Updated on 2022/07/19

写真a

 
OGATA Aika
 
Organization
Graduate School of Medicine Center for Research of Laboratory Animals and Medical Research Engineering Division Designated lecturer
Title
Designated lecturer

Degree 1

  1. 博士(医学) ( 2014.3   名古屋大学 ) 

Research Interests 6

  1. 間葉系幹細胞

  2. 心臓血管

  3. 大動脈瘤

  4. マクロファージ

  5. エクソソーム

  6. 炎症

Research Areas 1

  1. Life Science / Cardiovascular surgery

Research History 3

  1. Nagoya University   Designated lecturer

    2020.4

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    Country:Japan

  2. Nagoya University   Designated assistant professor

    2018.4 - 2020.3

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    Country:Japan

  3. Nagoya University   Researcher

    2014.4 - 2017.3

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    Country:Japan

Education 2

  1. Nagoya University   Graduate School, Division of Medical Sciences

    2011.4 - 2014.3

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    Country: Japan

  2. Suzuka University of Medical Science

    2009.4 - 2011.3

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    Country: Japan

Professional Memberships 4

  1. THE JAPANESE SOCIETY OF INFLAMMATION AND REGENERATION

  2. The Japanese Circulation Society

  3. THE JAPANESE SOCIETY FOR REGENERATIVE MEDICINE

  4. THE JAPANESE SOCIETY FOR BIOMATERIALS

 

Papers 36

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

    Wang Y, Kanie K, Takezawa T, Horikawa M, Kaneko K, Sugimoto A, Yamawaki-Ogata A, Narita Y, Kato R

    Carbohydrate polymers   Vol. 285   page: 119223   2022.6

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    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

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

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    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

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

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

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

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    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

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  4. 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. Reviewed

    Fujimoto KL, Yamawaki-Ogata A, Uto K, Usui A, Narita Y, Ebara M

    Acta biomaterialia   Vol. 123   page: 222 - 229   2021.3

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

    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

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  5. Therapeutic effect of allogeneic bone marrow-derived mesenchymal stromal cells on aortic aneurysms. Reviewed

    Akita N, Narita Y, Yamawaki-Ogata A, Usui A, Komori K

    Cell and tissue research   Vol. 383 ( 2 ) page: 781 - 793   2021.2

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    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 < 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

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  6. Performance of a Biodegradable Composite with Hydroxyapatite as a Scaffold in Pulp Tissue Repair. Reviewed

    Okamoto M, Matsumoto S, Sugiyama A, Kanie K, Watanabe M, Huang H, Ali M, Ito Y, Miura J, Hirose Y, Uto K, Ebara M, Kato R, Yamawaki-Ogata A, Narita Y, Kawabata S, Takahashi Y, Hayashi M

    Polymers   Vol. 12 ( 4 )   2020.4

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    DOI: 10.3390/polym12040937

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  7. 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

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    DOI: 10.1007/s11748-019-01195-3

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  8. The oral administration of colchicine prevents the progression of aortic aneurysm Reviewed

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

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

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

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

    BioMed research international   Vol. 2019   page: 9104680   2019

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    DOI: 10.1155/2019/9104680

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  10. 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

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    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

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

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

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    DOI: 10.3390/polym10090947

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  13. <Editors' Choice> Effects of exosomes derived from the induced pluripotent stem cells on skin wound healing. Reviewed

      Vol. 80 ( 2 ) page: 141-153   2018.5

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    DOI: 10.18999/nagjms.80.2.141

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  14. 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

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    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 &lt; 0.05). Levels of pNF-kB and pSTAT1 were reduced (pNF-kB: 0.28 versus 0.45 unit/mL, P &lt; 0.05, pSTAT1: 0.16 versus 0.34, P &lt; 0.05), whereas levels of pAkt and pSmad3 were elevated (pAkt: 0.13 versus 0.07, P &lt; 0.01, pSmad3: 1.07 versus 0.47, P &lt; 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

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

    Sato K, Yamawaki-Ogata A, Kanemoto I, Usui A, Narita Y

    Veterinary journal (London, England : 1997)   Vol. 216   page: 183 - 8   2016.10

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    DOI: 10.1016/j.tvjl.2016.08.009

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

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

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

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  17. 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

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    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 &gt; 0.01), and a significant improvement in percentage closure at 7, 10, 14, and 18 days compared with PBS-control wounds (P &gt; 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

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  18. 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

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    DOI: 10.4252/wjsc.v6.i3.278

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  19. 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

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    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 &lt; 0.05), and aortic diameter was reduced at 2 and 4 weeks (2 weeks: 1.40 vs 2.29 mm, P &lt; 0.001; 4 weeks: 1.73 vs 2.32 mm, P &lt; 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 &lt; 0.05; active-MMP-9: 0.16 vs 0.34 unit/ml, P &lt; 0.05). Inflammatory cytokines were down-regulated in the BM-MSC group (interleukin-6: 2 weeks: 1475.6 vs 3399.5 pg/ml, P &lt; 0.05; 4 weeks: 2184.7 vs 3712.8 pg/ml, P &lt; 0.05 and monocyte chemotactic protein-1: 2 weeks: 208.0 vs 352.7 pg/ml, P &lt; 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 &lt; 0.05; TIMP-2: 9.5 vs 4.0 ng/ml, P &lt; 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.

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  20. 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

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    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 &lt; 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

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  21. 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

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    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.

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  22. 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

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  23. 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

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    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.

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  24. Development of novel statin releasing biodegradable nano-scaled fiber for bone tissue engineering 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

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  25. Possibility of cell therapy for aortic aneurysm Reviewed

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

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

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  26. 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

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

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  28. 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

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    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 &lt; 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

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  29. 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

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    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 &lt; .05), MMP-9 (5.83 vs 9.70, P &lt; .05), and TNF-alpha (2.79 vs 3.38, P &lt; .05) expression in macrophages, and promoted elastin expression in SMCs (19.35 vs 3.23, P &lt; .05) in vitro. MSCs also decreased active MMP-2 activity (0.310 vs 0.0609 U/mu L, P &lt; .05) and preserved elastin content (68.05 vs 40.29 mu g/mg, P &lt; .05) ex vivo. AA development was site-specifically inhibited (0.73 vs 1.04 mm aortic diameter, P &lt; .05) and elastin content was preserved (46.9 vs 25.6 mu g/mg, P &lt; .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.)

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  30. 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

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    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

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  31. Biodegradable nanofibers in cardiovascular medicine: Drug delivery application Reviewed

    Mutsuga M.

    Nanomedicine and the Cardiovascular System     page: 345-369   2011.1

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

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

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

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    DOI: 10.1016/j.biomaterials.2010.08.069

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  33. 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

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    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

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  34. 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

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    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

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  35. 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

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    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 &lt;. 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.

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  36. 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

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    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.

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Books 1

  1. Biodegradable nanofibers in cardiovascular medicine: Drug delivery application

    Mutsuga M., Yamawaki-Ogata A., Satake M., Kaneko H., Ueda Y., Narita Y.( Role: Sole author)

    Nanomedicine and the Cardiovascular System  2011.1  ( ISBN:9781578087266

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    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.

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KAKENHI (Grants-in-Aid for Scientific Research) 29

  1. M2マクロファージによる効率的大動脈瘤治療法の確立

    Grant number:22K08933  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(C)

    所 正佳, 成田 裕司, 緒方 藍歌, 六鹿 雅登

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    本研究では、抗炎症性M2マクロファージ(M2MF)による大動脈瘤治療の最適化方法を確立することを目的とする。M2MF投与による効果や安全性は、先行研究で明らかにしたが、治療に効果的な投与方法はまだ検討されていない。将来的な臨床応用を目指すためには、大動脈瘤に対するM2MF治療法の最適化が必要である。本研究で得られる成果は、手術リスクの大きい大動脈瘤罹患患者に対する新しい低侵襲的治療法として提案できるだけでなく、関節リウマチなどの炎症性疾患の治療法としての発展性もあると考える。

  2. 大動脈瘤におけるマクロファージAIM炎症機構の解明と治療法の開発

    Grant number:22K08932  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(C)

    寺澤 幸枝, 成田 裕司, 緒方 藍歌, 六鹿 雅登

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    動脈硬化が主因である大動脈瘤は慢性炎症を呈する。慢性炎症の中心的役割を担うのはマクロファージであり、マクロファージが産生するアポトーシス抑制因子AIM の炎症機構を制御することができれば、AIM が新たな大動脈瘤の治療標的になりうると考えた。本研究では、大動脈瘤におけるAIM の炎症増悪メカニズムを解明し、AIM 制御による大動脈瘤治療の可能性について明らかにする。本研究で得られる成果は、大動脈瘤における全く新しい側面からの炎症機構に着目した治療法を提案し、臨床応用を目指すことが可能となる。加えて、新たな大動脈瘤の炎症機構の解明と病態の理解に寄与できる。

  3. 感染を予防・制御する抗菌性ポリマー人工血管の創出

    Grant number:22K08954  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(C)

    六鹿 雅登, 齋藤 明広, 成田 裕司, 小土橋 陽平, 緒方 藍歌

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    大動脈置換に用いるダクロン(ポリエステル)人工血管は、耐久性等に問題なくほぼ完成された人工臓器と言っても過言ではないが、唯一残った問題点として、感染に対する脆弱性が挙げられる。従って、感染を予防・制御をする材料や構造を持つ抗菌性人工血管の創出は、医学的に必要性の高い研究である。本研究では、抗菌作用を持つポリマー基材;Poly(METAC)-PVAを用い、感染を予防・制御をする抗菌性人工血管の創出を試みる。抗菌ポリマーによる人工血管作成の研究報告例はなく、本研究はこれまでに類をみないコンセプトを持つ。また、本基材は抗菌性被覆材としての応用性も見込まれる。

  4. 生体タンパク模倣短鎖ペプチドの創成と低侵襲的大動脈瘤治療法開発の試み

    Grant number:22H03155  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(B)

    成田 裕司, 荏原 充宏, 宇都 甲一郎, 加藤 竜司, 緒方 藍歌, 六鹿 雅登, 蟹江 慧

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    大動脈瘤に対する低侵襲治療法の開発として、間葉系幹細胞投与によるの臨床治験が米国で行われているが、細胞製剤は生物由来原料であるため、厳密な品質管理が求められるうえ、感染リスクや免疫反応などの有害事象が懸念される。一方で、ペプチド医薬は化学合成による安定した工業生産が可能である。本研究では、抗炎症作用をもつタンパクSLPIに由来する短鎖機能性ペプチド医薬を創成し、大動脈瘤に対する新たな低侵襲治療法を開発する。ペプチド医薬による治療効果が得られれは、患者に利する医学的意義は高く、国内外でも類を見ない治療法となる。また、本ペプチドは関節リウマチなどの慢性炎症疾患にも応用できる可能性がある。

  5. 材料的・流体的力学的挙動による大動脈解離発症メカニズムの解明と医療応用への試み

    Grant number:21H04955  2021.4 - 2026.3

    科学研究費助成事業  基盤研究(A)

    杉田 修啓, 中村 匡徳, 加藤 輝, 成田 裕司, 緒方 藍歌, 氏原 嘉洋

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    本研究では,大動脈解離発症機構の力学的解明を目指す.血管壁が層間で剥離する大動脈解離は,破裂時致死率が高い一方,発症機構が不明である.我々は,「内圧負荷時に,血管壁内の層間が互いにずれるせん断変形が生じる」「加圧により内腔から壁内への液体流入が増す」との知見を近年に得た.この結果から,血圧増加により「せん断変形が解離を生じさせる」「液体流入が解離を生じさせる」の2仮説を有している.そこで,大動脈解離モデルマウスを用い,せん断変形や間質流を調べることで,大動脈解離発症機構を明らかにしたい.また,臨床での測定法開発や投薬による影響等,応用にも取り組む.

  6. 生体吸収性ポリマーと機能性ペプチドの複合化による再生型癒着防止人工心膜の開発

    Grant number:21K08820  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    緒方 藍歌, 原 光生, 宇都 甲一郎, 加藤 竜司, 成田 裕司, 蟹江 慧

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    Grant amount:\4290000 ( Direct Cost: \3300000 、 Indirect Cost:\990000 )

    本研究では、生体吸収性ポリマーに心膜構成細胞の機能を制御するペプチドを化学修飾した、自己心膜再生を促す「再生型癒着防止人工心膜」を開発し、その有用性を検討する。具体的に、生体吸収性ポリマーのポリカプロラクトン(PCL)を用いてシートを作成し物性評価を行ったのち、シートに機能性ペプチドを化学的に修飾する。中皮細胞および線維芽細胞をペプチド修飾シート上に播種して細胞接着性等を評価する。良好な結果が得られたら、ペプチド修飾シートを心膜癒着モデル動物で有用性を評価する。

  7. マクロファージ形質制御性生体吸収性ポリマーによるin situ大動脈瘤拡大抑制

    Grant number:21K08821  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    柚原 悟史, 成田 裕司, 緒方 藍歌, 宇都 甲一郎

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    大動脈瘤は破裂すると救命が極めて困難な疾患で、現状の外科的・内科的治療には限界があり、新たな治療法の開発が望まれている。これまでに抗炎症性M2マクロファージ(M2MF)を腹腔内投与することで大動脈瘤病変部位のマクロファージ形質転換を誘導することを試みたが、病変部位への集積率は多くなく、誘導効率は定かでなかったことから、In situでM2MFへ形質転換させることができれば、より効率よく治療効果が得られる可能性がある。本研究では、マクロファージ形質制御性生体吸収性ポリマーシートを作成し、in situにて大動脈瘤拡大を抑制する新たな手術支援材料の開発を行う。

  8. 抗菌性ポリマーを利用した感染制御性人工血管の開発

    Grant number:20K21630  2020.7 - 2022.3

    科学研究費助成事業  挑戦的研究(萌芽)

    碓氷 章彦, 齋藤 明広, 成田 裕司, 小土橋 陽平, 緒方 藍歌

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    人工物を留置する手術では、術後感染が発症すると難治化しやすく、基本的にはその人工物を除去しなければ治癒しない。そのため、安定した抗菌作用を持った人工血管の開発が望まれている。本研究では、Poly[2-(methacryloyloxy) ethyl] trimethylammo-nium chloride) を基材とした長期安定的な抗菌作用を有する新規人工血管の創出を試みる。ポリマーの構造デザイン検討、細胞毒性試験や血液適合性、物性試験などを行ったのち、人工血管置換術による感染制御性などについて評価する。
    人工物を留置する手術では、術後感染が発症すると難治化しやすく、基本的にはその人工物を除去しなければ治癒しない。心臓血管外科領域では、人工心臓や人工弁、人工血管など人工臓器を用 いた手術が多く、感染に対するマネージメントは重要な課題である。中でも大動脈手術後の人工血管感染は生命予後に直接影響し、最も管理に難渋する疾患群であることから、安定した抗菌作用を持った人工血管の開発が望まれている。
    現在までに、抗菌性高分子であるpoly(METAC)を含有する種々の共重合体を合成し、それらの物理化学的な性質を評価した。共重合体は、METACユニット、カルボキシ基、ベンゾオキサボロール基を含有する。カルボキシ基およびベンゾオキサボロール基は、ポリビニルアルコール(PVA)との架橋構造を構築する為に導入された。
    人工血管の材料となる共重合体とウサギ由来の赤血球を接触させたところ、共重合体の組成を変化させることで、高い高分子濃度においても10%以下の溶血率を示し、比較的に高い血液適合性を有することが示唆された。もうひとつの材料であるPVAは高い血液適合性を示すことが知られている。また、人工血管に加工する為に、ポリビニルアルコール(PVA)と混合し熱架橋を行うことでフィルム化することに成功した。フィルムは、親水的な共重合体およびPVAから構成されるにもかかわらず、水に溶解しない。80℃の多量の水に3時間浸漬させてもほぼ100%残存した。架橋を施さない高分子フィルムは、同様の条件にて完全に水に溶解する。ガラス転移温度や融点、分解温度などを測定し、最適な共重合体および混合比を明らかにした。
    当初の計画通りに進んで成果を得られているため、概ね順調に進展していると判断した。
    異なる種類の架橋構造を導入することで、含水していても高い機械的な強度を発揮できることから、今後は、フィルム内に異なる架橋構造を導入するなど、機械的な強度の増加も試みる。また、in vitroにて黄色ブドウ球菌や緑膿菌などの細菌に対する抗菌性を評価する。その後、プロトタイプとして抗菌性高分子を血管型に成型加工を行い、動物実験にてプロトタイプを皮下埋植して経常評価や組織学的な評価も行う予定である。

  9. 生体吸収性・良操作性・骨再生能を持つ多機能骨髄止血材の開発

    Grant number:20K09124  2020.4 - 2023.3

    伊藤 英樹

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    骨切開を伴う手術では骨切断面から多くの出血を伴うため、一般的にはボーンワックスで骨切断面にパッキングする止血法が用いられている。しかしボーンワックスは非分解・非吸収性で、残存による骨癒合・治癒阻害や術後感染等の合併症、骨癒合・再生の遅延を助長する可能性がある。従って、新たな骨髄止血材料の開発は多くの患者に有益である。申請者らは、独自技術で開発したポリカプロラクトン(PCL)をベースとした生体吸収性ポリマーと骨再生誘導ペプチドによる新規骨髄止血材料を創出してきた。本研究では、材料の質的向上を図るため、各設計条件を見直す基礎研究を行い、前臨床研究も含めた動物実験にて有用性を検証する。

  10. "Peptide-polymer" combinatorial screening research for the creation of bone regeneration materials

    Grant number:20K05227  2020.4 - 2023.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

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  11. 心筋梗塞後急性炎症に対する炎症制御因子介入による心筋サルベージ療法

    Grant number:20K09145  2020.4 - 2021.3

    科学研究費助成事業  基盤研究(C)

    藤本 和朗, 碓氷 章彦, 徳田 順之, 成田 裕司, 緒方 藍歌

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    広範囲心筋梗塞では、壊死心筋の激しい炎症の後、線維化組織に置換され心腔拡大や収縮障害、最終的に重症心不全を引き起こす。梗塞部位では、集積した炎症性マクロファージ (M1MF)による過剰な炎症状態と、抗炎症性マクロファージ (M2MF)による血管新生・線維化組織の誘導が観察されるが、炎症/抗炎症バランスが改善されず梗塞後リモデリングが進行して心機能がさらに低下する。本研究では、心筋梗塞後急性炎症に対する抗炎症作用・組織修復に関わるProgranulin(PGRN)およびSecretory leukocyte proteinase inhibitor (SLPI)による心筋サルベージ療法を試みる。
    広範囲心筋梗塞では、壊死心筋の激しい炎症の後、線維化組織に置換され、時間とともにリモデリングが進行し、心腔拡大や収縮障害、最終的に重症心不全を引き起こす。心筋梗塞部位では過剰な炎症状態と血管新生・線維化組織の誘導が観察されるが、炎症/抗炎症バランスが改善されず梗塞後リモデリングが進行して心機能がさらに低下する。近年、研究代表者らは、慢性炎症を呈する動脈硬化性大動脈瘤モデルにおいて間葉系幹細胞(MSC)療法の有効性を示し、MSC産生因子に抗炎症作用・組織修復に関わるProgranulin(PGRN)およびセリンプロテアーゼ阻害因子 Secretory leukocyte proteinase inhibitor (SLPI)が含まれていることを見出した。この知見から、PGRN, SLPIは心筋梗塞における炎症/抗炎症バランスを改善し、梗塞後リモデリングを抑制しうる仮説を立てた。本研究では、PGRN, SLPIによる心筋梗塞治療効果を検証するため、In vitroにて培養マクロファージに対するrPGRN, SLPIの作用について調べた。LPSまたはTNF-α/INF-γで24時間炎症刺激した炎症性M1マクロファージ(M1MF)に対し、rPGRN, rSLPIを添加して24時間培養後にM1MFからRNA抽出して遺伝子発現の定量比較を行った(PGRN群、SLPI群、各n=5)。比較対象群には何も添加しない無添加群(n=5)を用いた。無添加群に比べ、PGRN群とSLPI群でIL-1β, IL-6, MCP-1, iNOS遺伝子発現量が有意に低下した。さらにSLPI群は、TNF-α遺伝子発現量が有意に低下した一方で、IL-10, TGF-β1遺伝子発現量が有意に上昇した。これらの結果から、SLPIは炎症/抗炎症バランスを改善させる可能性が示唆された。

  12. クラリスロマイシンとモンテルカストによる大動脈瘤治療と閉塞性肺疾患との逆説解明

    Grant number:19K09265  2019.4 - 2022.3

    科学研究費助成事業  基盤研究(C)

    成田 裕司, 碓氷 章彦, 緒方 藍歌, 内田 亘

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    小径大動脈瘤や大動脈瘤手術後の残存病変、慢性期B型大動脈解離(B型解離)などに対する積極的な予防治療法は確立されていない。我々は、クラリスロマイシン(CAM)とモンテルカスト(Mont)が、動物実験で大動脈瘤発症・瘤径拡大を抑制することを明らかにした。一方、CAMとMontは慢性閉塞性肺疾患(COPD)に対して用いられるが、COPDは大動脈瘤の罹患率、破裂等のリスクファクターである。本研究では、CAMとMont両剤併用による大動脈瘤への作用を動物実験で明らかにする。また、後ろ向き臨床研究で単剤または両剤を投与されたCOPD患者を追跡し、大動脈瘤・慢性B型解離に対する瘤拡大抑制効果を検討する。
    小径大動脈瘤や大動脈瘤手術後の残存病変、慢性期B型大動脈解離(B型解離)などに対しては血圧コントロールを中心とした保存的治療法が施行されているが、積極的な予防治療法は確立されていない。研究代表者らは、先行研究で抗生剤のクラリスロマイシンおよびロイコトリエン阻害薬のモンテルカストが、それぞれ動物実験において抗炎症作用を介し大動脈瘤発症・瘤径拡大を抑制することを明らかにした。一方、クラリスロマイシンとモンテルカストは慢性閉塞性肺疾患(COPD)に対してしばしば使われる治療薬であるが、COPDは大動脈瘤の罹患率、破裂や死亡のリスクファクターであることが知られている。本研究では、クラリスロマイシンとモンテルカストに対する、大動脈瘤予防効果とCOPDの大動脈瘤促進効果のパラドックスを解明するため、動物実験でクラリスロマイシンとモンテルカスト両剤併用が大動脈瘤に対しどのように作用するかを、病態生理を含め明らかにすることを目的とする。
    当初の研究計画では、大動脈瘤モデルマウスに対し、クラリスロマイシンとモンテルカストの両剤を服用させ、継時的観察および組織評価を行う予定であった。しかし、COPDは大動脈瘤の罹患率、破裂や死亡のリスクファクターであることことから、当初研究計画に含まれていなかったCOPDモデルマウスの作成を追加することとした。エラスターゼ溶液を気管内にスプレーまたは溶液を投与する方法が報告されているが、投与濃度は様々であることから、エラスターゼ誘発肺気腫モデル確立のために投与濃度を0.02U, 0.2U, 1.0Uに可変して投与し、肺気腫の増悪レベルを比較検討した。
    現在、当初計画の大動脈瘤モデルマウスを用いたクラリスロマイシンとモンテルカストの両剤投与の検討を行なっている。しかし、COPDは大動脈瘤の罹患率、破裂や死亡のリスクファクターであることことから、当初研究計画に含まれていなかったCOPDモデルマウスが必要であると判断した。本年度はCOPDモデルマウス確立のための事前検討を行っているが、まだ結果をまとめている最中であり、進捗状況はやや遅れていると評価した。
    当初計画である、大動脈瘤モデルマウスを用いたin vivo検討を進める。すなわち、大動脈瘤モデルに CAMとMontを経口投与し、瘤径拡大・瘤破裂を抑制できるかを検討する。 効果が得られなかった場合は、投与濃度や評価時期・項目を見直し再検討する。また、COPDと大動脈瘤を併発させたモデルマウスでの両剤服用時の有用性評価も行う。

  13. 補助人工心臓ドライブライン感染制御等のための抗菌ポリマーを用いた部材の開発

    Grant number:19K09240  2019.4 - 2022.3

    科学研究費助成事業  基盤研究(C)

    寺澤 幸枝, 成田 裕司, 緒方 藍歌, 小土橋 陽平, 齋藤 明広

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    植込型補助人工心臓は、駆動電源確保のための「ドライブライン」が皮膚を貫通して存在し、常に感染のリスクを包含している。人工臓器感染は難治性で、心不全患者においては致命的となることも少なくない。長期にわたっていかに感染を制御できるかが、患者の予後を大きく左右する。しかし現状のドライブライン管理に確立した方法はない。本研究では、殺菌性や化学的安定性を有するpoly([2-(methacryloyloxy)ethyl]trimethylammonium chlorideを基材とした長期安定的な抗菌作用を有する新規感染制御材料の創出を試み、動物実験での基礎的検討を主体にドライブライン管理材料を開発する。
    植込型補助人工心臓は、重症心不全患者の生命予後を劇的に改善する強力なデバイスだが、駆動電源確保のための「ドライブライン」が皮膚を貫通して存在し、常に感染のリスクを包含している。一般的に人工臓器感染は難治性で、心不全患者においては致命的となることも少なくない。また、心臓移植待機期間が 1000日を超える本邦において、いかに感染を制御できるかが、患者の予後 を大きく左右することに疑う余地はない。しかし現状のドライブライン管理に確立した方法はない。
    研究代表者らは、殺菌性や化学的安定性を有する抗菌性高分子 Poly[2-(methacryloyloxy) ethyl] trimethylammo- nium chloride; Poly(METAC) を基材とした長期安定的な抗菌作用を有する新規感染制御材料の創出を試みた。
    poly(METAC)を含有する各種共重合体を合成し、ポリビニルアルコール(PVA)と混合することで高分子フィルムや高分子繊維の成形加工に成功した。共重合体はPVAと複数種の架橋構造を形成するために、カルボキシ基およびベンゾオキサボロール基も含有する。この共重合体は、ヒト細胞や赤血球に対し高い生体適合性を示した。しかし、フィルム化および繊維化に伴ってpoly(METAC)の含有量が減少し、抗菌性が低下することが明らかとなった。これを解決するため、フィルムや繊維の表面を、簡便な手法を用いpoly(METAC)を高含有する高分子にて修飾することに成功した。また、修飾した高分子繊維上で大腸菌は膜破壊を起こし抗菌効果を示すことが示唆された。
    当初の研究計画どおりにすすんでいるため、おおむね順調に進展していると判断した。
    今後は、対象とする細菌を、緑膿菌、黄色ブドウ球菌、メチシリン耐性黄色ブドウ球菌に拡張し、補助人工心臓ドライブライン感染抑制等のためのプロトタイプを作成する。プロトタイプをラット皮下へ埋植し、高分子の形状観察や組織学的所見を行う予定である。

  14. 大動脈瘤に対する新規バイオ医薬の開発

    Grant number:19H03737  2019.4 - 2022.3

    科学研究費助成事業  基盤研究(B)

    碓氷 章彦, 荏原 充宏, 宇都 甲一郎, 加藤 竜司, 成田 裕司, 緒方 藍歌, 蟹江 慧

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    大動脈瘤に対する人工血管置換術は侵襲が大きく、新たな低侵襲な治療法の開発が望まれる。我々は、これまでに間葉系幹細胞(MSC)静脈内投与による大動脈瘤治療の有効性を示してきた。治癒メカニズムにはMSCのパラクライン作用が示唆され、MSC産生因子の中に抗炎症作用・組織修復に関わる因子としてProgranulin(PGRN)およびSLPIを同定し、それらによる大動脈瘤治療効果の可能性を見出した。
    本研究は、リコンビナントタンパクPGRN, SLPI投与による効果検証を行ったのち、合成ペプチド医薬として大動脈瘤治療の検討を行い、ペプチド医薬としての有効性を明らかにする。
    高齢化等を背景に、大動脈瘤患者数並びに手術件数は増加している。大動脈瘤に対する人工血管置換術は比較的侵襲が大きく、対象患者は高齢で予備能力の低い患者群で、Shaggy Aorta等重症例では手術適応に苦慮することが多い。従って、新たな低侵襲な治療法の開発が求められている。研究代表者らは、間葉系幹細胞(MSC)静脈内投与による大動脈瘤治療の有効性を示してきた。治癒メカニズムにはMSCのパラクライン作用が示唆され、MSC産生因子の中に抗炎症作用・組織修復に関わる因子としてProgranulin(PGRN)およびSecretory leukocyte proteinase inhibitor (SLPI)の重要性と、それらによる大動脈瘤治療効果の可能性を見出した。本研究では、リコンビナントタンパクrPGRNとrSLPI投与による大動脈瘤治療効果および分子メカニズムを明らかにしたのち、rPGRN, rSLPI由来の合成ペプチド医薬創薬による新たな低侵襲大動脈瘤治療法の開発と外科治療への応用を試みる。
    これまでのrPGRN, rSLPI腹腔内投与による効果の検証において、 生理食塩水を投与したcontrol群に比べて、rSLPI投与群で抗炎症効果や大動脈瘤拡大進展抑制効果が得られた。このことから、rSLPI投与による大動脈瘤拡大進展抑制のメカニズムをあきらかにするため、本年度では、大動脈瘤組織中タンパクを抽出し、大動脈瘤で関連が報告されているシグナル伝達経路NF-kB, JNKやSTAT, Smad, Akt, ERKなど のキナーゼやリン酸化タンパクについてELISA kitを用いて調べた。
    その結果、control群に比べ、rSLPI投与群でJNKおよびNF-kBのリン酸化タンパクの発現量が有意に低下していたことがわかった。JNKとNF-kBは炎症を引き起こす細胞内情報伝達系で重要な役割を果たす。rSLPI投与によってこれらシグナル経路の発現レベルが低下したことで抗炎症に働き、瘤進展拡大を抑制したと考えられた。
    当初の計画通り遂行していることから、おおむね順調に進展していると判断した。
    rSLPIのアミノ酸配列をリファレンスに合成ペプチド医薬候補を探索する。その後、候補となった合成ペプチド医薬による大動脈瘤治療効果を明らかにする。しかしペプチドは体内で分解されやすいため、効果を持続させるためのDDSメディカルデバイス(例えば大動脈瘤拡大予防ラッピング材料やナノ粒子による静脈内・皮下投与など)の開発を行う。

  15. M1マクロファージからM2マクロファージへの形質転換を介した大動脈瘤治療の試み

    Grant number:18K16384  2018.4 - 2022.3

    科学研究費助成事業  若手研究

    緒方 藍歌

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    Grant amount:\4160000 ( Direct Cost: \3200000 、 Indirect Cost:\960000 )

    大動脈瘤は破裂すると救命が極めて困難な疾患で、治療は破裂の予防であるが、現状の外科的・内科的治療には限界があり、新たな治療法の開発が望まれている。研究代表者らは、間葉系幹細胞(MSC)静脈内投与による大動脈瘤治療の有効性を示してきた。治癒メカニズムにはMSCのパラクライン作用が示唆され、大動脈瘤病変部位で直接作用しているのはMSCではなく、抗炎症性M2マクロファージ(M2MF)であると推察できた。そこで、通常、大動脈瘤病変部位には、炎症性M1マクロファージ(M1MF)が集積しており、これをM2MFへ形質転換させることが、治療戦略として成り立つのではないかと考えた。形質転換因子として、①M2MF誘導因子(IL-4/IL-13)、②M2MF細胞、③M2MF培養上清、④M2MF由来エクソソームに着目した。本研究では、M2MFによる大動脈瘤治療の是非と、どの因子がM1からM2への形質転換を促進し、大動脈瘤治療効果が得られるのかを明らかにすることを目的とする。
    これまでのin vitro, ex vivoの結果から②M2MF細胞が最も効果が得られたことから、in vivoにて大動脈瘤モデルマウスにM2MF腹腔内投与を行った。効果の比較のためcontrol群として生理食塩水を投与した。投与2, 4週間後にエコーで大動脈瘤径測定したところ、control群にくらべ M2MF群で有意に瘤径拡大を抑制した。4週間後に屠殺し、大動脈瘤組織中のタンパク発現量測定、MMPs活性測定を行ったところ、control群に比べてM2MF群で炎症性タンパクIL-1β, IL-6, TNF-α 発現量の低下や抗炎症性タンパクIL-4, IL-10発現量の増加、MMP-9活性の低下を認めた。また、組織切片のEVG染色を行い、エラスチンエリアを評価したところ、control群に比べM2MF群でエラスチン分解が有意に抑制された。
    当初の計画どおり遂行していることから、おおむね順調に進展していると判断した。
    組織切片評価やcell trackingなど、in vivo検討の評価を引き続き行う。また得られた成果を国内外で公表するため、学会発表や英語論文発表の準備を行う。

  16. M1マクロファージからM2マクロファージへの形質転換を介した大動脈瘤治療の試み

    2018.4 - 2021.3

    日本学術振興会  科学研究費補助金 若手研究 

    緒方 藍歌

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    Authorship:Principal investigator  Grant type:Competitive

  17. 間葉系幹細胞分泌分子による心臓移植後の新しい免疫寛容誘導の開発

    Grant number:17K10728  2017.4 - 2021.3

    科学研究費助成事業  基盤研究(C)

    藤本 和朗, 碓氷 章彦, 大島 英揮, 成田 裕司, 緒方 藍歌

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    現在の移植治療では、同種異系である臓器、細胞を使用するため、拒絶反応が生じる。そのため、この拒絶反応をコントロールするために免疫抑制剤が必要である。近年の免疫抑制剤開発によって、より安全で、より選択的(移植反応の主要なエフェクター細胞はリンパ球T細胞である)な効果の高い免疫抑制が可能となってきた。しかし、現在でもなおその非特異的免疫抑制作用による重症感染症、悪性腫瘍の発生は、解決すべき大きな課題である。研究代表者らは、免疫抑制能・抗炎症作用をもつ間葉系幹細胞(MSC)による抗炎症作用などを介した大動脈瘤治療効果を示してきた。MSCが産生する分泌分子には、抗炎症作用・免疫寛容・ 組織修復を担う因子、エクソソーム(MSC-exo)、progranulin (PGRN), Secretory Leukocyte Peptidase Inhibitor (SLPI)が含まれていることを同定した。これまでのIn vitro検討で、炎症性マクロファージに対してMSC-exoおよびSLPIがより炎症を抑制することが分かった。本年度では、急性拒絶反応モデルの作成と確立を試みた。Brown Norway 雄ラットをドナー、Lewis 雄ラットをレシピエントとし、ドナーラットから摘出した心臓を、レシピエントラットの下行大動脈と下大静脈に吻合したが、 移植心の再灌流、拍動が確認できなかった。モデル作成には、心臓摘出や血管吻合など高い技術を要するため、実験に耐えうる安定したモデルを確立するための修練を行ったが、良好な急性拒絶反応モデルを確立することに難儀し、MSC-exoまたはSLPIの投与による治療効果を検討することができなかった。

  18. Osteogenic-enhancing peptides-modified, polycaprolactone and polylactide copolymer, for a novel biodegradable bone hemostatic wax-like agent

    Grant number:17K10729  2017.4 - 2021.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    ITO Hideki

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    Bone wax is widely applied for sternal hemostasis after median sternotomy. However, it is known to be a cause of infection, interference of bone healing, and chronic infammation. In this study, we developed a novel biodegradable bone hemostatic agent using osteogenic enhancing peptides-modified polycaprolactone and polylactide copolymers. In animal experiments, our bone hemostatic wax-like agent stopped bone bleeding from tibias similar to bone wax in surgery. Although bone wax inhibited bone regeneration in tibias, our bone hemostatic wax-like agent promoted bone regeneration by osteogenic-enhancing peptides. These results suggested that our bone hemostatic wax-like agent is useful as a novel bone hemostatic material with abilities involving excellent surgical operability and biocompatibility.

  19. 心筋梗塞後リモデリングを抑制するクラリスロマイシン徐放性生体吸収性シートの開発

    Grant number:17K10727  2017.4 - 2019.3

    大島 英揮

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    昨年度は、クラリスロマイシン徐放性生体吸収性シート:5%CAM-PCLシートを作成し、クラリスロマイシンの溶出試験をin-vitroで行うと同時にパイロット試験としてラッ ト梗塞心臓への植込み試験も施行した。 植込み試験は、ラット心臓を用いて前下行枝を結紮して前壁梗塞を作成した。直ちに直径5mmの円状PCLシートを心筋梗塞部のパッチ状に縫着した。その結果、心エコーによる心機能評価では、(sham群 vs 0%CAM-PCLパッチ群 vs 5%CAM-PCLパッチ群) LVEF: 42% vs 41.5% vs 40.5% at 3wks, 35% vs 38% vs 44% at 6wks、と他群に比して5%CAM-PCL群で良好であった。また、左室リモデリングの指標としての左室拡張末期容積(LVEDV)を測定す ると、sham群 0.35ml vs 0% CAM-PCL群 0.37ml vs 5% CAM-PCL群 0.32ml at 6wks と5% CAM-PCL群でリモデリングは抑制されていた。 組織学的評価においても、5% CAM-PCL群ではパッチ逢着部に繊維化組織に加えて残存心筋細胞を一定量認めており(他群では認めなかった)、5% CAM-PCLシートを逢着することによって心筋虚血による心筋壊死が一部抑制され、左室リモデリングが抑制されたと考えられた。
    上記実績をもとに、10% CAM-PCLシートを作成し、同様のモデルを用いて心筋梗塞部に直径5mmの円状10% CAM-PCLパッチを移植する手術を施行した。術後3週間後の心エコー検査では、5% CAM-PCLパッチと同様に左室リモデリング抑制効果を認めた。これまでの実験からクラリスロマイシン徐放性生体吸収性シート移植による心筋梗塞後リモデリングの抑制効果を示す所見が得られた。

  20. Induction of myocardial regeneration by exosome administration for myocardial infarction

    Grant number:16K10624  2016.4 - 2020.3

    TERAZAWA Sachie

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    Several therapeutic strategies using cell-derived exosomes (exo) which have several functions, including anti-inflammatory and immunosuppressive activities have been reported. In this study, to investigate the character of exo which is used for induction of cardiac regeneration, we analyzed proteins and miRNAs in exo derived from cells including mesenchymal stem cells (MSC), fibroblasts (FB), cardiac myocytes (CM) and iPS-derived cardiac myocytes (iCM). Exo derived from each cell was isolated by ultracentrifugation. MSC-exo had 286 kinds of proteins and 526 kinds of miRNAs. Especially, exo derived from MSC, CM, or iCM were expressed miR-146 and miR-210 which are known as anti-apoptosis of cardiac myocytes, and miR-126 and miR-132 which are known as angiogenesis factors. We prepared to inject to the site of myocardial infarction in vivo. However, the amount of exo produced was small, and to establish an efficient culture method to isolate more exo was required.

  21. Proof of concept study of a novel excess chromosome elimination therapy to ameliorate and prevent trisomy 21 associated complications

    Grant number:16K09964  2016.4 - 2019.3

    Hashizume Ryotaro

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    Down syndrome is a chromosomal condition caused by an excess of chromosome 21, leading to an array of lifelong complications. The elimination of extra chromosome 21 could be directly linked to a primary intervention in this context for a person with Down syndrome. The overexpression of ZSCAN4 protein, a transcription factor previously reported as an aneuploidy correction effector, showed no significant extra chromosome elimination rate compared with no-treatment control trisomy 21 iPS cells in our in vitro setting. In an effort to delete extra chromosome, we next employ CRSPR/Cas9 system for DNA double-strand breaks on a single targeted chromosome 21, and found that 7% of entire chromosome loss rate on average by FISH analysis. The strategy to induce single chromosome cleavages at a multiple site using CRISPR/Cas9 thus may contribute to both basic and clinical science for aneuploidy-associated pathological condition, including Down syndrome and other autosomal trisomies.

  22. Possibility of Mesenchymal Stem Cells-derived Peptide Therapy for Aortic Aneurysm

    Grant number:15H04937  2015.4 - 2019.3

    Usui Akihiko

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    Aortic aneurysm (AA) is a life-threatening disease associated with risk of aortic rupture. AA is caused by atherosclerosis and chronic inflammation, which contribute to expansion of the aorta. We have reported that ATII-induced AA model mice that received intravenous injection of MSCs exhibited regression of AA via immunomodulation, anti-inflammatory and tissue repair properties, mediated by paracrine effects. To identify soluble proteins secreted from MSCs, the conditioned medium of MSCs was analyzed using a protein array. We identified Progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI) which participate in anti-inflammation. Intraperitoneal injection of recombinant protein PGRN and SLPI exhibited regression of AA. Using our original peptide array technology, we discovered a short-chain peptide derived from amino acids sequence of SLPI. We demonstrated that the short-chain peptide had a potency of anti-inflammation in vitro.

  23. Developing the device with biocompatible shape memory polymer for closing the entry of chronic type B aortic dissection

    Grant number:15K10239  2015.4 - 2019.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (C)

    Mutsuga Masato, Ebara Mitsuhiro

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    The purpose of this study was to develop the device which is biocompatible and shape memory made by poly caprolactone capable of entry closure for chronic type B aortic dissection.The final destination was clinical application. Using the poly (e-caprolactone) (PCL) derivative prepared in the same way as last year in 2018, we will try to establish the in-vitro and in-vivo experimental system, and examine the usefulness of the developed carrier. It was difficult to develop an ideal biocompatible shape memory polymer and could not be completed. Therefore, The plan for the large animal aortic model was not able to be set up, and the in-vitro experimental system was not created, and the in-vivo experiment with the large animal was completed without any success.

  24. 間葉系幹細胞由来エクソソームによる大動脈瘤治療の臨床応用を目指した研究

    2015

    公益財団法人 武田科学振興財団  2015年度医学系研究奨励 

    緒方 藍歌

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    Authorship:Principal investigator  Grant type:Competitive

  25. Development of novel elastic biodegradable material for improve cardiac function with regenerating cardiomyocytes post myocardial infarction

    Grant number:26462086  2014.4 - 2018.3

    FUJIMOTO KAZURO

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    We developed the biodegradable material for the preservation of the cardiac function to restrict cardiac remodeling post myocardial infarction. We synthesized the biodegradable material with the biochemical with are approved for the usage in Human. And we proved that the ratio of the compounds can change the physical property. Also we identified the most appropriate mechanical property of the material for the heart in Human. The suitable biocompatibility of the material was proven in the transplant into rat hearts.

  26. Therapeutic potential of mesenchymal stem cells for treatment of aortic aneurysm

    Grant number:26713043  2014.4 - 2018.3

    Ogata Aika

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    Grant amount:\23920000 ( Direct Cost: \18400000 、 Indirect Cost:\5520000 )

    An aortic aneurysm (AA) develops as a result of atherosclerosis and chronic inflammation. Surgical repair of AA is effective treatment to prevent rupture. However, the surgical procedures for thoracic and thoracoabdominal AA are extremely invasive and associated with high mortality and morbidity. We have reported that intravenous injection of mesenchymal stem cells (MSCs) could reduce the morbidity rate of aortic aneurysm by anti-inflammatory and tissue repair properties of MSCs. In this study, echographic measurements showed that the maximum aortic diameters of MSC-treated mice were significantly shorter than saline injection throughout 1 week after injection. In addition we demonstrated that the therapeutic mechanism of MSC-mediated AA regression contributed to regulation of the NF-kB, STAT, Smad3 and Akt signaling pathways, MSC-derived exosomes, and microRNAs secreted from MSC.

  27. 間葉系幹細胞による大動脈瘤治療の臨床応用を目指した研究

    2014.4 - 2018.3

    日本学術振興会  科学研究費補助金 若手研究A 

    緒方 藍歌

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    Authorship:Principal investigator  Grant type:Competitive

  28. Development of repairing procedure using temperature responsive polymer for post-infarction ventricular septal perforation

    Grant number:25462135  2013.4 - 2017.3

    Oshima Hideki

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    We developed the surgical method using the temperature-responsive polymer to repair post MI ventricular septal perforation more surely. We sew a patch to repair VSP, but it is likely that suture-lines will be ruptured because infarction cardiac muscle is very fragile tissue.
    In this study, we restored the tissue intensity by injecting a temperature-responsive polymer into infarction cardiac muscle, and improved the durability of damaged tissue against the stress of surgical suturing.In the in-vitro study, it became clear that tissue intensity of 3 times was obtained by injecting poly (N-isopropyl acrylic amide) (PNIPAM) polymer. In the rat MI model, thinning and tear injury of the cardiac tissue over time at the patch-suture sites were inhibited when we injected the polymer and sewed a ePTFE patch to rat infarction cardiac muscle.

  29. Stem Cell Therapy for Aortic Aneurysm

    Grant number:25462161  2013.4 - 2016.3

    Narita Yuji

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    We have reported intravenous administration of bone marrow-derived mesenchymal stem cells (BM-MSCs) reduce the incidence of aortic aneurysm. However, optimal injected cell number, injected interval, timing of administration and optimal cell sources were unknown. In this study, we tried to explore optimal stem cell therapy for aortic aneurysm.
    Intravenous administration of BM-MSCs not only prevented growth of aortic aneurysm, but conducted regression of aortic aneurysm. The aortic aneurysm was prevented by every 4 weeks administration of BM-MSC, however, it could not achieve by single administration. The regression of aortic aneurysm was maintained until 2 weeks after administration of BM-MSCs. The administration of BM-MSCs was better for regression of the aortic aneurysm than that of adipocyte-derived MSCs or fibroblast. The administration of allogenic BM-MSCs was effective treatment for aortic aneurysm as same as that of autologous BM-MSCs.

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Industrial property rights 1

  1. 骨髄止血剤

    緒方 藍歌

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    Application no:特願2017-066904  Date applied:2017.3

 

Teaching Experience (Off-campus) 1

  1. 医用材料工学

    大阪ハイテクノロジー専門学校)