during sonication. (Keyword) Liposomes / Molecular Dynamics Simulation / Phospholipids / Pressure / Sonication (Tokushima University Institutional Repository) ● Metadata: 2008165 (Link to Publication Site) ● Publication site (DOI): 10.1038/srep28164 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27306704 ● Search Scopus @ Elsevier (PMID): 27306704 ● Search Scopus @ Elsevier (DOI): 10.1038/srep28164 (Tokushima University Institutional Repository: 2008165, DOI: 10.1038/srep28164, PubMed: 27306704)
15.	Taiki Shigematsu, Kenichiro Koshiyama and Shigeo Wada : Effects of Stretching Speed on Mechanical Rupture of Phospholipid/Cholesterol Bilayers: Molecular Dynamics Simulation., Scientific Reports, 5, 2015. (Summary) Rupture of biological cell membrane under mechanical stresses is critical for cell viability. It is triggered by local rearrangements of membrane molecules. We investigated the effects of stretching speed on mechanical rupture of phospholipid/cholesterol bilayers using unsteady molecular dynamics simulations. We focused on pore formation, the trigger of rupture, in a 40 mol% cholesterol-including bilayer. The unsteady stretching was modeled by proportional and temporal scaling of atom positions at stretching speeds from 0.025 to 30 m/s. The effects of the stretching speed on the critical areal strain, where the pore forms, is composed of two regimes. At low speeds (<1.0 m/s), the critical areal strain is insensitive to speed, whereas it significantly increases at higher speeds. Also, the strain is larger than that of a pure bilayer, regardless of the stretching speeds, which qualitatively agrees with available experimental data. Transient recovery of the cholesterol and phospholipid molecular orientations was evident at lower speeds, suggesting the formation of a stretch-induced interdigitated gel-like phase. However, this recovery was not confirmed at higher speeds or for the pure bilayer. The different responses of the molecular orientations may help explain the two regimes for the effect of stretching speed on pore formation. (Keyword) 1,2-Dipalmitoylphosphatidylcholine / Cholesterol / Lipid Bilayers / Molecular Dynamics Simulation / Phase Transition / Phospholipids / Stress, Mechanical (Link to Publication Site) ● Publication site (DOI): 10.1038/srep15369 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 26471872 ● Search Scopus @ Elsevier (PMID): 26471872 ● Search Scopus @ Elsevier (DOI): 10.1038/srep15369 (DOI: 10.1038/srep15369, PubMed: 26471872)
16.	Kenichiro Koshiyama and Shigeo Wada : Mathematical model of a heterogeneous pulmonary acinus structure., Computers in Biology and Medicine, 62, 25-32, 2015. (Summary) The pulmonary acinus is a gas exchange unit distal to the terminal bronchioles. A model of its structure is important for the computational investigation of mechanical phenomena at the acinus level. We propose a mathematical model of a heterogeneous acinus structure composed of alveoli of irregular sizes, shapes, and locations. The alveoli coalesce into an intricately branched ductal tree, which meets the space-filling requirement of the acinus structure. Our model uses Voronoi tessellation to generate an assemblage of the alveolar or ductal airspace, and Delaunay tessellation and simulated annealing for the ductal tree structure. The modeling condition is based on average acinar and alveolar volume characteristics from published experimental information. By applying this modeling technique to the acinus of healthy mature rats, we demonstrate that the proposed acinus structure model reproduces the available experimental information. In the model, the shape and size of alveoli and the length, generation, tortuosity, and branching angle of the ductal paths are distributed in several ranges. This approach provides a platform for investigating the heterogeneous nature of the acinus structure and its relationship with mechanical phenomena at the acinus level. (Keyword) Animals / Blood-Air Barrier / Bronchioles / Models, Biological / Rats (Link to Publication Site) ● Publication site (DOI): 10.1016/j.compbiomed.2015.03.032 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25912985 ● Search Scopus @ Elsevier (PMID): 25912985 ● Search Scopus @ Elsevier (DOI): 10.1016/j.compbiomed.2015.03.032 (DOI: 10.1016/j.compbiomed.2015.03.032, PubMed: 25912985)
17.	Taiki SHIGEMATSU, Kenichiro Koshiyama and Shigeo WADA : Line tension of the pore edge in phospholipid/cholesterol bilayer from stretch molecular dynamics simulation, Journal of Biomechanical Science and Engineering, 11, 1, 15-00422-15-00422, 2015. (Summary) The line tension of the pore in a phospholipid bilayer is important for pore-mediated molecular transport techniques. To understand the cholesterol effects on the line tension of the pore edge at the molecular level, we perform molecular dynamics simulations of phospholipid bilayers with a pore containing cholesterol in different concentrations (0, 20, and 40 mol%). The bilayer with a pore is prepared by using an equibiaxial stretching simulation. The stretched bilayer with a pore is subsequently compressed and the pore spontaneously closes when the applied areal strain of the bilayer is below a certain value. Using the pore closure areal strain and a free energy model of a stretched bilayer with a pore, the upper and lower limits of the line tensions for the bilayers containing cholesterol at 0, 20, and 40 mol% are estimated to be 17.0-48.2, 54.5-100, and 170-261 pN, respectively. The increasing tendency of the line tension qualitatively agrees with that observed experimentally. The pores in the cholesterol-containing bilayers are lined with several cholesterol molecules, which might increase the bending rigidity of the pore edge, and result in the higher line tension of the cholesterol-containing bilayer. The considerable dependency of the line tension on the bilayer compositions might be useful to explain the large variations of the transduction efficiency observed with sonoporation treatment. (Keyword) Cell membrane / Sonoporation / Electroporation / DPPC bilayer / Membrane rupture / Pore closure (Link to Publication Site) ● Publication site (DOI): 10.1299/jbse.15-00422 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680239479424 ● Search Scopus @ Elsevier (DOI): 10.1299/jbse.15-00422 (DOI: 10.1299/jbse.15-00422, CiNii: 1390282680239479424)
18.	Yoshihiro Ujihara, Masanori Nakamura, Masatsugu Soga, Kenichiro Koshiyama, Hiroshi Miyazaki and Shigeo Wada : Computational studies on strain transmission from a collagen gel construct to a cell and its internal cytoskeletal filaments., Computers in Biology and Medicine, 56, 20-29, 2014. (Summary) We developed a mechanical tissue model containing a cell with cytoskeletal filaments inside to investigate how tissue deformation is reflected in the deformation of a cell and its internal cytoskeletal filaments. Tissue that assumes a collagen gel construct was depicted as an isotropic linear elastic material, and the cell was modeled as an assembly of discrete elements including a cell membrane, nuclear envelope, and cytoskeletal filaments. Mechanical behaviors were calculated based on the minimum energy principle. The results demonstrated the effects of the type of tissue deformation on deformations of cytoskeletal filaments. The distribution of strains of cytoskeletal filaments was skewed toward compression when a tissue was stretched, toward stretch when the tissue was compressed, and almost normal when the tissue was sheared. The results also addressed the dependency of deformations of a cell and cytoskeletal filaments on the ratio of the Young's modulus of a tissue to that of a cell. Upon tissue stretching, cell strain increased and the distribution of strains of cytoskeletal filaments broadened on both stretch and compression sides with an increase in the Young's modulus ratio. This suggested that the manner of tissue deformation and the tissue/cell Young's modulus ratio are reflected in the distribution pattern of strains of cytoskeletal filaments. The present model is valuable to understanding the mechanisms of cellular responses in a tissue. (Keyword) Animals / Collagen / Cytoskeleton / Elastic Modulus / Humans / Models, Biological (Link to Publication Site) ● Publication site (DOI): 10.1016/j.compbiomed.2014.10.015 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 25464345 ● Search Scopus @ Elsevier (PMID): 25464345 ● Search Scopus @ Elsevier (DOI): 10.1016/j.compbiomed.2014.10.015 (DOI: 10.1016/j.compbiomed.2014.10.015, PubMed: 25464345)
19.	Taiki Shigematsu, Kenichiro Koshiyama and Shigeo Wada : Molecular dynamics simulations of pore formation in stretched phospholipid/cholesterol bilayers., Chemistry and Physics of Lipids, 183, 43-49, 2014. (Summary) Molecular dynamics (MD) simulations of pore formation in stretched dipalmitoylphosphatidylcholine (DPPC) bilayers containing different concentrations of cholesterol (0, 20, 40, and 60 mol%) are presented. The stretched bilayers were simulated by constant NPZA\|\|T MD simulations with various constant areas. The effects of the cholesterol concentration on pore formation are examined in terms of the critical areal strain where the pore is formed, the processes of pore formation, and the change in molecular orientation of the DPPC molecules by analyzing the order parameters and radial distribution functions of the DPPC molecules. With increasing cholesterol concentration, the critical areal strain initially increases, peaks at 40 mol%, and then decreases, which agrees well with the available experimental data. For the bilayers containing cholesterol, DPPC molecules become disordered at low areal strains, whereas the order slightly increases when the areal strain exceeds a certain value depending on the cholesterol concentration. For 40 mol% cholesterol, the two monolayers in the bilayer interpenetrate under high areal strains, inducing an increase of the order parameters and the peak positions of the radial distribution function compared with their states at low areal strains, indicating the formation of an interdigitated gel-phase-like structure. The transient increasing of the order of the molecular orientations may inhibit water penetration into the bilayer, resulting in increased critical areal strain in the phospholipid/cholesterol bilayers. (Keyword) 1,2-Dipalmitoylphosphatidylcholine / Cholesterol / Computer Simulation / Lipid Bilayers / Membrane Fluidity / Models, Chemical / Molecular Conformation / Molecular Dynamics Simulation / Nanopores / Stress, Mechanical (Link to Publication Site) ● Publication site (DOI): 10.1016/j.chemphyslip.2014.05.005 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 24863643 ● Search Scopus @ Elsevier (PMID): 24863643 ● Search Scopus @ Elsevier (DOI): 10.1016/j.chemphyslip.2014.05.005 (DOI: 10.1016/j.chemphyslip.2014.05.005, PubMed: 24863643)
20.	Luosha Xiao, Toshihiro Sera, Kenichiro Koshiyama and Shigeo Wada : A semiautomatic segmentation algorithm for extracting the complete structure of acini from synchrotron micro-CT images., Computational and Mathematical Methods in Medicine, 2013, 2013. (Summary) Pulmonary acinus is the largest airway unit provided with alveoli where blood/gas exchange takes place. Understanding the complete structure of acinus is necessary to measure the pathway of gas exchange and to simulate various mechanical phenomena in the lungs. The usual manual segmentation of a complete acinus structure from their experimentally obtained images is difficult and extremely time-consuming, which hampers the statistical analysis. In this study, we develop a semiautomatic segmentation algorithm for extracting the complete structure of acinus from synchrotron micro-CT images of the closed chest of mouse lungs. The algorithm uses a combination of conventional binary image processing techniques based on the multiscale and hierarchical nature of lung structures. Specifically, larger structures are removed, while smaller structures are isolated from the image by repeatedly applying erosion and dilation operators in order, adjusting the parameter referencing to previously obtained morphometric data. A cluster of isolated acini belonging to the same terminal bronchiole is obtained without floating voxels. The extracted acinar models above 98% agree well with those extracted manually. The run time is drastically shortened compared with manual methods. These findings suggest that our method may be useful for taking samples used in the statistical analysis of acinus. (Keyword) Algorithms / Animals / Bronchioles / Image Processing, Computer-Assisted / Mice / Models, Anatomic / Pulmonary Alveoli / Software / Synchrotrons / X-Ray Microtomography (Link to Publication Site) ● Publication site (DOI): 10.1155/2013/575086 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 23533543 ● Search Scopus @ Elsevier (PMID): 23533543 ● Search Scopus @ Elsevier (DOI): 10.1155/2013/575086 (DOI: 10.1155/2013/575086, PubMed: 23533543)
21.	Masanori NAKAMURA, Yoshihiro UJIHARA, Masatsugu SOGA, Kenichiro Koshiyama, Hiroshi MIYAZAKI and Shigeo WADA : Effects of Cytoskeletal Orientations on Deformation of a Cell Residing in a Collagen Gel Construct, Journal of Biomechanical Science and Engineering, 7, 1, 2-14, 2012. (Summary) The effects of cytoskeleton orientation angle on strain transmission from a tissue to a cell and its internal cytoskeletons were investigated by using a model where a cell was integrated in a tissue that assumes a collagen gel construct. A cell with uni-directionally or randomly aligned cytoskeletons was embedded in a tissue, which was stretched to a strain of 0.1. When the initial orientation angle of the cytoskeleton was zero, which corresponded to the stretch direction of the tissue, cell strain was minimal and mean cytoskeletal strain was maximal. As the initial cytoskeleton orientation angle increased, mean cytoskeletal strain values decreased, while cell strain increased. Cell strain decreased at an initial cytoskeleton orientation angle of 60°. At this angle, the mean cytoskeletal strain value was nearly zero, which was absolutely minimal. Subsequent increases in the initial cytoskeleton orientation angle resulted in further decreases in cell and cytoskeletal strain. The present multi-scale model may help in achieving structural integration of the biomechanical organization and provide valuable information for understanding the mechanisms underlying cellular remodeling. (Link to Publication Site) ● Publication site (DOI): 10.1299/jbse.7.2 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680239519232 ● Search Scopus @ Elsevier (DOI): 10.1299/jbse.7.2 (DOI: 10.1299/jbse.7.2, CiNii: 1390282680239519232)
22.	Kenichiro Koshiyama and Shigeo Wada : Molecular dynamics simulations of pore formation dynamics during the rupture process of a phospholipid bilayer caused by high-speed equibiaxial stretching., Journal of Biomechanics, 44, 11, 2053-2058, 2011. (Summary) Rupture of a phospholipid bilayer under mechanical stresses is triggered by pore formation in an intact bilayer. To understand the molecular details of the dynamics of pore formation we perform molecular dynamics simulations of a phospholipid bilayer under two different equibiaxial stretching conditions: first, unsteady stretching with various stretching speeds in the range of 0.1-1.0m/s, and second, quasistatic stretching. We analyze (i) patterns of pore formation, (ii) the critical area where a pore forms, (iii) the deformation of the bilayer, and (iv) the apparent breaking force. With stretching, the bilayer deforms anisotropically due to lipid chain packing and water penetrating into the hydrophilic region of the bilayer, and when the area exceeds a critical value, water filled pore structure penetrating the bilayer forms and develops into a large pore, resulting in rupture. For a high stretching speed, small pores (multipore) can temporarily form in a small area. It has been statistically determined that the probability of the multipore formation, the critical areal strain, and the apparent breaking force increase with the stretching speed in the range of 0-50%, 0.8-2.0, and 250-400 pN, respectively. The results qualitatively agree with the experimental and other simulation results, and rationalize the leakage of hemoglobin from erythrocytes in shock wave experiments. (Keyword) Cell Membrane / Cell Membrane Permeability / Lipid Bilayers / Models, Biological / Molecular Dynamics Simulation / Phospholipids / Porosity / Stress, Mechanical / Water (Link to Publication Site) ● Publication site (DOI): 10.1016/j.jbiomech.2011.05.014 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 21658696 ● Search Scopus @ Elsevier (PMID): 21658696 ● Search Scopus @ Elsevier (DOI): 10.1016/j.jbiomech.2011.05.014 (DOI: 10.1016/j.jbiomech.2011.05.014, PubMed: 21658696)
23.	Masato YASUI, Kenichiro Koshiyama and Shigeo WADA : Modeling of Lung Microstructure Using Phase-Field Method, Transactions of the Japanese Society for Medical and Biological Engineering, 49, 1, 250-254, 2011. (Summary) We have developed a novel technique for modeling the realistic lung microstructure using phase-field method. In the phase-field method for the lung microstructure, the state (air and tissue) of a system is measured with an order parameter and the time-evolutions of the order parameters in the system, a tissue initially including seeds of the air, are obtained by solving the time-dependent bistable reaction-diffusion equations modified from the Allen-Cahn equation. The field of the order parameters is reconstructed as the 3D lung microstructure model by using the binalized slice images with a certain threshold of the order parameter between the two states (air and tissue) on the binalization. We found that irrespective of the number of the initial seeds, the results demonstrate isotropic evolution of alveolar regions (air) from the initial seeds, and the alveolar regions came closer with evolution, but were never merged because of the presence of alveolar wall (tissue). A further evolution of alveolar regions develops into spatially compartmentalized pore structure, which appeared to be similar to a natural lung. Variations in the number of, and the shape of the initial seeds, and the threshold of the order parameter for binalization result in various patterns of the ductal porous structure (i. e., alveolar duct or alveolar sac), satisfying the experimentally-obtained mean alveolar volume and mean alveolar wall thickness. Furthermore, the radial distribution function calculated from the centroids of alveoli were saturated to one without any significant peaks when the inter-alveolar distance exceeds a certain value, indicating that the alveoli in our model are disorderly distributed and repel each other with a certain distance. In conclusion, those results demonstrate that the method developed here is the promising method for parametric control and anatomically realistic production of lung microstructure model. (Link to Publication Site) ● Publication site (DOI): 10.11239/jsmbe.49.250 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390001205267211136 ● Summary page in Scopus @ Elsevier: 2-s2.0-83455205718 (DOI: 10.11239/jsmbe.49.250, CiNii: 1390001205267211136, Elsevier: Scopus)
24.	Kenichiro Koshiyama, Takeru Yano and Tetsuya Kodama : Self-organization of a stable pore structure in a phospholipid bilayer., Physical Review Letters, 105, 1, 2010. (Summary) We demonstrate the self-organization process of a stable pore structure in a phospholipid bilayer by unsteady and nonequilibrium molecular dynamics simulations. The simulation is started from an initial state including some amount of water molecules in its hydrophobic region, which is a model of a cell membrane stimulated by ultrasound radiation for the membrane permeabilization (sonoporation). We show that, in several nanoseconds, the bilayer-water system can spontaneously develop into a water-filled pore structure without any mechanical and electrical forcing from outside, when the initial number of water molecules in the hydrophobic region exceeds a critical value. The increase in the initial number of water molecules enhances the probability of pore formation, and sometimes induces the formation of transient micellelike structures of phospholipid molecules. (Keyword) Hydrophobic and Hydrophilic Interactions / Lipid Bilayers / Molecular Conformation / Molecular Dynamics Simulation / Phospholipids / Porosity / Time Factors / Water (Link to Publication Site) ● Publication site (DOI): 10.1103/PhysRevLett.105.018105 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 20867485 ● Search Scopus @ Elsevier (PMID): 20867485 ● Search Scopus @ Elsevier (DOI): 10.1103/PhysRevLett.105.018105 (DOI: 10.1103/PhysRevLett.105.018105, PubMed: 20867485)
25.	Tetsuya KODAMA, Yukio TOMITA, Yukiko WATANABE, Kenichiro Koshiyama, Takeru YANO and Shigeo FUJIKAWA : Cavitation Bubbles Mediated Molecular Delivery During Sonoporation, Journal of Biomechanical Science and Engineering, 4, 1, 124-140, 2009. (Summary) Molecular delivery using ultrasound (US) and nano/microbubbles (NBs), i.e., sonoporation, has applications in gene therapy and anticancer drug delivery. When NBs are destructed by ultrasound, the surrounding cells are exposed to mechanical impulsive forces generated by collapse of either the NBs or the cavitation bubbles created by the collapse of NBs. In the present study, experimental, theoretical and numerical analyses were performed to investigate cavitation bubbles mediated molecular delivery during sonoporation. Experimental observation using lipid NBs indicated that increasing US pressure increased uptake of fluorescent molecules, calcein (molecular weight: 622), into 293T human, and decreased survival fraction. Confocal microscopy revealed that calcein molecules were uniformly distributed throughout the some treated cells. Next, the cavitation bubble behavior was analyzed theoretically based on a spherical gas bubble dynamics. The impulse of the shock wave (i.e., the pressure integrated over time) generated by the collapse of a cavitation bubble was a dominant factor for exogenous molecules to enter into the cell membrane rather than bubble expansion. Molecular dynamics simulation revealed that the number of exogenous molecules delivered into the cell membrane increased with increasing the shock wave impulse. We concluded that the impulse of the shock wave generated by cavitation bubbles was one of important parameters for causing exogenous molecular uptake into living cells during sonoporation. (Link to Publication Site) ● Publication site (DOI): 10.1299/jbse.4.124 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680238299520 ● Search Scopus @ Elsevier (DOI): 10.1299/jbse.4.124 (DOI: 10.1299/jbse.4.124, CiNii: 1390282680238299520)
26.	Kenichiro Koshiyama, Tetsuya Kodama, Takeru Yano and Shigeo Fujikawa : Molecular dynamics simulation of structural changes of lipid bilayers induced by shock waves: Effects of incident angles., Biochimica et Biophysica Acta (BBA) - Biomembranes, 1778, 6, 1423-1428, 2008. (Summary) Unsteady and nonequilibrium molecular dynamics simulations of the response of dipalmitoylphosphatidylcholine (DPPC) bilayers to the shock waves of various incident angles are presented. The action of an incident shock wave is modeled by adding a momentum in an oblique direction to water molecules adjacent to a bilayer. We thereby elucidate the effects of incident shock angles on (i) collapse and rebound of the bilayer, (ii) lateral displacement of headgroups, (iii) tilts of lipid molecules, (iv) water penetration into the hydrophobic region of the bilayer, and (v) momentum transfer across the bilayer. The number of water molecules delivered into the hydrophobic region is found to be insensitive to incident shock angles. The most important structural changes are the lateral displacement of headgroups and tilts of lipid molecules, which are observed only in the half of the bilayer directly exposed to a shock wave for all incident shock angles studied here. As a result, only the normal component of the added oblique momentum is substantially transferred across the bilayer. This also suggests that the irradiation by shock waves may induce a jet-like streaming of the cytoplasm toward the nucleus. (Keyword) 1,2-Dipalmitoylphosphatidylcholine / Hydrophobic and Hydrophilic Interactions / Lipid Bilayers / Models, Chemical / Stress, Mechanical / Water (Link to Publication Site) ● Publication site (DOI): 10.1016/j.bbamem.2008.03.010 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 18405658 ● Search Scopus @ Elsevier (PMID): 18405658 ● Search Scopus @ Elsevier (DOI): 10.1016/j.bbamem.2008.03.010 (DOI: 10.1016/j.bbamem.2008.03.010, PubMed: 18405658)
27.	Kenichiro Koshiyama, Tetsuya Kodama, Takeru Yano and Shigeo Fujikawa : Structural change in lipid bilayers and water penetration induced by shock waves: molecular dynamics simulations., Biophysical Journal, 91, 6, 2198-2205, 2006. (Summary) The structural change of a phospholipid bilayer in water under the action of a shock wave is numerically studied with unsteady nonequilibrium molecular dynamics simulations. The action of shock waves is modeled by the momentum change of water molecules, and thereby we demonstrate that the resulting collapse and rebound of the bilayer are followed by the penetration of water molecules into the hydrophobic region of the bilayer. The high-speed phenomenon that occurs during the collapse and rebound of the bilayer is analyzed in detail, particularly focusing on the change of bilayer thickness, the acyl chain bend angles, the lateral fluidity of lipid molecules, and the penetration rate of water molecules. The result shows that the high-speed phenomenon can be divided into two stages: in the first stage the thickness of bilayer and the order parameter are rapidly reduced, and then in the second stage they are recovered relatively slowly. It is in the second stage that water molecules are steadily introduced into the hydrophobic region. The penetration of water molecules is enhanced by the shock wave impulse and this qualitatively agrees with a recent experimental result. (Keyword) 1,2-Dipalmitoylphosphatidylcholine / Biomechanical Phenomena / Cell Membrane Permeability / Computer Simulation / High-Energy Shock Waves / Lasers / Lipid Bilayers / Membrane Fluidity / Models, Biological / Models, Chemical / Molecular Conformation / Pressure / Thermodynamics / Water (Link to Publication Site) ● Publication site (DOI): 10.1529/biophysj.105.077677 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16798798 ● Search Scopus @ Elsevier (PMID): 16798798 ● Search Scopus @ Elsevier (DOI): 10.1529/biophysj.105.077677 (DOI: 10.1529/biophysj.105.077677, PubMed: 16798798)
28.	Tetsuya Kodama, Yukio Tomita, Kenichiro Koshiyama and K Martin J Blomley : Transfection effect of microbubbles on cells in superposed ultrasound waves and behavior of cavitation bubble., Ultrasound in Medicine & Biology, 32, 6, 905-914, 2006. (Summary) The combination of ultrasound and ultrasound contrast agents (UCAs) is able to induce transient membrane permeability leading to direct delivery of exogenous molecules into cells. Cavitation bubbles are believed to be involved in the membrane permeability; however, the detailed mechanism is still unknown. In the present study, the effects of ultrasound and the UCAs, Optison on transfection in vitro for different medium heights and the related dynamic behaviors of cavitation bubbles were investigated. Cultured CHO-E cells mixed with reporter genes (luciferase or beta-gal plasmid DNA) and UCAs were exposed to 1 MHz ultrasound in 24-well plates. Ultrasound was applied from the bottom of the well and reflected at the free surface of the medium, resulting in the superposition of ultrasound waves within the well. Cells cultured on the bottom of 24-well plates were located near the first node (displacement node) of the incident ultrasound downstream. Transfection activity was a function determined with the height of the medium (wave traveling distance), as well as the concentration of UCAs and the exposure time was also determined with the concentration of UCAs and the exposure duration. Survival fraction was determined by MTT assay, also changes with these values in the reverse pattern compared with luciferase activity. With shallow medium height, high transfection efficacy and high survival fraction were obtained at a low concentration of UCAs. In addition, capillary waves and subsequent atomized particles became significant as the medium height decreased. These phenomena suggested cavitation bubbles were being generated in the medium. To determine the effect of UCAs on bubble generation, we repeated the experiments using crushed heat-treated Optison solution instead of the standard microbubble preparation. The transfection ratio and survival fraction showed no additional benefit when ultrasound was used. These results suggested that cavitation bubbles created by the collapse of UCAs were a key factor for transfection, and their intensities were enhanced by the interaction of the superpose ultrasound with the decreasing the height of the medium. Hypothesizing that free cavitation bubbles were generated from cavitation nuclei created by fragmented UCA shells, we carried out numerical analysis of a free spherical bubble motion in the field of ultrasound. Analyzing the interaction of the shock wave generated by a cavitation bubble and a cell membrane, we estimated the shock wave propagation distance that would induce cell membrane damage from the center of the cavitation bubble. (Keyword) Acoustics / Albumins / Animals / CHO Cells / Cell Membrane Permeability / Cell Survival / Contrast Media / Cricetinae / Cricetulus / Fluorocarbons / Microbubbles / Transfection / Ultrasonics (Link to Publication Site) ● Publication site (DOI): 10.1016/j.ultrasmedbio.2006.03.004 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16785012 ● Search Scopus @ Elsevier (PMID): 16785012 ● Search Scopus @ Elsevier (DOI): 10.1016/j.ultrasmedbio.2006.03.004 (DOI: 10.1016/j.ultrasmedbio.2006.03.004, PubMed: 16785012)
29.	Tetsuya Kodama, Atsuko Aoi, Georges Vassaux, Shiro Mori, Hidehiro Morikawa, Kenichiro Koshiyama, Takeru Yano, Shigeo Fujikawa and Yukio Tomita : A non-invasive tissue-specific molecular delivery method of cancer gene therapy., Minimally Invasive Therapy & Allied Technologies, 15, 4, 226-229, 2006. (Summary) A Japanese word, monozukuri (literally translated "making things") is the philosophy of first having the idea and then the faith in the technical expertise and experience to accomplish the result. We believe that the concept of engineering is monozukuri. Through the process of monozukuri, engineered natural science based on mathematics and physics has been developed. Medicine is the field of study which has been developed for maintaining daily healthy life with diagnosis, treatment, examination, and protection. Biomedical engineering is the interdisciplinary study of engineering and medicine, and should be developed based on monozukuri. In this particular research, we have developed a physical molecular delivery method for cancer gene therapy using nano/microbubbles and ultrasound. First, the behavior of cavitation bubbles and subsequent shock wave phenomena involved in the mechanism of molecular delivery were analyzed, combining theory and computer simulation. In a second step, the methodology was optimized in vitro and in vivo. Finally, the therapeutic potential of the method in pre-clinical models was evaluated using transgenes relevant to cancer gene therapy instead of reporter genes, and whole body, non-invasive imaging using single photon emission computed tomography (SPECT/CT) was used to evaluate the selectivity of gene delivery in vivo. (Keyword) Animals / Cell Line, Tumor / Computer Simulation / Gene Transfer Techniques / Genes, Transgenic, Suicide / Genetic Therapy / Humans / Microbubbles / Neoplasms / Rodentia / Tomography, Emission-Computed, Single-Photon / Ultrasonics (Link to Publication Site) ● Publication site (DOI): 10.1080/13645700600836059 (Link to Search Site for Scientific Articles) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 16966136 ● Search Scopus @ Elsevier (PMID): 16966136 ● Search Scopus @ Elsevier (DOI): 10.1080/13645700600836059 (DOI: 10.1080/13645700600836059, PubMed: 16966136)

Academic Paper (Unrefereed Paper):

1.	重松大樹 and Kenichiro Koshiyama : せん断流れ下での脂質二重膜のダイナミクス:分子動力学シミュレーション, Journal of Japan Society of Fluid Mechanics, 39, 340-343, 2020. (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1520853834477340160 (CiNii: 1520853834477340160)

Review, Commentary:

1.	Kenichiro Koshiyama : Nonequilibrium Molecular Dynamics Study of Lipid Bilayers for the Development of Biomedical Engineering Techniques, MEMBRANE, 45, 5, 226-231, 2020. (Summary) Biomedical engineering is an integration of engineering and medicine to understand and treat biological, medical, and healthcare problems. The biomedical engineering techniques inherently involve various non–equilibrium phenomena in biological systems, and it is essential to understand the phenomenon for the safe, reliable, and effective use of them. Non–equilibrium molecular dynamics simulation is a potential tool to understand non–equilibrium phenomena at the molecular scale. In this review, we introduce the basis of molecular dynamics simulations of the lipid bilayer and the potential applications to the development of ultrasound and liposomal drug delivery systems based mainly on our previous studies. (Link to Publication Site) ● Publication site (DOI): 10.5360/membrane.45.226 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390004222621460864 ● Search Scopus @ Elsevier (DOI): 10.5360/membrane.45.226 (DOI: 10.5360/membrane.45.226, CiNii: 1390004222621460864)
2.	和田成生, Kenichiro Koshiyama, 肖蘿莎 and 世良俊博 : 肺のミクロ—マクロ力学場の統合に向けた肺細葉の形態解析と数理モデリング, Respiration & Circulation, 62, 12, 1179-1187, Dec. 2014. (Link to Publication Site) ● Publication site (DOI): 10.11477/mf.1404200054 (Link to Search Site for Scientific Articles) ● Search Scopus @ Elsevier (DOI): 10.11477/mf.1404200054 (DOI: 10.11477/mf.1404200054)
3.	Kenichiro Koshiyama : 細胞膜分子動力学シミュレーションと医工学技術開発の融合, 計算数理工学レビュー, 2013, 1, 27-33, Mar. 2013.

Proceeding of International Conference:

1.	Kenichiro Koshiyama : Molecular Dynamics Simulations of Shockwave Effects on Biological Membranes: Fundamentals and Limitations, 9th International Forum on Blast Injury Countermeasures Abstract Book, Tutorial3-1page, May 2025.
2.	Kenichiro Koshiyama : Mathematical modeling of pulmonary acinus structure: toward understanding acinar mechanics for neonates, IWACOM-IV Abstract Book, OW1-11-1pages, Sep. 2024.
3.	Kenichiro Koshiyama : Mathematical Modeling of Pulmonary Acinus Structure: Extension to Neonatal Lungs, 9th World Congress of Biomechanics Taipei, O-06056-2pages, Jul. 2022.
4.	Tsutsumi Yusuke and Kenichiro Koshiyama : Molecular dynamics simulations of a mechanosensitive channel under tension: Effects of hydrophobic molecules on the structural changes of the channel-embedded lipid bilayer, The 11th Asian-Pacific Conference on Biomechanics Abstract book, 1, Dec. 2021.
5.	Ishikawa Atsuki and Kenichiro Koshiyama : Mathematical modeling of pulmonary acinus structure: analysis of pathway structure in conical outer shapes, The 11th Asian-Pacific Conference on Biomechanics Abstract book, 1, Dec. 2021.
6.	Kenichiro Koshiyama, Keisuke Nishimoto, Satoshi Ii and Shigeo Wada : MECHANICAL ANALYSIS OF PULMONARY ACINAR INFLATION WITH HETEROGENEOUS ACINAR STRUCTURE MODELS, CMBE19 proceedings, 2, 703-704, Jun. 2019.
7.	Kenichiro Koshiyama, Keisuke Nishimoto, Satoshi Ii, Toshihiro Sera and Shigeo Wada : Anisotropic deformation of pulmonary acinar tissues for inflation with surface tension effects, 8th World Congress of Biomechanics, Dublin, Ireland, Jul. 2018.

Proceeding of Domestic Conference:

1.	DOI Shuto and Kenichiro Koshiyama : 温度上昇により誘導されるナノリポソーム形成:分子動力学解析, 日本機械学会第37回バイオエンジニアリング講演会抄録集, P2-45-1page, May 2025.
2.	YAMAJI Ryota and Kenichiro Koshiyama : 肺成熟に伴う肺胞上皮細胞の空間分布変化に関する数理モデリング, 日本機械学会第37回バイオエンジニアリング講演会抄録集, P2-18-1page, May 2025.
3.	FUJITA Seiya and Kenichiro Koshiyama : マルチ肺細葉数理構造モデリング:肺細葉クラスタ形成メカニズム解明に向けて, 日本機械学会第37回バイオエンジニアリング講演会抄録集, P1-18-1page, May 2025.
4.	Kenichiro Koshiyama : Shockwave Induced Transition from Bicelle to Vesicle of Lipid Aggregate: Molecular Dynamics Study, 2024年度衝撃波シンポジウム講演論文集, 2B2-3-2pages, Mar. 2025.
5.	SATO Kodai and Kenichiro Koshiyama : セルロースナノファイバーの機械的解繊メカニズム解明に向けた粗視化分子動力学シミュレーション, 日本機械学会中国四国学生会第55回学生員卒業研究発表講演会予稿集, 12A4-2pages, Mar. 2025.
6.	DOI Shuto and Kenichiro Koshiyama : 温度制御によるナノリポソーム形成に関する分子動力学解析, 日本機械学会中国四国学生会第55回学生員卒業研究発表講演会予稿集, 12A3-2pages, Mar. 2025.
7.	YOSHITOMI Seiya and Kenichiro Koshiyama : 仔肺微細構造内力学場に対する肺サーファクタント欠乏の影響:有限要素解析, 日本機械学会中国四国学生会第55回学生員卒業研究発表講演会予稿集, 12A2-2pages, Mar. 2025.
8.	NISHIOKA Kanta and Kenichiro Koshiyama : 仔肺微小領域における気道分岐構造変化の定量化に向けた日齢の異なるマウスの放射光CT画像解析, 日本機械学会中国四国学生会第55回学生員卒業研究発表講演会予稿集, 12A1-2pages, Mar. 2025.
9.	Kenichiro Koshiyama and YASUKAWA Takumi : 生後のマウス仔肺の日齢の異なる肺細葉実形状モデルを用いた有限要素解析, 日本機械学会第35回バイオフロンティア講演会予稿集, 2C14-4pages, Dec. 2024.
10.	Kenichiro Koshiyama and MIYAZAKI Ryosuke : ナノリポソーム形成に伴う低分子の封入に関する分子動力学シミュレーション, 日本機械学会第35回バイオフロンティア講演会予稿集, 2C13-4pages, Dec. 2024.
11.	Kenichiro Koshiyama and FURUKAWA Shunya : 放射光X線マイクロCTを用いたマウス仔肺微細構造の定量化 :内圧負荷による構造変化, 日本機械学会第35回バイオフロンティア講演会予稿集, 1B17-4pages, Dec. 2024.
12.	Kenichiro Koshiyama and FUJITA Kensuke : 呼吸細気管支を含む肺細葉構造の数理モデリング:ロジスティック関数を利用した肺胞分布の制御, 日本機械学会第35回バイオフロンティア講演会予稿集, 1B08-4pages, Dec. 2024.
13.	Kenichiro Koshiyama and KAKUNO Yugo : 平面衝撃波による脂質ナノ粒子の構造変化に関する分子動力学シミュレーション, 日本流体力学会年会2024 予稿集, Sep. 2024.
14.	Kenichiro Koshiyama and KAKUNO Yugo : 衝撃波による脂質バイセル構造変化に対する分子動力学解析, 日本機械学会 2024年度年次大会講演論文集, J022-06-3pages, Sep. 2024.
15.	FURUKAWA Shunya, Kenichiro Koshiyama, 世良俊博 and FUJITA Kensuke : 放射光X線マイクロCTを⽤いた⽇齢の異なるマウス仔肺微細構造の定量化, 日本機械学会第35回バイオエンジニアリング講演会抄録集, 2P74-1page, May 2024.
16.	KAKUNO Yugo and Kenichiro Koshiyama : Effect of lipid bilayers on shock wave propagation: molecular dynamics analysis, 2023年度衝撃波シンポジウム講演論文集, 2B2-4-3pages, Mar. 2024.
17.	TAKAMI Yudai and Kenichiro Koshiyama : Molecular Dynamics Study on Nanoliposomes under Cyclic T ensile Loading : toward Understanding Ultrasound Induced Drug Release, 日本機械学会第34回バイオフロンティア講演会講演論文集, 1E21-4pages, Dec. 2023.
18.	RYO Shintaro, FUJITA Kensuke and Kenichiro Koshiyama : Finite Element Analysis with Mathematical Shape Model of Centri acinar Emphysema, 日本機械学会第34回バイオフロンティア講演会講演論文集, 1B17-4pages, Dec. 2023.
19.	MIYAZAKI Ryosuke and Kenichiro Koshiyama : Molecular Dynamics Simulations of Nanoliposomes Encapsulating Small Molecules: Effects of Molecular Concentration on Encapsulation Efficiency, 日本機械学会第36回計算力学講演会講演論文集, OS-1811-4pages, Oct. 2023.
20.	RYO Shintaro, FUJITA Kensuke and Kenichiro Koshiyama : Mathematical Modeling of Pulmonary Acinus Structure in Emphysema: Effects of Emphysema Types on Mechanical Fields, 日本機械学会第36回計算力学講演会講演論文集, OS-1810-4pages, Oct. 2023.
21.	FUJITA Kensuke, RYO Shintaro and Kenichiro Koshiyama : Ma t hematical Modeling of Pulmonary Acinus Structure: An Algorithm of Implementing Airway Path Length Dependent Alve olarization, 日本機械学会第36回計算力学講演会講演論文集, OS-1804-4pages, Oct. 2023.
22.	Kenichiro Koshiyama and KAKUNO Yugo : Molecular Dynamics Simulations of a Lipid Assembly under Shock Wave: Toward Understanding Pulse Width Effects, 日本機械学会2023年度年次大会講演論文集, J022-07-4pages, Sep. 2023.
23.	Kensuke Fujita, SHINTAROH Ryo and Kenichiro Koshiyama : 肺細葉構造の数理モデル開発:肺胞・気道領域の制御に向けた改良, 日本機械学会第35回バイオエンジニアリング講演会抄録集, P208-2-1page, Jun. 2023.
24.	Kenichiro Koshiyama : 局所力学物性制御によるナノリポソーム形成の誘導, 日本機械学会第35回バイオエンジニアリング講演会抄録集, OS-B3-1page, Jun. 2023.
25.	Kenichiro Koshiyama, Shintaroh Ryo and Kensuke Fujita : 肺胞壁発達を考慮した肺細葉構造の数理アルゴリズムの提案:周産期仔肺細葉構造モデリングに向けて, 第30回バイオフィジオロジー研究会抄録集, 6-7, Mar. 2023.
26.	Kenichiro Koshiyama : Planar Shock Wave Interaction with nanoliposome: Molecular Dynamics Simulations, 2022年度衝撃波シンポジウム講演論文集, 3C3-2-2pages, Mar. 2023.
27.	SHINTAROH Ryo and Kenichiro Koshiyama : Mathematical Modelling of Pulmonary Acinus Structure Representing Lung Tissue Destruction: Toward Modelling of Emphysematous Acinus, 日本機械学会第33回バイオフロンティア講演会講演論文集, 1F19-4Pages, Dec. 2022.
28.	木下敦斗 and Kenichiro Koshiyama : Identifying Material Model of Lung Tissues Based on Uniaxial Tensile Tests and Optimization with Finite Element Analysis: Effects of Specimen Dimension, 日本機械学会第33回バイオフロンティア講演会講演論文集, 1D05-4Pages, Dec. 2022.
29.	仲田一輝 and Kenichiro Koshiyama : Molecular Dynamics Study of Transition from Bicelle to Vesicle Induced by Changing Local Mechanical Properties: Effects of Lipid Saturation, 日本機械学会第33回バイオフロンティア講演会講演論文集, 1D08-4Pages, Dec. 2022.
30.	岸上夏輝 and Kenichiro Koshiyama : Effects of Lipid Compositions on Lipid Monolayer Buckling: Molecular Dynamics Study, 日本機械学会第33回バイオフロンティア講演会講演論文集, 1D01-4Pages, Dec. 2022.
31.	Kenichiro Koshiyama : Planar Shock Wave Interaction with a Lipid Assembly: Molecular Dynamics Simulations, 日本機械学会2022年度年次大会講演論文集, C000432-4pages, Sep. 2022.
32.	岸上夏輝 and Kenichiro Koshiyama : 肺サーファクタント層の座屈現象に対する脂質組成の影響:分子動力学解析, 日本機械学会第32回バイオフロンティア講演会講演論文集, 2D16-4Pages, Jan. 2022.
33.	仲田一輝 and Kenichiro Koshiyama : 飽和/不飽和リン脂質混合ナノリポソーム形成の分子動力学解析, 日本機械学会第32回バイオフロンティア講演会講演論文集, 2A11-4Pages, Jan. 2022.
34.	木下敦斗 and Kenichiro Koshiyama : 単軸引張試験と有限要素解析を用いた肺組織力学モデルの同定, 日本機械学会第32回バイオフロンティア講演会講演論文集, 1B32-4Pages, Jan. 2022.
35.	Shin Kusano and Kenichiro Koshiyama : 肺胞隔壁の発達に伴う肺胞内力学場変化の理解に向けた有限要素解析, 日本機械学会第32回バイオフロンティア講演会講演論文集, 1B27-4Pages, Jan. 2022.
36.	Kenichiro Koshiyama : 生体医工学技術開発:非平衡脂質分子動力学シミュレーションからの示唆, 第6回ソフトマター工学分科会講演会講演論文集, 1-4, Nov. 2021.
37.	重松大樹 and Kenichiro Koshiyama : せん断流れにより誘起されるリン脂質二重膜の張力:分子動力学シミュレーション, 日本流体力学会年会2021 講演論文集, 2pages, Sep. 2021.
38.	Atsuki Ishikawa and Kenichiro Koshiyama : 円錐状肺細葉構造の数理モデル:肺細葉気道分布の解析, 日本機械学会第34回計算力学講演会講演論文集, 172, Sep. 2021.
39.	Kenichiro Koshiyama : Molecular Dynamics Simulations of Structural Changes of Lipid Bilayers Under High Pressure, 日本機械学会2021年度年次大会講演論文集, J022-04, Sep. 2021.
40.	Kenichiro Koshiyama : 小児肺細葉メカニクス構築に向けた不均質肺微小構造数理モデリング, 日本機械学会第33回バイオエンジニアリング講演会予稿集, 1B1-03, Jun. 2021.
41.	重松大樹 and Kenichiro Koshiyama : せん断流れが脂質二重膜のうねりの特性に与える影響:分子動力学シミュレーション, 第34回数値流体力学シンポジウム講演論文集, B07-4-3pages, Dec. 2020.
42.	Yusuke Tsutsumi and Kenichiro Koshiyama : 張力負荷下での疎水性分子含有脂質二重膜の分子動力学シミュレーション:麻酔機序解明に向けて, 日本機械学会第31回バイオフロンティア講演会講演論文集, 1C23-4Pages, Dec. 2020.
43.	Atsuki Ishikawa and Kenichiro Koshiyama : Mathematical Modeling of Pulmonary Acinus Structure: Heterogeneity of the Microstructure Based on the Homogeneity, 日本機械学会第31回バイオフロンティア講演会講演論文集, 1C12-4Pages, Dec. 2020.
44.	Shin Kusano and Kenichiro Koshiyama : Analysis for Stress Environment in MultiAlveoli Model: for Understanding Mechanics during Alveologenesis, 日本機械学会第31回バイオフロンティア講演会講演論文集, 1C11-4Pages, Dec. 2020.
45.	重松大樹 and Kenichiro Koshiyama : せん断流れ下での脂質二重膜のダイナミクス:分子動力学シミュレーション, 日本流体力学会年会2020 講演論文集, 2pages, Sep. 2020.
46.	Kenichiro Koshiyama, 和田成生, 伊井仁志 and 世良俊博 : Mechanical Analysis of Pulmonary Acinar Inflation: Toward Understanding Infant Acinar Mechanics, 日本機械学会第32回バイオエンジニアリング講演会講演論文集, U00127, Dec. 2019.
47.	Kenichiro Koshiyama : 次世代医工学技術開発を支援する非平衡生体分子動力学研究, 第26回次世代医工学研究会プログラム, Dec. 2019.
48.	Kenichiro Koshiyama : Molecular Dynamics Simulations of Mechanosensitive Channel in Lipid Bilayers under Dynamic Mechanical Loading, 日本流体力学会第33回数値流体力学シンポジウム講演論文集, F03-4, Nov. 2019.
49.	Kenichiro Koshiyama : Molecular Dynamics Simulations of Mechanosensitive Channel in Lipid Bilayers, 日本機械学会2019年度年次大会講演論文集, J02106, Sep. 2019.
50.	石本慶太, 重松大輝, 和田成生 and Kenichiro Koshiyama : Molecular Dynamics Simulation of Peptide-embedded Liposome Formation, 日本機械学会第30回バイオフロンティア講演会講演論文集, 1A33, Jul. 2019.
51.	Kenichiro Koshiyama, 伊井仁志, 世良俊博 and 和田成生 : 吸気時の肺細葉内局所力学場に関する数値的検討:表面張力効果, 第27回バイオフィジオロジー研究会抄録集, 10-11, Mar. 2019.
52.	種子尾将希, Kenichiro Koshiyama, 重松大輝, Kenichiro Koshiyama and 和田成生 : 局所脂質分子組成の制御によるナノリポソーム形成に関する分子動力学解析, 日本機械学会第31回バイオエンジニアリング講演会講演論文集, 1G33, Dec. 2018.
53.	竹田圭佑, 伊井仁志, 吉永司, Kenichiro Koshiyama and 和田成生 : 気道および肺実質内の音響伝播モデルを用いた肺音伝播メカニズムの考察, 日本機械学会第31回バイオエンジニアリング講演会講演論文集, 1G13, Dec. 2018.
54.	重松大輝, Kenichiro Koshiyama and 和田成生 : 混合脂質二重膜の線張力推定の分子動力学シミュレーション:細胞膜中に形成した微小孔の挙動制御に向けて, 日本機械学会第31回バイオエンジニアリング講演会講演論文集, 1A24, Dec. 2018.
55.	Kenichiro Koshiyama : All atom molecular dynamics simulations of ceramide bilayers under compressive loading, 日本機械学会2018年度年次大会講演論文集, J0250001, Sep. 2018.
56.	伊井仁志, 竹田圭佑, Kenichiro Koshiyama and 和田成生 : Understanding the lung crackle sounds by fluid-structure-acoustic interaction analysis, 計算工学講演会論文集 Proceedings of the Conference on Computational Engineering and Science, 23, 3p, Jun. 2018. (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1520290883711773952 (CiNii: 1520290883711773952)
57.	Kenichiro Koshiyama and Shigeo WADA : Molecular Dynamics Simulations of Lipid Coated Nanobubble under Cyclic Pressure Changes, The Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME, 2018, 0, 1G04, 2018. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebio.2018.30.1G04 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390845712969144704 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebio.2018.30.1G04 (DOI: 10.1299/jsmebio.2018.30.1G04, CiNii: 1390845712969144704)
58.	Masaki TANEO, Kenichiro Koshiyama, Taiki SHIGEMATSU and Shigeo WADA : The Formation of Nanoliposome Composed of Binary Mixture Lipids::Molecular Dynamics Simulation, The Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME, 2018, 0, 1G07, 2018. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebio.2018.30.1G07 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390845712969143296 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebio.2018.30.1G07 (DOI: 10.1299/jsmebio.2018.30.1G07, CiNii: 1390845712969143296)
59.	Taiki SHIGEMATSU, Kenichiro Koshiyama and Shigeo WADA : Molecular Partitioning and Line Tension of Pore Edge in Mixed-Lipid Bilayers::Molecular Dynamics Simulation, The Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME, 2018, 0, 1G08, 2018. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebio.2018.30.1G08 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282763015995520 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebio.2018.30.1G08 (DOI: 10.1299/jsmebio.2018.30.1G08, CiNii: 1390282763015995520)
60.	Keisuke TAKEDA, Tsukasa YOSHINAGA, Kenichiro Koshiyama, Satoshi II and Shigeo WADA : Acoustic analysis of lung sound distribution using airway branching model in pulmonary lobes based on real shape, The Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME, 2018, 0, 2F05, 2018. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebio.2018.30.2F05 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390001288038484864 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebio.2018.30.2F05 (DOI: 10.1299/jsmebio.2018.30.2F05, CiNii: 1390001288038484864)
61.	Ryogo ENOSAKI, Satoshi II, Naoki TAKEISHI, Kenichiro Koshiyama, Daiki SHIGEMATSU and Shigeo WADA : Computer simulation of fibrin clot formation using protofibril aggregation model::evaluation of the morphological characteristics, The Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME, 2018, 0, 2E07, 2018. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebio.2018.30.2E07 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390845712969160832 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebio.2018.30.2E07 (DOI: 10.1299/jsmebio.2018.30.2E07, CiNii: 1390845712969160832)
62.	Kenichiro Koshiyama : Molecular dynamics simulations of ceramide bilayer failure, The Proceedings of Mechanical Engineering Congress, Japan, 2017, 0, J0220105, 2017. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmemecj.2017.J0220105 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680820265856 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmemecj.2017.J0220105 (DOI: 10.1299/jsmemecj.2017.J0220105, CiNii: 1390282680820265856)
63.	Ryogo ENOSAKI, Satoshi II, Naoki TAKEISHI, Kenichiro Koshiyama, Taiki SHIGEMATSU and Shigeo WADA : Mesoscopic numerical approach for fibrin clot formation using discrete element model, The Proceedings of The Computational Mechanics Conference, 2017, 0, 67, 2017. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmecmd.2017.30.067 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390001205858572288 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmecmd.2017.30.067 (DOI: 10.1299/jsmecmd.2017.30.067, CiNii: 1390001205858572288)
64.	Keisuke TAKEDA, Tsukasa YOSHINAGA, Kenichiro Koshiyama, Satoshi II and Shigeo WADA : Sound analysis using airway branching model based on real shape, The Proceedings of the JSME Conference on Frontiers in Bioengineering, 2017, 0, 2C12, 2017. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebiofro.2017.28.2C12 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390001205872251264 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebiofro.2017.28.2C12 (DOI: 10.1299/jsmebiofro.2017.28.2C12, CiNii: 1390001205872251264)
65.	Masaki TANEO, Kenichiro Koshiyama, Taiki SHIGEMATSU and Shigeo WADA : Effect of Lipid Composition on Nanoliposome Formation: Molecular Dynamics Simulation, The Proceedings of the JSME Conference on Frontiers in Bioengineering, 2017, 0, 1B22, 2017. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebiofro.2017.28.1B22 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680848664832 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebiofro.2017.28.1B22 (DOI: 10.1299/jsmebiofro.2017.28.1B22, CiNii: 1390282680848664832)
66.	Taiki SHIGEMATSU, Kenichiro Koshiyama and Shigeo WADA : Effects of Phase Transition on Pore Formation in Stretched Phospholipid/Cholesterol Bilayer:Molecular Dynamics Simulation, The Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME, 2017, 0, 1F34, 2017. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebio.2017.29.1F34 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680852320896 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebio.2017.29.1F34 (DOI: 10.1299/jsmebio.2017.29.1F34, CiNii: 1390282680852320896)
67.	Naoya ANDO, Kenichiro Koshiyama, Manabu KINOSHITA and Shigeo WADA : 1H15 Real time observations of the molecular delivery in in vitro sonoporation : effects of ultrasound conditions on the delivery timing, The Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME, 2016, 0, _1H15-1_-_1H15-5_, 2016. (Summary) Understanding the time when molecular delivery occurs during sonoporation is important to improve the efficiency of successful sonoporation and fraction of viable cells. Here, we report how ultrasound conditions affect the time for sonoporation. We employed real-time observations of propidium iodide (PI) delivery to 3T3-Swiss albino cells under 5 seconds 1 MHz continuous ultrasound waves treatment with fluorescence (PI) and microbubbles SONAZOID^[○!R]. Sonoporation timing was evaluated by analyzing the time courses of the altering fluorescence intensity of the cells. Three ultrasound intensity conditions, 0.15, 0.20 and 0.30 W/cm^2, were examined. Fluorescence intensity increased for 0.20 and .30 W/cm^2-sonication, indicating PI delivery into the cells, while no apparent increase was observed for 0.15 W/cm^2-sonication. Fluorescence intensity clearly started to increase earlier for 0.30 W/cm^2 than for 0.20 W/cm^2-sonication. Sonoporation timing ranged from 2 to 6 seconds for 0.30 W/cm^2-sonication. The most delayed timing was obtained for cells that had the largest adhesion area. As a conclusion, different microbubble responses stimulated by various ultrasound conditions may cause different sonoporation timing. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebio.2016.28._1H15-1_ (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680853080960 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebio.2016.28._1H15-1_ (DOI: 10.1299/jsmebio.2016.28._1H15-1_, CiNii: 1390282680853080960)
68.	Ryotaro KURUMATANI, Kenichiro Koshiyama and Shigeo WADA : Molecular Dynamics Simulations of PEGylated-liposome Rupture Induced by High-speed Mechanical Loading, The Proceedings of Mechanical Engineering Congress, Japan, 2016, 0, J0210101, 2016. (Summary) <p>To understand the mechanical response of PEGylated liposomes is critical for the development of drug delivery system (DDS) using liposomes. We perform molecular dynamics (MD) simulations of dipalmitoylphophatidylethanolamine (DPPE)/PEGylated DPPE (DPPE-PEG) bilayers under quasi-static and unsteady stretching. The quasi-static stretching is modeled by constant temperature and bilayer normal pressure MD simulations with various constant areas. The unsteady stretching is modeled by scaling atom positions with various stretching speeds, 0.5, 1.0, and 2.0 m/s. We analyze the effects of stretching speeds and DPPE-PEG concentrations (0, 50, 100 mol%) on the bilayer rupture. The rupturing areal strain decreases with increasing the DPPE-PEG concentration and it increases with increasing the stretching speed, regardless of the DPPE-PEG concentrations. Under the quasi-static stretching, the rupturing tension decreases with increasing the DPPE-PEG concentration. However, under the unsteady stretching, it increases with the DPPE-PEG concentration. These results suggest that viscoelastic properties of a DPPE/DPPE-PEG bilayer may affect the rupture of the liposomes.</p> (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmemecj.2016.J0210101 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390001205837764736 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmemecj.2016.J0210101 (DOI: 10.1299/jsmemecj.2016.J0210101, CiNii: 1390001205837764736)
69.	Keisuke NISHIMOTO, Kenichiro Koshiyama, Satoshi II and Shigeo WADA : Deformation Analysis of Heterogeneous Pulmonary Acinus Structure with Considering Effects of Surface Tension, The Proceedings of the JSME Conference on Frontiers in Bioengineering, 2016, 0, C213, 2016. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebiofro.2016.27.C213 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390001205870938240 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebiofro.2016.27.C213 (DOI: 10.1299/jsmebiofro.2016.27.C213, CiNii: 1390001205870938240)
70.	Taiki SHIGEMATSU, Kenichiro Koshiyama and Shigeo WADA : 1C42 Molecular dynamics simulation of water permeability through stretched phospholipid/cholesterol bilayer, The Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME, 2015, 0, 127-128, 2015. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebio.2015.27.127 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680853923584 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebio.2015.27.127 (DOI: 10.1299/jsmebio.2015.27.127, CiNii: 1390282680853923584)
71.	Asuka NISHIKAWA, Kenichiro Koshiyama and Shigeo WADA : 2F33 Modeling of heterogeneous micro vasculature network at the pulmonary acinus level, The Proceedings of the Bioengineering Conference Annual Meeting of BED/JSME, 2015, 0, 535-536, 2015. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebio.2015.27.535 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680854632704 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebio.2015.27.535 (DOI: 10.1299/jsmebio.2015.27.535, CiNii: 1390282680854632704)
72.	Taiki SHIGEMATSU, Kenichiro Koshiyama and Shigeo WADA : 617 Mutual Effects of Cholesterol and Stretching Speed on Rupture of Phospholipid Bilayers under Stretching : Molecular Dynamics Simulation, The Proceedings of Conference of Kansai Branch, 2015, 0, 259-260, 2015. (Summary) Molecular dynamics simulations of pure DPPC and DPPC/cholesterol bilayers under stretching with various stretching speeds were performed. The lower the stretching speed, the more ordered the DPPC molecules, which tendency was more prominent in the DPPC/cholesterol bilayer. The critical areal strain, where the rupture occurs, in the pure DPPC bilayer significantly increased with the increase of the stretching speed, whereas that in the DPPC/cholesterol bilayer did not. The difference of the process of the molecular orientation changes under stretching might cause the difference of the stretching speed effects on the critical areal strain. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmekansai.2015.90.259 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390001205853521664 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmekansai.2015.90.259 (DOI: 10.1299/jsmekansai.2015.90.259, CiNii: 1390001205853521664)
73.	Yukiho ISHIDA, Satoshi II, Hideo HIRAKATA, Naoko SUGITA, Kenichiro Koshiyama and Shigeo WADA : P016 A blood-clot formation model considering biochemical reactions and viscoelasticity of thrombus, The Proceedings of Conference of Kansai Branch, 2015, 0, 434, 2015. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmekansai.2015.90.434 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680829838464 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmekansai.2015.90.434 (DOI: 10.1299/jsmekansai.2015.90.434, CiNii: 1390282680829838464)
74.	Kenichiro Koshiyama and Shigeo WADA : 0313 Molecular Dynamics Simulations of Lipid Coated Nanobubble, The Proceedings of the Fluids engineering conference, 2015, 0, _0313-1_-_0313-2_, 2015. (Summary) We investigate the collapsing mechanisms of a lipid coated nanobubble and the subsequent lipid vesicle formation by coarse grained molecular dynamics (CGMD) simulations. A preformed nanobubble coated by lipid monolayer in water is a model of an aqueous dispersion of phospholipids under negative pressure in sonication. Relaxing to a positive pressure, the spherical bubble shape deforms into irregular prolate ellipsoidal shape and the monolayer starts to fold from an apsis of the ellipsoid. The local folding is rapidly propagated in the ellipsoid, pushing gas core, and a discoidal membrane forms. The discoidal membrane develops into a unilamellar vesicle via bowl shape. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmefed.2015._0313-1_ (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680859250304 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmefed.2015._0313-1_ (DOI: 10.1299/jsmefed.2015._0313-1_, CiNii: 1390282680859250304)
75.	Ryotaro KURUMATANI, Taiki SHIGEMATSU, Kenichiro Koshiyama and Shigeo WADA : J0270201 Molecular Dynamics Study about Water Permeability Change of Lipid Membranes under Stretching : toward Development of Liposomes for Drug Delivery, The Proceedings of Mechanical Engineering Congress, Japan, 2015, 0, _J0270201--_J0270201-, 2015. (Summary) In order to develop drug delivery systems (DDS) using liposomes, it is important to understand the effects of mechanical stresses on the water permeability of liposomes. We perform a series of molecular dynamics simulations of stretched palmitoyl-oleoyl phosphatidylcoline (POPC) lipid bilayers, which is the fundamental shell component of the liposomes. The stretched bilayers are simulated by constant temperature and bilayer normal pressure MD simulations with various constant areas. Under stretching, the bilayer thickness becomes thin. In the core of the bilayer, the lipid density increases, resulted in the smaller diffusion coefficient and the larger potential of mean force of water in the core region. This leads to the increase in the local resistance for water permeation. However, the apparent water permeability, which is the inverse of the integrated value of the resistance profile across the bilayer, shows the increase trend as the thickness decreases, although it depends on the applied stretch. This indicates that the water permeability and the permeation mechanism might be affected by mechanical stresses. As the DDS liposomes experience various mechanical stresses during blood circulation, it may be important to evaluate the leakage of drugs from the liposome considering the history of the stresses and the apparent permeability change. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmemecj.2015._J0270201- (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390001205843235712 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmemecj.2015._J0270201- (DOI: 10.1299/jsmemecj.2015._J0270201-, CiNii: 1390001205843235712)
76.	Ryotaro KURUMATANI, Taiki SHIGEMATSU, Kenichiro Koshiyama and Shigeo WADA : B211 Coarse grained molecular dynamics simulations of nano-liposome rupture induced by mechanical stresses, The Proceedings of the JSME Conference on Frontiers in Bioengineering, 2015, 0, 121-122, 2015. (Link to Publication Site) ● Publication site (DOI): 10.1299/jsmebiofro.2015.26.121 (Link to Search Site for Scientific Articles) ● CiNii @ National Institute of Informatics (CRID): 1390282680849666048 ● Search Scopus @ Elsevier (DOI): 10.1299/jsmebiofro.2015.26.121 (DOI: 10.1299/jsmebiofro.2015.26.121, CiNii: 1390282680849666048)

Grants-in-Aid for Scientific Research (KAKEN Grants Database @ NII.ac.jp)

局所力学物性制御によるリポソーム形成誘導 (Project/Area Number: 24K22408 )
小児肺微小構造の成熟と力学場の関係 (Project/Area Number: 23K28401 )
Evaluation of mechanical environment and cell response at alveolar region for lung remodeling (Project/Area Number: 19H04444 )
Generation of Biomechanics for Infant Lung Acinus (Project/Area Number: 18K19921 )
Therapeutic system for metastatic lymph nodes at early stages (Project/Area Number: 17H00865 )
What is the reason to form the thrombi with different internal structures and mechanical characteristics? (Project/Area Number: 15K12510 )
Next-generation ultrasound contrast agent development platform based on elucidating the physical phenomenon of lipid coated nanobubbles (Project/Area Number: 15K01284 )
Multiscale mechanical modeling and analysis of the lung for better understanding of the pathological remodeling mechanism (Project/Area Number: 24240073 )
Molecular mechanisms about ultrasound neuromodulation (Project/Area Number: 23686031 )
Three dimensional measurements of collagen structure in a vascular tissue subject to abnormal mechanical remodeling (Project/Area Number: 23650261 )
Towards the establishment of hemolysis simulator by a multi-scale analysis and experimental observations of damages on a red blood cell membrane and (Project/Area Number: 22300155 )
Molecular Mechanisms about Changes of Cell Membranes Functions : Induced by Shear Forces (Project/Area Number: 20760114 )
Computational studies on the development of intracranial aneurysms considering arterial wall remodeling induced by hemodynamics factors (Project/Area Number: 17300138 )
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Associate Professor : Koshiyama, Kenichiro

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Grants-in-Aid for Scientific Research (KAKEN Grants Database @ NII.ac.jp)