Faculty Profiles - OGATA Aika

Papers - OGATA Aika

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Modification of Antibacterial Copolymers on the Surface of PVA-Based Microfibers via Thermal Cross-Linking and Their Antibacterial Properties. Invited Reviewed

Saito S, Matsuno S, Saito A, Mutsuga M, Yamawaki-Ogata A, Narita Y, Kotsuchibashi Y

ACS omega Vol. 9 ( 46 ) page： 45961 - 45969 2024.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：ACS Omega

Bacterial infections on material surfaces are a serious public health concern worldwide. Although poly(vinyl alcohol) (PVA)-based materials have great potential as medical devices, they lack antibacterial properties on their surfaces and pose bacterial infection risks during implantation surgery. Copolymers containing antibacterial [2-(methacryloyloxy)ethyl]trimethylammonium chloride (METAC) units were used to modify the surfaces of chemically cross-linked water-insoluble PVA-based microfibers. The copolymers also had carboxy units that were used to react with the hydroxy group of the PVA-based microfibers via a simple thermal treatment at 135 °C. PVA-based materials containing METAC units exhibit significant swelling due to electrostatic repulsions. Because the copolymers were modified on the extreme surface of the microfibers, no difference in the diameters between unmodified microfibers (PM-fiber) and copolymers with METAC unit-modified microfibers (PM-METAC-fiber), in both the dry and swollen states, was observed. The viable bacterial cell numbers, which were evaluated by colony counting, decreased by exposure to the poly(METAC-co-methacrylic acid (MAAc)) aqueous solution or PM-METAC-fibers. The value of CFU/mL decreased to 0.1% (against B. subtilis) and 3.9% (against E. coli) after contact with the PM-METAC-fibers compared to the PM-fibers. The percentage of hemolysis against rabbit red blood cells was equivalent to that of the negative control, suggesting that PM-METAC-fibers can selectively exhibit antibacterial properties. This modification method can be applied to various PVA-based materials if hydroxy groups are present on their surface. This study provides a facile, cost-effective, and promising strategy to impart antibacterial properties to the surface of PVA-based materials without significantly affecting their physicochemical properties.

DOI： 10.1021/acsomega.4c05637

Administration of an antibody against apoptosis inhibitor of macrophage prevents aortic aneurysm progression in mice. Invited Reviewed

Fujii T, Yamawaki-Ogata A, Terazawa S, Narita Y, Mutsuga M

Scientific reports Vol. 14 ( 1 ) page： 15878 2024.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports

Apoptosis inhibitor of macrophage (AIM) is known to induce apoptosis resistance in macrophages and to exacerbate chronic inflammation, leading to arteriosclerosis. The role of AIM in aortic aneurysm (AA) remains unknown. This study examined the effects of an anti-AIM antibody in preventing AA formation and progression. In apolipoprotein E-deficient mice, AA was induced by subcutaneous angiotensin II infusion. Mice were randomly divided into two groups: (i) AIM group; weekly anti-murine AIM monoclonal antibody injection (n = 10), and (ii) IgG group; anti-murine IgG antibody injection as control (n = 14). The AIM group, compared with the IgG group, exhibited reduced AA enlargement (aortic diameter at 4 weeks: 2.1 vs. 2.7 mm, respectively, p = 0.012); decreased loss of elastic lamellae construction; reduced expression levels of IL-6, TNF-α, and MCP-1; decreased numbers of AIM-positive cells and inflammatory M1 macrophages (AIM: 1.4 vs. 8.0%, respectively, p = 0.004; M1 macrophages: 24.5 vs. 55.7%, respectively, p = 0.017); and higher expression of caspase-3 in the aortic wall (22.8 vs. 10.5%, respectively, p = 0.019). Our results suggest that administration of an anti-AIM antibody mitigated AA progression by alleviating inflammation and promoting M1 macrophage apoptosis.

DOI： 10.1038/s41598-024-66791-7

Development of novel waxy bone haemostatic agents composed of biodegradable polymers with osteogenic-enhancing peptides in rabbit models Invited Reviewed

Tsukasa Ohno, Hiroto Suenaga, Aika Yamawaki-Ogata, Kei Kanie, Ryuji Kato, Koichiro Uto, Mitsuhiro Ebara, Hideki Ito, Yuji Narita, Akihiko Usui, Masato Mutsuga

Interdisciplinary CardioVascular and Thoracic Surgery Vol. 37 ( 5 ) 2023.11

Language：English Publishing type：Research paper (scientific journal)

<jats:title>Abstract</jats:title>
<jats:p />
<jats:sec>
<jats:title>OBJECTIVES</jats:title>
<jats:p>The use of bone wax (BW) is controversial for sternal haemostasis because it increases the risk of wound infection and inhibits bone healing. We developed new waxy bone haemostatic agents made from biodegradable polymers containing peptides and evaluated them using rabbit models.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>METHODS</jats:title>
<jats:p>We designed 2 types of waxy bone haemostatic agents: peptide wax (PW) and non-peptide wax (NPW), which used poly(ε-caprolactone)-based biodegradable polymers with or without an osteogenesis-enhancing peptide, respectively. Rabbits were randomly divided into 4 groups based on treatment with BW, NPW, PW or no treatment. In a tibial defect model, the bleeding amount was measured and bone healing was evaluated by micro-computed tomography over 16 weeks. Bone healing in a median sternotomy model was assessed for 2 weeks using X-ray, micro-computed tomography, histological examination and flexural strength testing.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>RESULTS</jats:title>
<jats:p>The textures of PW and NPW (n = 12 each) were similar to that of BW and achieved a comparable degree of haemostasis. The crevice area of the sternal fracture line in the BW group was significantly larger than that in other groups (n = 10 each). The PW group demonstrated the strongest sternal flexural strength (n = 10), with complete tibial healing at 16 weeks. No groups exhibited wound infection, including osteomyelitis.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>CONCLUSIONS</jats:title>
<jats:p>Waxy biodegradable haemostatic agents showed satisfactory results in haemostasis and bone healing in rabbit models and may be an effective alternative to BW.</jats:p>
</jats:sec>

DOI： 10.1093/icvts/ivad170

Fabrication of pH-responsive poly(vinyl alcohol)-based microfibers crosslinked with copolymers containing benzoxaborole and carboxy groups Invited Reviewed

Momose, T; Takeuchi, K; Uchida, H; Saito, S; Nakada, K; Mutsuga, M; Yamawaki-Ogata, A; Narita, Y; Kotsuchibashi, Y

POLYMER Vol. 283 2023.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Polymer

Water-insoluble pH-responsive poly (vinyl alcohol) (PVA)-based microfibers were prepared using terpolymer of poly ([2-(methacryloyloxy)ethyl]trimethylammonium chloride (METAC)-co-methacrylic acid (MAAc)-co-5-methacrylamido-1,2-benzoxaborole (MAAmBO)) (TP) containing a quaternary ammonium cation, as well as carboxy and benzoxaborole groups. The surface of the microfibers could be positively charged by the permanent positive charge of the METAC units owing to the presence of the quaternary ammonium cation. The MAAc units formed a covalent bond with the hydroxy group of the vinyl alcohol unit by thermal treatment at 135 °C for 24 h, and the MAAmBO units formed a dynamic covalent bond with the diol group in PVA. After thermal crosslinking for 24 h, the PVA/TP microfibers exhibited almost 100% of the residual weight after immersion in water at 80 °C for 30 min. The diameters of the dried PVA/TP_25 wt% fibers were 21.4 ± 3.9 μm, and the swelling ratio was 1.65 ± 0.16 after immersing in water for 24 h. All microfibers showed a low degree of hemolysis (<5%). The PVA/TP_25 wt% fibers were strongly dyed with anionic acid red 1 (AR1) molecules at pH 3 and with cationic methylene blue (MB) molecules at pH 12, since the balance of the surface charge depend on the solution pH. These microfibers could be bundled and twisted to improve their mechanical properties; the required fracture energy after twisting was 2.30 ± 0.91 times higher than that before twisting.

DOI： 10.1016/j.polymer.2023.126236

A review of current status of cell-based therapies for aortic aneurysms. Invited Reviewed

Yamawaki-Ogata A, Mutsuga M, Narita Y

Inflammation and regeneration Vol. 43 ( 1 ) page： 40 2023.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Inflammation and Regeneration

An aortic aneurysm (AA) is defined as focal aortic dilation that occurs mainly with older age and with chronic inflammation associated with atherosclerosis. The aneurysmal wall is a complex inflammatory environment characterized by endothelial dysfunction, macrophage activation, vascular smooth muscle cell (VSMC) apoptosis, and the production of proinflammatory molecules and matrix metalloproteases (MMPs) secreted by infiltrated inflammatory cells such as macrophages, T and B cells, dendritic cells, neutrophils, mast cells, and natural killer cells. To date, a considerable number of studies have been conducted on stem cell research, and growing evidence indicates that inflammation and tissue repair can be controlled through the functions of stem/progenitor cells. This review summarizes current cell-based therapies for AA, involving mesenchymal stem cells, VSMCs, multilineage-differentiating stress-enduring cells, and anti-inflammatory M2 macrophages. These cells produce beneficial outcomes in AA treatment by modulating the inflammatory environment, including decreasing the activity of proinflammatory molecules and MMPs, increasing anti-inflammatory molecules, modulating VSMC phenotypes, and preserving elastin. This article also describes detailed studies on pathophysiological mechanisms and the current progress of clinical trials.

DOI： 10.1186/s41232-023-00280-8

Development of tissue adhesion barrier sheet functionalized with cell-selective adhesion peptides Invited Reviewed

Sugiyama, A; Kanie, K; Uto, K; Ebara, M; Ogata, A; Narita, Y; Kato, R

TISSUE ENGINEERING PART A Vol. 29 ( 13-14 ) 2023.7

Combinatorial analysis of tag peptides for enhancement of cell-adhesion short peptides Invited Reviewed

Fujimoto, A; Kanie, K; Ogata, A; Narita, Y; Kato, R

TISSUE ENGINEERING PART A Vol. 29 ( 13-14 ) 2023.7

Novel Functional Peptide for Next-Generation Vital Pulp Therapy Invited Reviewed

M. Watanabe, M. Okamoto, S. Komichi, H. Huang, S. Matsumoto, K. Moriyama, J. Ohshima, S. Abe, M. Morita, M. Ali, K. Takebe, I. Kozaki, A. Fujimoto, K. Kanie, R. Kato, K. Uto, M. Ebara, A. Yamawaki-Ogata, Y. Narita, Y. Takahashi, M. Hayashi

Journal of Dental Research Vol. 102 ( 3 ) page： 322 - 330 2023.3

Language：English Publishing type：Research paper (scientific journal)

Although vital pulp therapy should be performed by promoting the wound-healing capacity of dental pulp, existing pulp-capping materials were not developed with a focus on the pulpal repair process. In previous investigations of wound healing in dental pulp, we found that organic dentin matrix components (DMCs) were degraded by matrix metalloproteinase-20, and DMC degradation products containing protein S100A7 (S100A7) and protein S100A8 (S100A8) promoted the pulpal wound-healing process. However, the direct use of recombinant proteins as pulp-capping materials may cause clinical problems or lead to high medical costs. Thus, we hypothesized that functional peptides derived from recombinant proteins could solve the problems associated with direct use of such proteins. In this study, we identified functional peptides derived from the protein S100 family and investigated their effects on dental pulp tissue. We first performed amino acid sequence alignments of protein S100 family members from several mammalian sources, then identified candidate peptides. Next, we used a peptide array method that involved human dental pulp stem cells (hDPSCs) to evaluate the mineralization-inducing ability of each peptide. Our results supported the selection of 4 candidate functional peptides derived from proteins S100A8 and S100A9. Direct pulp-capping experiments in a rat model demonstrated that 1 S100A8-derived peptide induced greater tertiary dentin formation compared with the other peptides. To investigate the mechanism underlying this induction effect, we performed liquid chromatography–tandem mass spectrometry analysis using hDPSCs and the S100A8-derived peptide; the results suggested that this peptide promotes tertiary dentin formation by inhibiting inflammatory responses. In addition, this peptide was located in a hairpin region on the surface of S100A8 and could function by direct interaction with other molecules. In summary, this study demonstrated that a S100A8-derived functional peptide promoted wound healing in dental pulp; our findings provide insights for the development of next-generation biological vital pulp therapies.

DOI： 10.1177/00220345221135766

Administration of anti-inflammatory M2 macrophages suppresses progression of angiotensin II-induced aortic aneurysm in mice. Reviewed

Ashida S, Yamawaki-Ogata A, Tokoro M, Mutsuga M, Usui A, Narita Y

Scientific reports Vol. 13 ( 1 ) page： 1380 2023.1

Bi-layered carboxymethyl cellulose-collagen vitrigel dual-surface adhesion-prevention membrane Invited Reviewed

Yue Wang, Kei Kanie, Toshiaki Takezawa, Miki Horikawa, Kyoshiro Kaneko, Ayako Sugimoto, Aika Yamawaki-Ogata, Yuji Narita, Ryuji Kato

CARBOHYDRATE POLYMERS Vol. 285 page： 119223 2022.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

During wound regeneration, both cell adhesion and adhesion-inhibitory functions must be controlled in parallel. We developed a membrane with dual surfaces by merging the properties of carboxymethyl cellulose (CMC) and collagen using vitrification. A rigid membrane was formed by vitrification of a bi-layered CMC and collagen hydrogel without using cross-linking reagents, thus providing dual functions, strong cell adhesion-inhibition with the CMC layer, and cell adhesion with the collagen layer. We referred to this bi-layered CMC-collagen vitrigel membrane as "Bi-C-CVM" and optimized the process and materials. The introduction of the CMC layer conferred a "tough but stably wet" property to Bi-C-CVM. This enables Bi-C-CVM to cover wet tissue and make the membrane non-detachable while preventing tissue adhesion on the other side. The bi-layered vitrification procedure can expand the customizability of collagen vitrigel devices for wider medical applications.

DOI： 10.1016/j.carbpol.2022.119223

Alternative therapeutic strategy for existing aortic aneurysms using mesenchymal stem cell-derived exosomes. Invited Reviewed

Kozakai M, Narita Y, Yamawaki-Ogata A, Fujimoto KL, Mutsuga M, Tokuda Y, Usui A

Expert opinion on biological therapy Vol. 22 ( 1 ) page： 95 - 104 2022.1

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：Expert Opinion on Biological Therapy

Background: Several studies demonstrated the therapeutic potential of mesenchymal stem cell–derived exosomes (MSC-exs) based on their anti-inflammatory properties. The objective was to determine the therapeutic effects of MSC-exs on aortic aneurysms (AAs) caused by atherosclerosis. Research design and methods: Apolipoprotein E knockout mice with AAs induced by angiotensin II were injected with MSC-exs or saline as a control. The change in the diameter of the aorta was measured. The expression of AA-related proteins and the histology of the aortic wall were investigated at 1 week after treatment. MicroRNA and protein profiles of MSC-exs were examined. Results: MSC-exs significantly attenuated AA progression (2.04 ± 0.20 mm in the saline group and 1.34 ± 0.13 mm in the MSC-ex group, P = 0.004). In the MSC-ex group, the expression of IL-1β, TNF-α and MCP-1 decreased, and expression of IGF-1 and TIMP-2 increased. MSC-ex induced the M2 phenotype in macrophages and suppressed the destruction of the elastic lamellae in the aortic wall. MSC-exs contained high levels of 10 microRNAs that inhibit AA formation and 13 proteins that inhibit inflammation and promote extracellular matrix synthesis. Conclusions: MSC-ex might be a novel alternative therapeutic tool for treatment of existing AAs.

DOI： 10.1080/14712598.2022.2005575

Fabrication of Cationic Poly(vinyl alcohol) Films Cross-Linked Using Copolymers Containing Quaternary Ammonium Cations, Benzoxaborole, and Carboxy Groups. Invited Reviewed

Fujimoto K, Yamawaki-Ogata A, Narita Y, Kotsuchibashi Y

ACS omega Vol. 6 ( 27 ) page： 17531 - 17544 2021.7

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：ACS Omega

Water-insoluble cationic poly(vinyl alcohol) (PVA) films were fabricated using a mixed aqueous solution of PVA and poly([2-(methacryloyloxy)ethyl]trimethylammonium chloride (METAC)-co-methacrylic acid (MAAc)-co-5-methacrylamido-1,2-benzoxaborole (MAAmBO)) copolymer (3D). The surface of the PVA film is typically negatively charged, and simple fabrication methods for water-insoluble PVA films with cationic surface charges are required to expand their application fields. METAC, which has a permanent positive charge owing to the presence of a quaternary ammonium cation, was selected as the cationic unit. The MAAc and MAAmBO units were used as two types of cross-linking structures for the thermal cross-linking of the hydroxy and carboxy groups of the MAAc unit (covalent bonding) as well as the diol and benzoxaborole groups of the MAAmBO unit (dynamic covalent bonding). The films were thermally cross-linked at 135 °C for 4 h without the addition of materials. After immersion in surplus water at 80 °C for 3 h, the cross-linked PVA/3D films retained almost 100% of their weights. The ζ-potential of the water-insoluble PVA/3D film was 9.4 ± 0.8 mV. The PVA/3D film was strongly dyed using anionic acid red 1 (AR1) because of its positively charged surface. Interestingly, it could also be slightly dyed using cationic methylene blue (MB) and became transparent (original state) after immersion in water for 2 days. These results suggested that positive and negative charges coexisted in the PVA/3D film, and the surface properties were positively inclined. Moreover, the degree of hemolysis of the PVA/3D films was similar to that of the negative control, which showed high blood compatibility. To our knowledge, this is the first report on the fabrication of water-insoluble cationic PVA films using two types of cross-linking structures containing carboxy and benzoxaborole groups. The cross-linked PVA films were analyzed using Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), and contact angle (CA) and ζ-potential measurement, as well as by determining the mechanical properties, adsorption of charged molecules, and biocompatibility. These readily fabricated water-insoluble PVA films with positive charges can show potential applications in sensors, adsorption systems, and antimicrobial materials.

DOI： 10.1021/acsomega.1c02013

Long term efficacy and fate of a right ventricular outflow tract replacement using an elastomeric cardiac patch consisting of caprolactone and D,L-lactide copolymers Invited Reviewed

Kazuro L. Fujimoto, Aika Yamawaki-Ogata, Koichiro Uto, Akihiko Usui, Yuji Narita, Mitsuhiro Ebara

Acta Biomaterialia Vol. 123 page： 222 - 229 2021.3

Language：English Publishing type：Research paper (scientific journal)

For decades, researchers have investigated the ideal material for clinical use in the cardiovascular field. Several substitute materials are used clinically, but each has drawbacks. Recently we developed biodegradable and elastic poly(ε-caprolactone-co-D,L-lactide) (P(CL-DLLA)) copolymers by adjusting the CL/DLLA composition, and evaluated the long-term efficacy and outcomes of these copolymers when used for right ventricular outflow tract (RVOT) replacement. This P(CL-DLLA) material was processed into a circular patch and used to replace a surgical defect in the RVOT of adult rats. Control rats were implanted with expanded polytetrafluoroethylene (ePTFE). Histologic evaluation was performed at 8, 24, and 48 weeks post-surgery. All animals survived the surgery with no aneurysm formation or thrombus. In all periods, ePTFE demonstrated fibrous tissue. In contrast, at 8 weeks P(CL-DLLA) showed infiltration of macrophages and fibroblast-like cells into the remaining material. At 24 weeks, P(CL-DLLA) was absorbed completely, and muscle-like tissue was present with positive staining for α-sarcomeric actinin and cardiac troponin T (cTnT). At 48 weeks, the cTnT-positive area had increased. The biodegradable and elastic P(CL-DLLA) induced cardiac regeneration throughout the 48-week study period. Future application of this material as a cardiovascular scaffold seems promising. Statement of significance: Biomaterials for reconstruction of tissue deficiencies in cardiovascular surgery require having suitable mechanical properties for cardiac tissue and biodegradation resulting in native tissue growth. Several biodegradable polymers such as poly-ε-caprolactone (PCL) and polylactic acid (PLA) have excellent biocompatibility and already been widely used clinically. In general, PCL and PLA are quite mechanically rigid. Meanwhile, significant elasticity is required in the high-pressure environment of the heart while the material is being replaced by new tissue. The present study provides a novel four-armed crosslinked poly(ε-caprolactone-co-D,L-lactide) (i.e., P(CL-DLLA)) material for cardiac patch, which was demonstrated properties including tissue-compatible, super-elastic nature, that made it suitable for long-term, in vivo RVOT repair. This super-elastic biomaterial could be useful for reconstruction of various muscular tissues deficiencies.

DOI： 10.1016/j.actbio.2021.01.022

Therapeutic effect of allogeneic bone marrow–derived mesenchymal stromal cells on aortic aneurysms Invited Reviewed

Naohiro Akita, Yuji Narita, Aika Yamawaki-Ogata, Akihiko Usui, Kimihiro Komori

Cell and Tissue Research Vol. 383 ( 2 ) page： 781 - 793 2021.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media Deutschland GmbH

We previously reported the effectiveness of autologous mesenchymal stromal cells (MSCs) for the treatment of aortic aneurysm (AA), mediated mainly by these cells’ anti-inflammatory properties. In this study, we investigate whether the therapeutic effects of allogeneic MSCs on AA are the same as those of autologous MSCs. To examine the immune response to allogeneic MSCs, C57BL/6 lymphocytes were co-cultured with BALB/c MSCs for 5 days in vitro. Apolipoprotein E-deficient C57BL/6 mice with AA induced by angiotensin II were randomly divided into three groups defined by the following intravenous injections: (i) 0.2 ml of saline (n = 10, group S) as a control, (ii) 1 × 106 autologous MSCs (isolated from C57BL/6, n = 10, group Au) and (iii) 1 × 106 allogeneic MSCs (isolated from BALB/c, n = 10, group Al). Two weeks after injection, aortic diameters were measured, along with enzymatic activities of MMP-2 and MMP-9 and cytokine concentrations in AAs. Neither allogenic (BALB/c) MSCs nor autologous (C57BL/6) MSCs accelerated the proliferation of lymphocytes obtained from C57BL/6. Compared with group S, groups Au and Al had significantly shorter aortic diameters (group S vs Au vs Al
2.29 vs 1.40 vs 1.36 mm, respectively, p &lt
0.01), reduced MMP-2 and MMP-9 activities, downregulated IL-6 and MCP-1 and upregulated expression of IGF-1 and TIMP-2. There were no differences in these results between groups Au and Al. Thus, our study suggests that treatment with allogeneic MSCs improves chronic inflammation and reduced aortic dilatation. These effects were equivalent to those of autologous MSCs in established mouse models of AA.

DOI： 10.1007/s00441-020-03295-6

Performance of a biodegradable composite with hydroxyapatite as a scaffold in pulp tissue repair Reviewed

Motoki Okamoto, Sayako Matsumoto, Ayato Sugiyama, Kei Kanie, Masakatsu Watanabe, Hailing Huang, Manahil Ali, Yuki Ito, Jiro Miura, Yujiro Hirose, Koichiro Uto, Mitsuhiro Ebara, Ryuji Kato, Aika Yamawaki-Ogata, Yuji Narita, Shigetada Kawabata, Yusuke Takahashi, Mikako Hayashi

Polymers Vol. 12 ( 4 ) page： 937 - 937 2020.4

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

Vital pulp therapy is an important endodontic treatment. Strategies using growth factors and biological molecules are effective in developing pulp capping materials based on wound healing by the dentin-pulp complex. Our group developed biodegradable viscoelastic polymer materials for tissue-engineered medical devices. The polymer contents help overcome the poor fracture toughness of hydroxyapatite (HAp)-facilitated osteogenic differentiation of pulp cells. However, the composition of this novel polymer remained unclear. This study evaluated a novel polymer composite, P(CL-co-DLLA) and HAp, as a direct pulp capping carrier for biological molecules. The biocompatibility of the novel polymer composite was evaluated by determining the cytotoxicity and proliferation of human dental stem cells in vitro. The novel polymer composite with BMP-2, which reportedly induced tertiary dentin, was tested as a direct pulp capping material in a rat model. Cytotoxicity and proliferation assays revealed that the biocompatibility of the novel polymer composite was similar to that of the control. The novel polymer composite with BMP-2-induced tertiary dentin, similar to hydraulic calcium-silicate cement, in the direct pulp capping model. The BMP-2 composite upregulated wound healing-related gene expression compared to the novel polymer composite alone. Therefore, we suggest that novel polymer composites could be effective carriers for pulp capping.

DOI： 10.3390/polym12040937

Hydrogen water alleviates obliterative airway disease in mice. Reviewed

Ozeki N, Yamawaki-Ogata A, Narita Y, Mii S, Ushida K, Ito M, Hirano SI, Kurokawa R, Ohno K, Usui A

General thoracic and cardiovascular surgery Vol. 68 ( 2 ) page： 158 - 163 2020.2

The oral administration of colchicine prevents the progression of aortic aneurysm Invited Reviewed

Okawa H., Yamawaki-Ogata A., Narita Y., Munakata H., Hashizume R., Usui A.

EUROPEAN HEART JOURNAL Vol. 40 page： 1882 - 1882 2019.10

Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation. Invited Reviewed

Kawai Y, Narita Y, Yamawaki-Ogata A, Usui A, Komori K

BioMed research international Vol. 2019 page： 9104680 2019

The oral administration of clarithromycin prevents the progression and rupture of aortic aneurysm. Reviewed International journal

Uchida W, Narita Y, Yamawaki-Ogata A, Tokuda Y, Mutsuga M, Lee Fujimoto K, Abe T, Oshima H, Usui A

Journal of vascular surgery Vol. 68 ( 6S ) page： 82S - 92S.e2 2018.12

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: The pathogenesis of aortic aneurysm (AA) is associated with chronic inflammation in the aortic wall with increased levels of matrix metalloproteinases (MMPs). Clarithromycin (CAM) has been reported to suppresses MMP activity. In this study, we investigated whether CAM could prevent the formation and rupture of AA. METHODS: Male apolipoprotein E-deficient mice (28-30 weeks of age) were infused with angiotensin II for 28 days. CAM (100 mg/kg/d) or saline (as a control) was administered orally to the mice every day (CAM group, n = 13; control group, n = 13). After the administration period, the aortic diameter, elastin content, macrophage infiltration, MMP levels, and levels of inflammatory cytokines, including nuclear factor κB (NF-κB), were measured. RESULTS: The aortic diameter was significantly suppressed in the CAM group (P < .001). No rupture death was observed in the CAM group in contrast to five deaths (38%) in the control group (P < .01). CAM significantly suppressed the degradation of aortic elastin (56.3% vs 16.5%; P < .001) and decreased the infiltration of inflammatory macrophages (0.05 vs 0.16; P < .01). Compared with the controls, the enzymatic activity of MMP-2 and MMP-9 was significantly reduced in the CAM group (MMP-2, 0.15 vs 0.56 [P < .01]; MMP-9, 0.12 vs 0.60 [P < .01]), and the levels of interleukin 1β (346.6 vs 1066.0; P < .05), interleukin 6 (128.4 vs 346.2; P < .05), and phosphorylation of NF-κB were also decreased (0.3 vs 2.0; P < .01). CONCLUSIONS: CAM suppressed the progression and rupture of AA through the suppression of inflammatory macrophage infiltration, a reduction in MMP-2 and MMP-9 activity, and the inhibition of elastin degradation associated with the suppression of NF-κB phosphorylation.

DOI： 10.1016/j.jvs.2017.12.047

The Possibility of Clarithromycin for the Treatment of Type B Aortic Dissection. Invited Reviewed

Uchida Wataru, Yamawaki-Ogata Aika, Hideki Ito, Sachie Tarazawa, Tokuda Yoshiyuki, Mutsuga Masato, Fujimoto Kazuro L., Yuji Narita, Usui Akihiko

CIRCULATION Vol. 138 page： . 2018.11

Evaluation of the Bactericidal and Fungicidal Activities of Poly([2-(methacryloyloxy)ethyl]trimethyl Ammonium Chloride)(Poly (METAC))-Based Materials. Invited Reviewed

Shiga T, Mori H, Uemura K, Moriuchi R, Dohra H, Yamawaki-Ogata A, Narita Y, Saito A, Kotsuchibashi Y

Polymers Vol. 10 ( 9 ) 2018.8

Effects of exosomes derived from the induced pluripotent stem cells on skin wound healing Invited Reviewed

Hitoshi Kobayashi, Katsumi Ebisawa, Miki Kambe, Takatoshi Kasai, Hidetaka Suga, Kae Nakamura, Yuji Narita, Aika Ogata, Yuzuru Kamei

Nagoya Journal of Medical Science Vol. 80 ( 2 ) page： 141 - 153 2018.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Nagoya University

Recently, the effects of stem cell supernatants or exosomes, such as skin wounds, have attracted attention. However, the effects of the induced pluripotent stem (iPS) cell-derived exosomes (iPS-Exos) have not been investigated in detail. Here, we investigated the effects of iPS-Exos on skin wound healing using an animal model. We isolated iPS-Exos from the iPS cell culture media. Control exosomes were isolated from unused iPS cell culture media (M-Exos). We first observed the morphologic characteristics of the isolated exosomes and examined the expression of surface antigens. The effects of these exosomes on the migratory response and proliferation of fibroblasts were analyzed as well. Additionally, using a diabetic ulcer model, the effects of iPS-Exos and M-Exos on skin wound healing were investigated. Transmission electron microscope analysis demonstrated that the size of iPS-Exos (120 ± 25 nm) was significantly larger than that of M-Exos (≤ 100 nm). Flow cytometry analyses showed that iPS-Exos were positive for CD9, CD63, and CD81, whereas they were negative for HLA-ABC and -DR expression. The migratory ability of fibroblasts cocultured with iPS-Exos was shown to be higher than that of the cells cocultured with M-Exos, as demonstrated using scratch assay. Skin wound healing model results showed that the administration of iPS-Exos results in a faster wound closure compared with that observed in the M-Exo group. In conclusion, the results obtained here indicate that iPS-Exos may promote the migration of fibroblasts in vitro and in vivo, suggesting the possibility of using iPS-Exos for the treatment of diabetic ulcer.

DOI： 10.18999/nagjms.80.2.141

Bone marrow-derived mesenchymal stromal cells regress aortic aneurysm via the NF-kB, Smad3 and Akt signaling pathways Reviewed

Aika Yamawaki-Ogata, Hideki Oshima, Akihiko Usui, Yuji Narita

CYTOTHERAPY Vol. 19 ( 10 ) page： 1167 - 1175 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

Background aims. We have confirmed that aortic aneurysm (AA) can be regressed by the administration of bone marrow derived mesenchymal stromal cells (BM-MSCs). We investigated the kinetics of signaling pathways in AA following treatment with BM-MSCs. Methods. Angiotensin II-infused apolipoprotein E-deficient mice were treated by intravenous injection of 1 x 10(6) BM-MSCs in 0.2 mL saline (BM-MSCs group, n = 5) or 0.2 mL saline (saline group, n = 5). Mice were sacrificed 2 weeks after injection and subjected to measurements of the incidence of AA and levels of phosphorylated proteins. Levels of proteins in conditioned media of BM-MSCs were also measured. Results. The incidence of AA in the BM-MSCs group was reduced (BM-MSC 40% versus saline 100%, P < 0.05). Levels of pNF-kB and pSTAT1 were reduced (pNF-kB: 0.28 versus 0.45 unit/mL, P < 0.05, pSTAT1: 0.16 versus 0.34, P < 0.05), whereas levels of pAkt and pSmad3 were elevated (pAkt: 0.13 versus 0.07, P < 0.01, pSmad3: 1.07 versus 0.47, P < 0.05) in the BM-MSCs group. The levels of pNF-kB, pAkt, and pSmad3 were correlated with aortic diameters. Trophic factors including IGFPB-3, NRF, Activin A and PDGF-AA were secreted from BM-MSCs (IGFBP-3: 35.2 pg/mL, NRF: 3.1 pg/mL, Activin A: 3.1 pg/mL, PDGF-AA: 0.45 pg/mL). Conclusions. Our findings suggested that the therapeutic mechanism of BM-MSC mediated AA regression could contribute to regulation of the NF-kB, Smad3 and Akt signaling pathways. In addition, paracrine actions by factors including NRF, IGFBP-3, Activin A and PDGF-AA might have affected these signaling pathways.

DOI： 10.1016/j.jcyt.2017.07.010

Clarithromycinの大動脈瘤発生抑制効果の作用機序の解明 Invited Reviewed

内田亘, 成田裕司, 緒方藍歌, 伊藤英樹, 山名孝治, 寺澤幸枝, 徳田順之, 六鹿雅登, 藤本和朗, 阿部知伸, 大島英揮, 碓氷章彦

日本心臓血管外科学会学術総会抄録集 Vol. 47回 page： 850 - 850 2017.2

Isolation and characterisation of peripheral blood-derived feline mesenchymal stem cells Reviewed

Keiichi Sato, Aika Yamawaki-Ogata, Isamu Kanemoto, Akihiko Usui, Yuji Narita

VETERINARY JOURNAL Vol. 216 page： 183 - 8 2016.10

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

The aim of this study was to isolate mesenchymal stem cells (MSCs) from feline peripheral blood (fPB-MSCs) and to characterise the cells' in vitro properties. The mononuclear cell fractions were isolated from venous blood of cats by density gradient centrifugation and cultured on plastic dishes under various culture conditions to isolate MSCs. When these cells were cultured with 5% autologous plasma (AP) and 10% foetal bovine serum (FBS), adherent spindle shaped fibroblast-like cells (fPB-MSCs) were obtained from 15/22 (68%) cats. These cells were isolated only from medium containing both AP and FBS. The morphology of these MSCs was similar to those isolated from other species and from other feline tissues. fPB-MSCs expanded steadily up to 5-6 passages, but had increased population doubling time during passaging and almost all cells stopped proliferation at passages 7-9. These cells expressed CD44 and CD90, and were mostly negative for major histocompatibility class II and CD4. The cells could be induced to differentiate into adipogenic, osteogenic and chondrogenic cell lineages. These findings indicate that fPB-MSCs can be generated but appear to require specific culture conditions. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tvjl.2016.08.009

大動脈瘤に対する幹細胞療法効果のメカニズムに関して Invited Reviewed

成田裕司, 緒方藍歌, 小坂井基史, 藤本和朗, 六鹿雅登, 阿部知伸, 大島英揮, 碓氷章彦

日本心臓血管外科学会学術総会抄録集 Vol. 46回 page： OP10 - 2 2016.2

Exosomes Obtained from Mesenchymal Stem Cells as a Novel Therapeutic Tool for Aortic Aneurysm Invited Reviewed

A. Yamawaki-ogata, M. Kosakai, A. Usui, Y. Narita

TISSUE ENGINEERING PART A Vol. 21 page： S211 - S212 2015.9

Skin-Derived Precursor Cells Promote Wound Healing in Diabetic Mice Reviewed

Hideyoshi Sato, Katsumi Ebisawa, Keisuke Takanari, Shunjiro Yagi, Kazuhiro Toriyama, Aika Yamawaki-Ogata, Yuzuru Kamei

ANNALS OF PLASTIC SURGERY Vol. 74 ( 1 ) page： 114 - 20 2015.1

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Background: Impaired wound healing as one of the complications arising from diabetes mellitus is a serious clinical issue. Recently, various cell therapies have been reported for promotion of wound healing. Skin-derived precursor cells (SKPs) are multipotent adult stem cells with the tendency to differentiate into neurons. We investigated the potency of promoting diabetic wound healing by the application of SKPs.
Methods: Skin-derived precursor cells isolated from diabetic murine skin were cultured in sphere formation medium. At passage 2, they were suspended in phosphate-buffered saline (PBS), and applied topically to full-thickness excisional cutaneous wounds in diabetic mice. Application of PBS served as controls (n = 21 for each group; n = 42 total).
Time to closure and percentage closure were calculated by morphometry. Wounds were harvested at 10 and 28 days and then processed, sectioned, and stained (CD31, alpha-smooth muscle actin, and neurofilament heavy chain) to quantify vascularity and neurofilaments.
Results: Wounds treated with SKPs demonstrated a significantly decreased time to closure (18.63 days) compared with PBS-control wounds (21.72 days, P > 0.01), and a significant improvement in percentage closure at 7, 10, 14, and 18 days compared with PBS-control wounds (P > 0.01). Histological analysis showed that the Capillary Score (the number of vessels/mm(2)) was significantly higher in SKP-treated wounds at day 10 but not at day 28. Nerve Density (the number of neurofilaments/mm(2)) had increased significantly in SKP-treated wounds at day 28 compared with control group. Some applied SKPs were stained by neurofilament heavy chain, which demonstrates that SKPs directly differentiated into neurons.
Conclusions: Skin-derived precursor cells promoted diabetic wound healings through vasculogenesis at the early stage of wound healing. Skin-derived precursor cells are a possible therapeutic tool for diabetic impaired wound healing.

DOI： 10.1097/SAP.0000000000000342

Mesenchymal stem cells for treatment of aortic aneurysms. Reviewed

Yamawaki-Ogata A, Hashizume R, Fu XM, Usui A, Narita Y

World journal of stem cells Vol. 6 ( 3 ) page： 278 - 87 2014.7

Therapeutic potential of bone marrow-derived mesenchymal stem cells in formed aortic aneurysms of a mouse model Reviewed

Aika Yamawaki-Ogata, Xianming Fu, Ryotaro Hashizume, Kazuro L. Fujimoto, Yoshimori Araki, Hideki Oshima, Yuji Narita, Akihiko Usui

EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY Vol. 45 ( 5 ) page： e156 - 65 2014.5

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS INC

An aortic aneurysm (AA) is caused by atherosclerosis with chronic inflammation. Mesenchymal stem cells (MSCs) have potential anti-inflammatory properties. In this study, we examined whether an already-formed AA can be treated by intravenous injection of bone marrow-derived (BM)-MSCs in a mouse model.
AA was induced in apolipoprotein E-deficient mice by angiotensin II-infusion for 28 days through sub-cutaneous osmotic mini-pumps. After that, 1 x 10(6) BM-MSCs (in 0.2 ml saline) or 0.2 ml saline as a control was injected via the tail vein. Mice were sacrificed at 2 (saline group n = 10, BM-MSC group n = 10), 4 (saline group n = 6, BM-MSC group n = 7) or 8 weeks (saline group n = 5, BM-MSC group n = 6) after injection. The aortic tissues of each group were dissected. Aortic diameter, elastin content, matrix metalloproteinase (MMP)-2 and -9 enzymatic activity and cytokine concentrations were measured, as was macrophage infiltration, which was also evaluated histologically.
The incidence of AA in the BM-MSC group was reduced at 2 weeks (BM-MSC 40% vs saline 100%, P < 0.05), and aortic diameter was reduced at 2 and 4 weeks (2 weeks: 1.40 vs 2.29 mm, P < 0.001; 4 weeks: 1.73 vs 2.32 mm, P < 0.05). The enzymatic activities of MMP-2 and -9 were reduced in the BM-MSC group at 2 weeks (active-MMP-2: 0.28 vs 0.45 unit/ml, P < 0.05; active-MMP-9: 0.16 vs 0.34 unit/ml, P < 0.05). Inflammatory cytokines were down-regulated in the BM-MSC group (interleukin-6: 2 weeks: 1475.6 vs 3399.5 pg/ml, P < 0.05; 4 weeks: 2184.7 vs 3712.8 pg/ml, P < 0.05 and monocyte chemotactic protein-1: 2 weeks: 208.0 vs 352.7 pg/ml, P < 0.05) and insulin-like growth factor (IGF)-1 and tissue inhibitor of metalloproteinase (TIMP)-2 were up-regulated in the BM-MSC group at 2 weeks (IGF-1: 4.7 vs 2.0 ng/ml, P < 0.05; TIMP-2: 9.5 vs 4.0 ng/ml, P < 0.001). BM-MSC injection inhibited infiltration of M1 macrophages and preserved the construction of elastin.
Our results suggest that BM-MSCs might be an effective treatment for AA. Further investigation is necessary to optimize the injected dosage and the frequency of BM-MSCs to prevent a transient effect.

DOI： 10.1093/ejcts/ezu018

大動脈瘤に対する幹細胞療法投与法による大動脈瘤進展抑制効果の違い Invited Reviewed

成田裕司, 緒方藍歌, 符顕明, 荒木善盛, 阿部知伸, 大島英揮, 碓氷章彦

日本心臓血管外科学会雑誌 Vol. 43 ( Suppl. ) page： 263 - 263 2014.1

Intravenous administration of mesenchymal stem cells prevents angiotensin II-induced aortic aneurysm formation in apolipoprotein E-deficient mouse Reviewed

Xian-ming Fu, Aika Yamawaki-Ogata, Hideki Oshima, Yuichi Ueda, Akihiko Usui, Yuji Narita

JOURNAL OF TRANSLATIONAL MEDICINE Vol. 11 ( 1 ) page： 175 2013.7

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Mesenchymal stem cells (MSCs) are known to be capable of suppressing inflammatory responses. We previously reported that intra-abdominal implantation of bone marrow-derived MSCs (BM-MSCs) sheet by laparotomy attenuated angiotensin II (AngII)-induced aortic aneurysm (AA) growth in apolipoprotein E-deficient (apoE(-/-)) mice through anti-inflammation effects. However, cell delivery by laparotomy is invasive; we here demonstrated the effects of multiple intravenous administrations of BM-MSCs on AngII-induced AA formation.
Methods: BM-MSCs were isolated from femurs and tibiae of male apoE(-/-) mice. Experimental AA was induced by AngII infusion for 28 days in apoE(-/-) mice. Mice received weekly intravenous administration of BM-MSCs (n=12) or saline (n=10). After 4 weeks, AA formation incidence, aortic diameter, macrophage accumulation, matrix metalloproteinase (MMP)' activity, elastin content, and cytokines were evaluated.
Results: AngII induced AA formation in 100% of the mice in the saline group and 50% in the BM-MSCs treatment group (P < 0.05). A significant decrease of aortic diameter was observed in the BM-MSCs treatment group at ascending and infrarenal levels, which was associated with decreased macrophage infiltration and suppressed activities of MMP-2 and MMP-9 in aortic tissues, as well as a preservation of elastin content of aortic tissues. In addition, interleukin (IL)-1 beta, IL-6, and monocyte chemotactic protein-1 significantly decreased while insulin-like growth factor-1 and tissue inhibitor of metalloproteinases-2 increased in the aortic tissues of BM-MSCs treatment group.
Conclusions: Multiple intravenous administrations of BM-MSCs attenuated the development of AngII-induced AA in apoE(-/-) mice and may become a promising alternative therapeutic strategy for AA progression.

DOI： 10.1186/1479-5876-11-175

Prevention of arterial graft spasm in rats using a vasodilator-eluting biodegradable nano-scaled fibre Reviewed

Kei Yagami, Aika Yamawaki-Ogata, Makoto Satake, Hiroaki Kaneko, Hideki Oshima, Akihiko Usui, Yuichi Ueda, Yuji Narita

Interactive Cardiovascular and Thoracic Surgery Vol. 17 ( 1 ) page： 16 - 22 2013.7

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVESArterial graft spasm occasionally causes circulatory collapse immediately following coronary artery bypass graft. The aim of this study is to evaluate the efficacy of our developed materials, which were composed of milrinone (phosphodiesterase III inhibitor) or diltiazem (calcium-channel blocker), with nano-scaled fibre made of biodegradable polymer to prevent arterial spasm.METHODSMilrinone- or diltiazem-releasing biodegradable nano-scaled fibres were fabricated by an electrospinning procedure. In vivo milrinone- or diltiazem-releasing tests were performed to confirm the sustained release of the drugs. An in vivo arterial spasm model was established by subcutaneous injection of noradrenalin around the rat femoral artery. Rats were randomly divided into four groups as follows: those that received 5 mg of milrinone-releasing biodegradable nano-scaled fibre (group M, n = 14)
5 mg of diltiazem-releasing biodegradable nano-scaled fibre (group D, n = 12)
or those that received fibre without drugs (as a control
group C, n = 14) implanted into the rat femoral artery. In the fourth group, sham operation was performed (group S, n = 10). One day after the implantation, noradrenalin was injected in all groups. The femoral arterial blood flow was measured continuously before and after noradrenalin injection. The maximum blood flow before noradrenalin injection and minimum blood flow after noradrenalin injection were measured.RESULTSIn vivo drug-releasing test revealed that milrinone-releasing biodegradable nano-scaled fibre released 78% of milrinone and diltiazem-releasing biodegradable nano-scaled fibre released 50% diltiazem on the first day. The ratios of rat femoral artery blood flow after/before noradrenalin injection in groups M (0.74 ± 0.16) and D (0.72 ± 0.05) were significantly higher than those of groups C (0.54 ± 0.09) and S (0.55 ± 0.16) (P &lt
0.05).CONCLUSIONNoradrenalin-induced rat femoral artery spasm was inhibited by the implantation of milrinone-releasing biodegradable nano-scaled fibre or diltiazem-releasing biodegradable nano-scaled fibre. These results suggested that our materials might be effective for the prevention of arterial graft spasm after coronary artery bypass graft. © 2013 The Author. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

DOI： 10.1093/icvts/ivt092

Long-term results of tissue-engineered small-caliber vascular grafts in a rat carotid arterial replacement model Reviewed

KUWABARA Fumiaki, NARITA Yuji, YAMAWAKI OGATA Aika, SATAKE Makoto, KANEKO Hiroaki, OSHIMA Hideki, USUI Akihiko, UEDA Yuichi

Vol. 15 ( 4 ) page： 399 - 405 2012.12

Long-term results of tissue-engineered small-caliber vascular grafts in a rat carotid arterial replacement model Reviewed

Fumiaki Kuwabara, Yuji Narita, Aika Yamawaki-Ogata, Makoto Satake, Hiroaki Kaneko, Hideki Oshima, Akihiko Usui, Yuichi Ueda

JOURNAL OF ARTIFICIAL ORGANS Vol. 15 ( 4 ) page： 399 - 405 2012.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

The concept of tissue engineered small-caliber vascular grafts (TE-SCVGs) is theoretically ideal. In this study, we evaluated the long-term (more than 1 year) course of TE-SCVGs using a rat carotid arterial replacement model. We fabricated a TE-SCVG scaffold (0.7 mm in diameter) with electrospun nano-scale fibers. Poly-epsilon-caprolactone was used as a biodegradable polymer. These artificial vessels were then used in carotid arterial replacement performed on Sprague-Dawley rats. The implanted grafts were removed at an early phase (1, 2, 6 weeks), middle phase (12, 24 weeks), and late phase (48, 72 weeks) after implantation. Twenty-nine patent grafts from among the 40 implanted grafts (patency 72.5 %) could be evaluated. No aneurysm formation was observed during the follow-up period. Endothelial cells positive for immunostaining with von Willebrand factor were found to be already attached to the inner surface of the TE-SCVGs in the early phase. The percentage of smooth muscle cell specific marker (a-smooth muscle actin and calponin with fluorescent immunostaining) positive cells, which seemed to be mesenchymal cells in the graft wall, increased with time, while, in contrast, the scaffold material decreased. Even after 72 weeks, however, although the scaffold material had degraded, it had not disappeared completely. These results show that the novel TE-SCVGs we developed were still functioning in the rat carotid arterial circulation after more than 1 year. However, further investigations will be required with regard to regeneration of the SMC layer and the complete degradation of graft materials.

DOI： 10.1007/s10047-012-0652-6

Development of novel statin releasing biodegradable nano-scaled fiber for bone tissue engineering Invited Reviewed

Wadagaki R., Mizuno D., Yamawaki-Ogata A., Fu X., Satake M., Kaneko H., Ueda M., Narita Y.

JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE Vol. 6 page： 329 - 329 2012.9

Possibility of cell therapy for aortic aneurysm Invited Reviewed

A. Yamawaki-Ogata, X. Fu, R. Hashizume, H. Oshima, A. Usui, Y. Narita

JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE Vol. 6 page： 149 - 149 2012.9

PS-106-2 動脈グラフと攣縮予防のための血管拡張薬徐放生体吸収性ナノファイバーの開発(PS-106 心血管基礎,ポスターセッション,第112回日本外科学会定期学術集会) Reviewed

八神啓, 成田裕司, 緒方藍歌, 佐竹真, 兼子博章, 大島英揮, 碓氷章彦, 上田裕一

日本外科学会雑誌 Vol. 113 ( 2 ) page： 703 2012.3

Effect of GDF-5 and BMP-2 on the expression of tendo/ligamentogenesis-related markers in human PDL-derived cells. Invited Reviewed

Inoue M, Ebisawa K, Itaya T, Sugito T, Yamawaki-Ogata A, Sumita Y, Wadagaki R, Narita Y, Agata H, Kagami H, Ueda M

Oral diseases Vol. 18 ( 2 ) page： 206 - 12 2012.3

Novel Small-Caliber Vascular Grafts With Trimeric Peptide for Acceleration of Endothelialization Reviewed

Fumiaki Kuwabara, Yuji Narita, Aika Yamawaki-Ogata, Kei Kanie, Ryuji Kato, Makoto Satake, Hiroaki Kaneko, Hideki Oshima, Akihiko Usui, Yuichi Ueda

ANNALS OF THORACIC SURGERY Vol. 93 ( 1 ) page： 156 - 63; discussion 163 2012.1

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Background. Both rapid endothelialization and the prevention of intimal hyperplasia are essential to improve the patency of small-caliber vascular grafts (SCVGs). Using the peptide array based screening system, we identified the peptide CAG (cysteine-alanine-glycine), which has a high affinity for endothelial cells and a low adhesive property for smooth muscle cells (SMCs). In this article, we report an in vivo analysis of novel vascular grafts that were constructed with a biodegradable polymer (poly-epsilon-caprolactone [PCL]) containing CAG peptide.
Methods. The novel SCVG, which measured 0.7 mm in diameter and 7 mm in length, was fabricated using the electrospinning technique. Carotid arterial replacement was performed on Sprague-Dawley rats using SCVGs with (group CAG) or without CAG (group C). Histologic and biochemical assessments were performed at 1, 2, and 6 weeks after implantation.
Results. The ratio of endothelialization was significantly higher in group CAG compared with group C (CAG versus C, 64.4 +/- 20.0% versus 42.1 +/- 8.9% at 1 week; p = 0.017; 98.2 +/- 2.3% versus 72.7 +/- 12.9% at 2 weeks; p = 0.001; and 97.4 +/- 4.6% versus 76.7 +/- 5.4% at 6 weeks; p < 0.001). Additionally, Western blot analysis showed that the level of endothelial nitric oxide synthase (eNOS) at 1 week in group CAG was significantly higher than that in group C (CAG versus C, 1.20 +/- 0.37 versus 0.34 +/- 0.16; p = 0.013), and that alpha-smooth muscle actin (ASMA) at 6 weeks in group CAG was significantly lower than that in group C (CAG versus C, 0.89 +/- 0.06 versus 1.25 +/- 0.22; p = 0.04).
Conclusions. The graft with CAG promoted rapid endothelialization and the potential for inhibition of intimal hyperplasia. (Ann Thorac Surg 2012;93:156-63) (C) 2012 by The Society of Thoracic Surgeons

DOI： 10.1016/j.athoracsur.2011.07.055

Mesenchymal stem cells attenuate angiotensin II-induced aortic aneurysm growth in apolipoprotein E-deficient mice Reviewed

Ryotaro Hashizume, Aika Yamawaki-Ogata, Yuichi Ueda, William R. Wagner, Yuji Narita

JOURNAL OF VASCULAR SURGERY Vol. 54 ( 6 ) page： 1743 - 52 2011.12

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

01,Objective:Aortic aneurysm (AA) is associated with loss of elastin and structural integrity, accompanied by increased matrix metalloproteinase (MMP) expression. These processes are supported by inflammatory macrophages, with mediators such as tumor necrosis factor-alpha (TNF-alpha). Mesenchymal stem cells (MSCs) contribute to aortic remodeling. Therefore, to clarify whether MSCs might be useful for AA cell therapy, we examined the effect of MSCs on vascular smooth muscle cells (SMCs) and macrophages in vitro, on aortic tissue ex vivo, and on aorta in vivo.
Methods: Murine macrophages and SMCs were cultured, with or without bone marrow-derived murine MSCs, for 96 hours in vitro. Gene expression of MMPs and TNF-alpha from macrophages and that of elastin from SMCs were measured. The murine aortic tissues were cultured with or without MSCs for up to 14 days, followed by measurement of MMP enzyme activity and elastin content. The in vivo aneurysm model used apolipoprotein E-deficient (apoE(-/-)) male mice receiving angiotensin (Ang II) infusion for 28 days. MSCs were implanted by laparotomy to the abdominal aortic adventitial surface from the superior mesenteric artery origin to the left renal artery. Age-matched apoE(-/-) mice with or without Ang II infusion were used for control groups. At the end point, aortic diameter, elastin content, MMPs' activity, and cytokines expressed, including interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), TNF-alpha, insulin-like growth factor-1 (IGF-1), and tissue inhibitor of metalloproteinases-1 (TIMP-1) were quantified.
Results: MSCs suppressed MMP-2 with or without MSCs (2.59 vs 3.94, P < .05), MMP-9 (5.83 vs 9.70, P < .05), and TNF-alpha (2.79 vs 3.38, P < .05) expression in macrophages, and promoted elastin expression in SMCs (19.35 vs 3.23, P < .05) in vitro. MSCs also decreased active MMP-2 activity (0.310 vs 0.0609 U/mu L, P < .05) and preserved elastin content (68.05 vs 40.29 mu g/mg, P < .05) ex vivo. AA development was site-specifically inhibited (0.73 vs 1.04 mm aortic diameter, P < .05) and elastin content was preserved (46.9 vs 25.6 mu g/mg, P < .05) at 4 weeks. Downregulation of MMPs and IL-6, MCP-1, and TNF-alpha, and upregulation of IGF-1 and TIMP-1 were demonstrated with MSC implantation in vivo.
Conclusions: MSC implantation inhibits Ang II-induced AA development in apoE(-/-) mice through elastin preservation in the aortic wall and is associated with attenuated levels of MMTs and inflammatory cytokines. (J Vase Surg 2011;54:1743-52.)

DOI： 10.1016/j.jvs.2011.06.109

Osteogenic Induction of Bone Marrow-Derived Stromal Cells on Simvastatin-Releasing, Biodegradable, Nano- to Microscale Fiber Scaffolds Reviewed

Ryu Wadagaki, Daiki Mizuno, Aika Yamawaki-Ogata, Makoto Satake, Hiroaki Kaneko, Sumitaka Hagiwara, Noriyuki Yamamoto, Yuji Narita, Hideharu Hibi, Minoru Ueda

ANNALS OF BIOMEDICAL ENGINEERING Vol. 39 ( 7 ) page： 1872 - 81 2011.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Tissue engineering is an effective approach for the treatment of bone defects. Statins have been demonstrated to promote osteoblastic differentiation of bone marrow-derived stromal cells (BMSCs). Electrospun biodegradable fibers have also shown applicability to drug delivery in the form of bone tissue engineered scaffolds with nano- to microscale topography and high porosity similar to the natural extracellular matrix (ECM). The aim of this study was to investigate the feasibility of a simvastatin-releasing, biodegradable, nano- to microscale fiber scaffold (SRBFS) for bone tissue engineering with BMSCs. Simvastatin was released from SRBFS slowly. BMSCs were observed to spread actively and rigidly adhere to SRBFS. BMSCs on SRBFS showed an increase in alkaline phosphatase activity 2 weeks after cell culture. Furthermore, osteoclastogenesis was suppressed by SRBFS in vitro. The new bone formation and mineralization in the SRBFS group were significantly better than in the biodegradable fiber scaffold (BFS) without simvastatin 12 weeks after implantation of the cell-scaffold construct into an ectopic site on the murine back. These results suggest that SRBFS promoted osteoblastic differentiation of BMSCs in vitro and in vivo, and demonstrate feasibility as a bone engineering scaffold.

DOI： 10.1007/s10439-011-0327-0

Biodegradable nanofibers in cardiovascular medicine: Drug delivery application Invited Reviewed

Masato Mutsuga, Aika Yamawaki-Ogata, Makoto Satake, Hiroaki Kaneko, Yuichi Ueda, Yuji Narita

Nanomedicine and the Cardiovascular System page： 345 - 369 2011.1

Language：English Publishing type：Part of collection (book) Publisher：CRC Press

Nanotechnology will play a great role in the field of cardiovascular disease in the near future. It will be a very useful tool in drug delivery approaches to treat cardiovascular disease. Nanomedicine (medical treatment using nanotechnology) can be considered a refinement of molecular medicine and integrates advances in genomics and proteomics to facilitate the development of personalized medicine. Nanomedicine for cardiovascular disease has focused on materials at super-molecular levels to deliver increased therapeutic efficacy and diminish adverse effects, which have ultimately resulted in their clinical application. All the aforementioned developments have revolutionized the application of nanotechnologies and have led to improved understanding of the possibilities for drug delivery to diseased tissues and organs. In this chapter we introduce a novel drug delivery system (DDS) using biodegradable nano-scaled fiber for use in cardiovascular medicine. Occasionally, systemic administration of the drug for cardiovascular diseases not only fails to work sufficiently, but also causes adverse side effects due to the limited effective threshold of the drug. Therefore, these medicines may need to be released locally and gradually. Our newly developed DDS applied biodegradable polymer mixed with a drug used for surgical treatment of cardiovascular diseases, to achieve sustained release. The mechanisms of sustained release of a drug are quite simple
the drug is released with diffusion, hydrolysis of the biodegradable polymer and/or degradation of polymer by enzymatic or phagocytotic effects in vivo. An electrospinning procedure is used to fabricate the nanofiber configurations for these materials. In this chapter, we review the DDS scaffold using electrospinning nanofiber technology, and also highlight our recent results using our new DDS with biodegradable nano-scaled fiber for cardiovascular diseases to prevent anastomotic stricture and treat aortic aneurysm.

A doxycycline loaded, controlled-release, biodegradable fiber for the treatment of aortic aneurysms Reviewed

A. Yamawaki-Ogata, R. Hashizume, M. Satake, H. Kaneko, S. Mizutani, T. Moritan, Y. Ueda, V. Narita

BIOMATERIALS Vol. 31 ( 36 ) page： 9554 - 64 2010.12

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCI LTD

The pathogenesis of aortic aneurysm (AA) is characterized by degradation of extracellular matrix with Increased matrix metalloproteinases (MMPs) and inflammatory reaction Doxycycline (DOXY) has been reported to control the extension of AA by regulation of MMP However systemic administration may cause adverse side effects In this study we demonstrated the possibility of local administration of DOXY controlled-release biodegradable fiber (DCRBF) for AA in mice DCRBF was fabricated by biodegradable polymer (polylactic acid PLA) mixed with DOXY using an electrospinning technique DCRBF was cocultured with SMCs macrophages and aortic tissue and placed on an abdominal aortic aneurysm which induced apolipoprotein E-deficient mice We evaluated gene and protein expression of proteases elastin and inflammatory markers In the presence of DCRBF MMP-12 was significantly decreased TGF-beta 1 and Lox were significantly increased in SMC gene expression MMP-9 and -12 significantly decreased gene expression of macrophages The DCRBF preserved elastin content and decreased MMP-2 and -9 in aortic tissue In addition IGF-1 and TIMP-1 were significantly increased and IL-6 and TNF-alpha were significantly decreased with DCRBF in vivo In conclusion our results suggested that local administration of DCRBF may become a promising alternative therapeutic strategy for AA (C) 2010 Elsevier Ltd All rights reserved

DOI： 10.1016/j.biomaterials.2010.08.069

Effects of Extracellular Matrix on Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells into Smooth Muscle Cell Lineage: Utility for Cardiovascular Tissue Engineering Reviewed

Shuichi Suzuki, Yuji Narita, Aika Yamawaki, Yosuke Murase, Makoto Satake, Masato Mutsuga, Hideki Okamoto, Hideaki Kagami, Minoru Ueda, Yuichi Ueda

CELLS TISSUES ORGANS Vol. 191 ( 4 ) page： 269 - 280 2010

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Background: Bone marrow-derived mesenchymal stem cells (MSCs) can differentiate into various types of cell, and the extracellular matrix (ECM) is acknowledged to be important for the regulation of cell functions. In this study, we demonstrated the effects of ECMs on the differentiation of human bone marrow-derived MSCs into a smooth muscle cell (SMC) lineage. Methods: Human MSCs (hMSCs) were cultured on dishes coated with 3 types of ECM including laminin (LM), collagen type IV (Col-IV) and fibronectin for 7 days, and simultaneously cultured on a noncoated dish as a control. Cell numbers of these cultured hMSCs were counted, and their expression of SMC-specific genes and proteins was evaluated. hMSCs were then seeded on LM-coated biodegradable sheets and implanted into rat subcutaneous space. After 2 weeks of implantation, these tissues were evaluated. Results: The number of hMSCs was significantly increased by culture on Col-IV-coated dishes. The expression of SMC-specific genes and proteins (alpha-smooth muscle actin, ASMA; h1-calponin, CALP) in hMSC was significantly upregulated from culture on LM-coated dishes. LM-coated sheets showed
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a significantly increased expression of ASMA and CALP protein in vivo. Moreover, a fully differentiated marker (SM2) was expressed in the in vivo implanted hMSCs in the course of 2 weeks on the LM-coated sheet. Conclusion: These results suggest that the signal transduction of the cell-matrix interaction for the differentiation of hMSCs into SMCs was activated when cultured with LM. LM-coated materials may thus be useful for cardiovascular tissue engineering. Copyright (C) 2009 S. Karger AG, Basel

DOI： 10.1159/000260061

Institutional report - Congenital development of novel drug-eluting biodegradable nano-fiber for prevention of postoperative pulmonary venous obstruction Reviewed

Masato Mutsuga, Yuji Narita, Aika Yamawaki, Makoto Satake, Hiroaki Kaneko, Akihiko Usui, Yuichi Ueda

Interactive Cardiovascular and Thoracic Surgery Vol. 8 ( 4 ) page： 402 - 406 2009.4

Language：English Publishing type：Research paper (international conference proceedings)

Pulmonary venous obstruction (PVO) after correction of total anomalous pulmonary venous connection (TAPVC) frequently occurs due to intimal-hyperplasia and the required re-operation. We have developed a novel sustained-release drug delivery system, using Tacrolimuseluting biodegradable nano-fiber (TEBN). It consists of nano-scale fiber composed of biodegradable polymer and Tacrolimus. This study evaluated the effects of TEBN for prevention of venous anastomotic stricture in a rat model to apply to PVO operation. Tacrolimus was incorporated into poly (L-lactide-co-glycolide). The venous stricture model was made by rat inferior vena cava anastomosis. The IVC anastomosis was covered with TEBN with 1.0 wt% Tacrolimus (n=12) or without TEBN as a control (n=12), and evaluated histologically at 1, 2, and 4 weeks after operation. The ratio of intimal area was significantly reduced in the TEBN group compared with the control group (ratio
1 week: 0.43 ± 0.26 vs. 0.07 ± 0.04, P=0.04, 2 weeks: 0.39 ± 0.19 vs. 0.05 ± 0.02, P=0.01, 4 weeks: 0.31±0.15 vs. 0.09 ± 0.04, P=0.03, control vs. TEBN, respectively). Histological findings showed endothelialization along the inner surface of the vein even in TEBN. The TEBN reduced intimal hyperplasia and preserved endothelialization even in a venous stricture. These results suggested that this strategy might be useful for prevention of recurrent PVO after TAPVC correction. © 2009 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.

DOI： 10.1510/icvts.2008.192831

A new strategy for prevention of anastomotic stricture using tacrolimus-eluting biodegradable nanofiber Reviewed

Masato Mutsuga, Yuji Narita, Aika Yamawaki, Makoto Satake, Hiroaki Kaneko, Yoshihiro Suematsu, Akihiko Usui, Yuichi Ueda

JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Vol. 137 ( 3 ) page： 703 - 709 2009.3

Language：English Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

Objective: We developed a novel sustained drug-eluting device using tacrolimus-eluting biodegradable nanofiber to prevent anastomotic stricture and evaluated the effects in a rat abdominal aortic anastomosis model.
Methods: In vitro and in vivo tacrolimus release tests for tacrolimus-eluting biodegradable nanofiber were performed to confirm its sustained release. To verify the prevention of anastomotic stricture, tacrolimus-eluting biodegradable nanofiber was placed around the end-to-end anastomosis of abdominal aorta in rats. Five rats were allocated to the following 5 groups: ( 1) control without tacrolimus-eluting biodegradable nanofiber, ( 2) 5 mg of nanofiber only ( 0 wt% of tacrolimus), ( 3) 5 mg of tacrolimus-eluting biodegradable nanofiber containing 0.04 wt% of tacrolimus, ( 4) 5 mg of tacrolimus-eluting biodegradable nanofiber containing 0.1 wt% of tacrolimus, and ( 5) 5 mg of tacrolimus-eluting biodegradable nanofiber containing 1.0 wt% of tacrolimus. Morphometric and histologic analyses including immunohistochemistry were performed in each of the groups 2 weeks after the operation.
Results: The tacrolimus-eluting biodegradable nanofiber gradually released tacrolimus for at least 1 month in vitro and in vivo. The ratio of intimal area was significantly reduced in the 1.0 wt% tacrolimus-eluting biodegradable nanofiber group compared with the other groups (0.26, 0.24, 0.25, 0.21, and 0.08 in control, 0 wt%, 0.04 wt%, 0.1 wt%, and 1.0 wt%, respectively, P <. 05). The cells, which constitute intimal hyperplasia, were positive for smooth muscle actin and SMemb, and factor VIII revealed that endothelial cells covered the surface of the aortic lumen even in the 1.0 wt% tacrolimus-eluting biodegradable nanofiber group in immunohistochemistry.
Conclusion: Tacrolimus-eluting biodegradable nanofiber reduced neointimal hyperplasia and preserved endothelialization. This device may be useful in the prevention of anastomotic stricture.

DOI： 10.1016/j.jtcvs.2008.11.017

Effects of transforming growth factor-beta 1 and ascorbic acid on differentiation of human bone-marrow-derived mesenchymal stem cells into smooth muscle cell lineage Reviewed

Yuji Narita, Aika Yamawaki, Hideaki Kagami, Minoru Ueda, Yuichi Ueda

CELL AND TISSUE RESEARCH Vol. 333 ( 3 ) page： 449 - 459 2008.9

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Bone-marrow-derived mesenchymal stem cells (MSCs) can differentiate into a variety of cell types including smooth muscle cells (SMCs). We have attempted to demonstrate that, following treatment with transforming growth factor-beta 1 (TGF-beta 1) and ascorbic acid (AA), human bone-marrow-derived MSCs differentiate into the SMC lineage for use in tissue engineering. Quantitative polymerase chain reaction for SMC-specific gene (alpha smooth muscle actin, h1-calponin, and SM22 alpha) expression was performed on MSCs, which were cultured with various concentrations of TGF-beta 1 or AA. TGF-beta 1 had a tendency to up-regulate the expression of SMC-specific genes in a dose-dependent manner. The expression of SM22 alpha was significantly up-regulated by 30 mu M AA. We also investigated the additive effect of TGF-beta 1 and AA for differentiation into SMCs and compared this effect with that of other factors including platelet-derived growth factor BB (PDGF-BB). In addition to SMC-specific gene expression, SMC-specific proteins increased by two to four times when TGF-beta 1 and AA were used together compared with their administration alone. PDGF did not increase the expression of SMC-specific markers. MSCs cultured with TGF-beta 1 and AA did not differentiate into osteoblasts and adipocytes. These results suggest that a combination of TGF-beta 1 and AA is useful for the differentiation of MSCs into SMCs for use in tissue engineering.

DOI： 10.1007/s00441-008-0654-0

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