Faculty Profiles - HARA EMILIO SATOSHI

Papers - HARA EMILIO SATOSHI

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The cell membrane as biofunctional material for accelerated bone repair. Reviewed International journal

Emi Hatano, Nahid Akhter, Risa Anada, Mitsuaki Ono, Toshitaka Oohashi, Takuo Kuboki, Hiroshi Kamioka, Masahiro Okada, Takuya Matsumoto, Emilio Satoshi Hara

Acta biomaterialia 2024.7

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

The cell (plasma) membrane is enriched with numerous receptors, ligands, enzymes, and phospholipids that play important roles in cell-cell and cell-extracellular matrix interactions governing, for instance, tissue development and repair. We previously showed that plasma membrane nanofragments (PMNFs) act as nucleation sites for bone formation in vivo, and induce in vitro mineralization within 1 day. In this study, we optimized the methods for generating, isolating, and applying PMNFs as a cell-free therapeutic to expedite bone defect repair. The PMNFs were isolated from different mouse cell lines (chondrocytes, osteoblasts, and fibroblasts), pre-conditioned, lyophilized, and subsequently transplanted into 2 mm critical-sized calvarial defects in mice (n = 75). The PMNFs from chondrocytes, following a 3-day pre-incubation, significantly accelerated bone repair within 2 weeks, through a coordinated attraction of macrophages, endothelial cells, and osteoblasts to the healing site. In vitro experiments confirmed that PMNFs enhanced cell adhesion. Comparison of the PMNF efficacy with phosphatidylserine, amorphous calcium phosphate (ACP), and living cells confirmed the unique ability of PMNFs to promote accelerated bone repair. Importantly, PMNFs promoted nearly complete integration of the regenerated bone with native tissue after 6 weeks (% non-integrated bone area = 15.02), contrasting with the partial integration (% non-integrated bone area = 56.10; p < 0.01, Student's test) with transplantation of ACP. Vickers microhardness tests demonstrated that the regenerated bone after 6 weeks (30.10 ± 1.75) exhibited hardness similar to native bone (31.07 ± 2.46). In conclusion, this is the first study to demonstrate that cell membrane can be a promising cell-free material with multifaceted biofunctional properties that promote accelerated bone repair. STATEMENT OF SIGNIFICANCE.

DOI： 10.1016/j.actbio.2024.07.037

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Re-Evaluation of Initial Bone Mineralization from an Engineering Perspective Reviewed International journal

Emilio Satoshi Hara, Masahiro Okada, Noriyuki Nagaoka, Takayoshi Nakano, Takuya Matsumoto

Tissue Engineering Part B: Reviews 28 ( 1 ) 246 - 255 2022.2

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Mary Ann Liebert Inc

Bone regeneration was one of the earliest fields to develop in the context of tissue regeneration, and currently, repair of small-sized bone defects has reached a high success rate. Future researches are expected to incorporate more advanced techniques toward achieving rapid bone repair and modulation of the regenerated bone quality. For these purposes, it is important to have a more integrative understanding of the mechanisms of bone formation and maturation from multiple perspectives and to incorporate these new concepts into the development and designing of novel materials and techniques for bone regeneration. This review focuses on the analysis of the earliest stages of bone tissue development from the biology, material science, and engineering perspectives for a more integrative understanding of bone formation and maturation, and for the development of novel biology-based engineering approaches for tissue synthesis in vitro. More specifically, the authors describe the systematic methodology that allowed the understanding of the different nucleation sites in intramembranous and endochondral ossification, the space-making process for mineral formation and growth, as well as the process of apatite crystal cluster growth in vivo in the presence of suppressing biomolecules. Impact Statement A detailed understanding of the developmental process of bone tissue leads to the acquisition of useful information for the bone tissue fabrication. This review summarizes the study of the calcification process of the calvaria and epiphyses from an engineering perspective and provides useful information for the realization of bone tissue biofabrication. Here, we describe the new mechanism of space formation for mineralization such as rupture of chondrocytes and disruption of cell-cell adhesion. We also describe the roles of nucleation site such as cell membrane nanofragments and matrix vesicles.

DOI： 10.1089/ten.teb.2020.0352

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Other Link： https://www.liebertpub.com/doi/pdf/10.1089/ten.teb.2020.0352

Biohybrid Variable‐Stiffness Soft Actuators that Self‐Create Bone Reviewed

Danfeng Cao, Jose G. Martinez, Emilio Satoshi Hara, Edwin W. H. Jager

Advanced Materials 34 ( 8 ) 2107345 - 2107345 2022.2

Effect of Biomechanical Environment on Degeneration of Meckel’s Cartilage Reviewed

Mahmoud Farahat, Gulsan A.S. Kazi, Emilio S. Hara, Takuya Matsumoto

Journal of Dental Research 100 ( 2 ) 171 - 178 2021.2

Publishing type：Research paper (scientific journal) Publisher：SAGE Publications

During orofacial tissue development, the anterior and posterior regions of the Meckel’s cartilage undergo mineralization, while the middle region undergoes degeneration. Despite the interesting and particular phenomena, the mechanisms that regulate the different fates of Meckel’s cartilage, including the effects of biomechanical cues, are still unclear. Therefore, the purpose of this study was to systematically investigate the course of Meckel’s cartilage during embryonic development from a biomechanical perspective. Histomorphological and biomechanical (stiffness) changes in the Meckel’s cartilage were analyzed from embryonic day 12 to postnatal day 0. The results revealed remarkable changes in the morphology and size of chondrocytes, as well as the occurrence of chondrocyte burst in the vicinity of the mineralization site, an often-seen phenomenon preceding endochondral ossification. To understand the effect of biomechanical cues on Meckel’s cartilage fate, a mechanically tuned 3-dimensional hydrogel culture system was used. At the anterior region, a moderately soft environment (10-kPa hydrogel) promoted chondrocyte burst and ossification. On the contrary, at the middle region, a more rigid environment (40-kPa hydrogel) enhanced cartilage degradation by inducing a higher expression of MMP-1 and MMP-13. These results indicate that differences in the biomechanical properties of the surrounding environment are essential factors that distinctly guide the mineralization and degradation of Meckel’s cartilage and would be valuable tools for modulating in vitro cartilage and bone tissue engineering.

DOI： 10.1177/0022034520960118

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Other Link： http://journals.sagepub.com/doi/full-xml/10.1177/0022034520960118

Bone Marrow Cells Inhibit BMP‐2‐Induced Osteoblast Activity in the Marrow Environment Reviewed

Ha Thi Nguyen, Mitsuaki Ono, Yasutaka Oida, Emilio Satoshi Hara, Taishi Komori, Kentaro Akiyama, Ha Thi Thu Nguyen, Kyaw Thu Aung, Hai Thanh Pham, Ikue Tosa, Takeshi Takarada, Koichi Matsuo, Toshihide Mizoguchi, Toshitaka Oohashi, Takuo Kuboki

Journal of Bone and Mineral Research 34 ( 2 ) 327 - 332 2019.2

Rapid bioinspired mineralization using cell membrane nanofragments and alkaline milieu Reviewed

Emilio Satoshi Hara, Masahiro Okada, Takuo Kuboki, Takayoshi Nakano, Takuya Matsumoto

Journal of Materials Chemistry B 6 ( 38 ) 6153 - 6161 2018.9

Bioinspired Mineralization Using Chondrocyte Membrane Nanofragments Reviewed International journal

Emilio Satoshi Hara, Masahiro Okada, Noriyuki Nagaoka, Takako Hattori, Takuo Kuboki, Takayoshi Nakano, Takuya Matsumoto

ACS Biomaterials Science & Engineering 4 ( 2 ) 617 - 625 2018.2

Biocompatible nanostructured solid adhesives for biological soft tissues Reviewed

Okada, M., Nakai, A., Hara, E.S., Taguchi, T., Nakano, T., Matsumoto, T.

Acta Biomaterialia 57 404 - 413 2017

Fluocinolone Acetonide Is a Potent Synergistic Factor of TGF‐β3–Associated Chondrogenesis of Bone Marrow–Derived Mesenchymal Stem Cells for Articular Surface Regeneration Reviewed

Emilio Satoshi Hara, Mitsuaki Ono, Hai Thanh Pham, Wataru Sonoyama, Satoshi Kubota, Masaharu Takigawa, Takuya Matsumoto, Marian F Young, Bjorn R Olsen, Takuo Kuboki

Journal of Bone and Mineral Research 30 ( 9 ) 1585 - 1596 2015.9

Novel chondrogenic and chondroprotective effects of the natural compound harmine Reviewed

Emilio Satoshi Hara, Mitsuaki Ono, Satoshi Kubota, Wataru Sonoyama, Yasutaka Oida, Takako Hattori, Takashi Nishida, Takayuki Furumatsu, Toshifumi Ozaki, Masaharu Takigawa, Takuo Kuboki

Biochimie 95 ( 2 ) 374 - 381 2013.2

BMP-2 generates a functional bone marrow niche by inducing the differentiation of local mesenchymal cells into CAR cells Reviewed

Ikue Tosa, Mitsuaki Ono, Anh Tuan Dang, Ziyi Wang, Maiko Kimura, Wakana Kitagawa, Kei Ishibashi, Hang Thuy Do, Kun Zhao, Emilio Satoshi Hara, Noboru Asada, Takashi Nagasawa, Toshitaka Oohashi, Naoya Ohara, Takuo Kuboki

Blood Advances 2025.7

Local E-rhBMP-2/β-TCP Application Rescues Osteocyte Dendritic Integrity and Reduces Microstructural Damage in Alveolar Bone Post-Extraction in MRONJ-like Mouse Model Reviewed

Anh Tuan Dang, Mitsuaki Ono, Ziyi Wang, Ikue Tosa, Emilio Satoshi Hara, Akihiro Mikai, Wakana Kitagawa, Tomoko Yonezawa, Takuo Kuboki, Toshitaka Oohashi

International Journal of Molecular Sciences 25 ( 12 ) 6648 - 6648 2024.6

Publishing type：Research paper (scientific journal) Publisher：MDPI AG

The pathology of medication-related osteonecrosis of the jaw (MRONJ), often associated with antiresorptive therapy, is still not fully understood. Osteocyte networks are known to play a critical role in maintaining bone homeostasis and repair, but the exact condition of these networks in MRONJ is unknown. On the other hand, the local application of E-coli-derived Recombinant Human Bone Morphogenetic Protein 2/β-Tricalcium phosphate (E-rhBMP-2/β-TCP) has been shown to promote bone regeneration and mitigate osteonecrosis in MRONJ-like mouse models, indicating its potential therapeutic application for the treatment of MRONJ. However, the detailed effect of BMP-2 treatment on restoring bone integrity, including its osteocyte network, in an MRONJ condition remains unclear. Therefore, in the present study, by applying a scanning electron microscope (SEM) analysis and a 3D osteocyte network reconstruction workflow on the alveolar bone surrounding the tooth extraction socket of an MRONJ-like mouse model, we examined the effectiveness of BMP-2/β-TCP therapy on the alleviation of MRONJ-related bone necrosis with a particular focus on the osteocyte network and alveolar bone microstructure (microcrack accumulation). The 3D osteocyte dendritic analysis showed a significant decrease in osteocyte dendritic parameters along with a delay in bone remodeling in the MRONJ group compared to the healthy counterpart. The SEM analysis also revealed a notable increase in the number of microcracks in the alveolar bone surface in the MRONJ group compared to the healthy group. In contrast, all of those parameters were restored in the E-rhBMP-2/β-TCP-treated group to levels that were almost similar to those in the healthy group. In summary, our study reveals that MRONJ induces osteocyte network degradation and microcrack accumulation, while application of E-rhBMP-2/β-TCP can restore a compromised osteocyte network and abrogate microcrack accumulation in MRONJ.

DOI： 10.3390/ijms25126648

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Electrochemical control of bone microstructure on electroactive surfaces for modulation of stem cells and bone tissue engineering Reviewed International journal

Danfeng Cao, Jose G. Martinez, Risa Anada, Emilio Satoshi Hara, Hiroshi Kamioka, Edwin W. H. Jager

Science and Technology of Advanced Materials 24 ( 1 ) 2183710 - 2183710 2023.12

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Controlling stem cell behavior at the material interface is crucial for the development of novel technologies in stem cell biology and regenerative medicine. The composition and presentation of bio-factors on a surface strongly influence the activity of stem cells. Herein, we designed an electroactive surface that mimics the initial process of trabecular bone formation, by immobilizing chondrocyte-derived plasma membrane nanofragments (PMNFs) on its surface for rapid mineralization within 2 days. Moreover, the electroactive surface was based on the conducting polymer polypyrrole (PPy), which enabled dynamic control of the presentation of PMNFs on the surface via electrochemical redox switching, further resulting in the formation of bone minerals with different morphologies. Furthermore, bone minerals with contrasting surface morphologies had differential effects on the differentiation of human bone marrow-derived stem cells (hBMSCs) cultured on the surface. Together, this electroactive surface showed multifunctional characteristics, not only allowing dynamic control of PMNF presentation but also promoting the formation of bone minerals with different morphologies within 2 days. This electroactive substrate could be valuable for more precise control of stem cell growth and differentiation, and further development of more suitable microenvironments containing bone apatite for housing a bone marrow stem cell niche, such as biochips/bone-on-chips.

DOI： 10.1080/14686996.2023.2183710

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Tunable electroactive biomimetic bone-like surfaces for bone marrow-on-chips Reviewed

Danfeng Cao, Jose G. Martinez, Laetitia Skalla, Erik Hultin, Jan-Ingvar Jönsson, Risa Anada, Hiroshi Kamioka, Edwin W. H. Jager, Emilio Satoshi Hara

2023 IEEE BioSensors Conference (BioSensors) 1 - 4 2023.7

Variable Stiffness Actuators with Covalently Attached Nanofragments that Induce Mineralization Reviewed International journal

Danfeng Cao, Jose G. Martinez, Emilio Satoshi Hara, Edwin W. H. Jager

Advanced Materials Technologies 2201651 - 2201651 2023.4

Important roles of odontoblast membrane phospholipids in early dentin mineralization Reviewed International journal

Risa Anada, Emilio Satoshi Hara, Noriyuki Nagaoka, Masahiro Okada, Hiroshi Kamioka, Takuya Matsumoto

Journal of Materials Chemistry B 11 ( 3 ) 657 - 666 2023.1

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Royal Society of Chemistry (RSC)

The objective of this study was to first identify the timing and location of early mineralization of mouse first molar, and subsequently, to characterize the nucleation site for mineral formation...

DOI： 10.1039/d2tb02351b

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Fabrication of initial trabecular bone inspired three-dimensional structure with cell membrane nanofragments Reviewed

Koichi Kadoya, Emilio Satoshi Hara, Masahiro Okada, Yu Yang Jiao, Takayoshi Nakano, Akira Sasaki, Takuya Matsumoto

Regenerative Biomaterials 2022.11

Publishing type：Research paper (scientific journal) Publisher：Oxford University Press (OUP)

Abstract

The extracellular matrix of trabecular bone has a large surface exposed to the bone marrow and plays important roles such as hematopoietic stem cell niche formation and maintenance. In vitro reproduction of trabecular bone microenvironment would be valuable not only for developing a functional scaffold for bone marrow tissue engineering but also for understanding its biological functions. Herein, we analyzed and reproduced the initial stages of trabecular bone formation in mouse femur epiphysis. We identified that the trabecular bone formation progressed through the following steps: (1) partial rupture of hypertrophic chondrocytes; (2) calcospherite formation on cell nanofragments (CNFs) derived from the ruptured cell membranes; and (3) calcospherite growth and fusion to form the initial three-dimensional (3D) structure of trabecular bones. For reproducing the initial trabecular bone formation in vitro, we collected CNFs from cultured cells and used as nucleation sites for biomimetic calcospherite formation. Strikingly, almost the same 3D structure of the initial trabecular bone could be obtained in vitro by using additional CNFs as a binder to fuse biomimetic calcospherites.

DOI： 10.1093/rb/rbac088

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Distinct Morphologies of Bone Apatite Clusters in Endochondral and Intramembranous Ossification Reviewed

Emilio Satoshi Hara, Noriyuki Nagaoka, Masahiro Okada, Takayoshi Nakano, Takuya Matsumoto

Advanced Biology 6 ( 11 ) 2200076 - 2200076 2022.11

Soft actuators that self-create bone for biohybrid (micro)robotics Reviewed

Danfeng Cao, Jose G. Martinez, Emilio Satoshi Hara, Edwin W. H. Jager

2022 International Conference on Manipulation, Automation and Robotics at Small Scales (MARSS) 2022.7

Mechanotransductive Mechanisms of Biomimetic Hydrogel Cues Modulating Meckel's Cartilage Degeneration Reviewed

Mahmoud Farahat, Emilio S. Hara, Risa Anada, Gulsan A.S. Kazi, Nahid M. Akhter, Takuya Matsumoto

Advanced Biology 2101315 - 2101315 2022.6

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Papers - HARA EMILIO SATOSHI