Accelerated recruitment of bone marrow cells to the repair site in the parabiosed rat by LIPUS

• Project/Area Number: 17K11922
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Kanagawa Dental College
• Principal Investigator: Takeuchi Ryohei 神奈川歯科大学, 歯学部, 特任教授 (30236442)
• Co-Investigator(Kenkyū-buntansha): 熊谷 研 横浜市立大学, 医学部, 准教授 (10468176) ; 川股 亮太 神奈川歯科大学, 歯学部, 診療科教授 (40329199) ; 高垣 裕子 神奈川歯科大学, 歯学部, 特任教授 (60050689) ; 日高 恒輝 神奈川歯科大学, 歯学部, 助手 (90760041)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 骨折治癒 / 低出力超音波 / 力学刺激 / 全身性効果 / 液性因子 / 低出力超音波パルス / 骨髄 / M2マクロファージ / LIPUS / 低出力超音波 パルス / 骨形成 / 体液性 / マクロファージ / サイトカイン / 顎骨壊死 / 超音波 / bisphosphonate / 歯周病 / 細菌 / 骨髄細胞 / parabiosis / GFP / 骨再生 / リモデリング / 顎骨 / 血管吻合 / 骨欠損

Outline of Final Research Achievements

It is essential to have enough cells for bone regeneration. We have reported LIPUS exposure of fractured femur and tooth extraction socket recruit cells for regeneration through peripheral blood vessels from the remote sites to the wound in mice and rats, respectively (Kumagai, Takeuchi et al., 2011 and Hidaka et al., 2015). In this study, we confirmed LIPUS exerted its anabolic action not only locally but also systemically on the implanted beta-TCP discs in the back of rats, which were not directly treated with LIPUS and elucidated the molecular mechanisms. Message expression and (immuno-)histochemical localization of proteins and cells using antibodies against M1 and M2 macrophage, and cytokines showed the involved entities. In the discs of LIPUS-untreated parabiosed rat, we observed invaded cells including M2 macrophages and blood vessels present in numbers between those of the LIPUS-exposed and the control rats. We were able to present the systemic effect of LIPUS.

Academic Significance and Societal Importance of the Research Achievements

低出力超音波の照射は骨折治癒期間を約40％短縮することが知られ、国内でも標準治療として用いられている。我々は、これまでに、治癒の促進が局所の細胞の活性化、サイトカイン産生ばかりでなく骨髄細胞の循環を通じて全身性にも誘導されることを示した。これは、炎症の制御が健康寿命に大きな役割を持つことが判明した現在広範な応用価値を示唆するもので、詳細なメカニズムの理解は、薬に頼らない医療の突破口としての可能性を約束する。

Research Products

• [Journal Article] Hybrid closed wedge high tibial osteotomy(HCWHTO)の手術ピットフォール (2021)
  • Author(s): 藤間 保晶, 竹内 良平, 大澤 克成
  • Journal Title: Journal of Japanese Orthopaedic Society of Knee, Arthroscopy and Sports Volume: 46 Pages: 611-617
  • Peer Reviewed
• [Journal Article] Outcome after treatment of osteoarthritis with open-wedge high-tibial osteotomy with a plate: 2-year results of a Japanese cohort study. (2020)
  • Author(s): Sawaguchi T, Takeuchi R, Nakamura R, Yonekura A, Akiyama T, Kerstan M, Goldhahn S:
  • Journal Title: J Orthop Surgery Volume: 28(1) Issue: 1 Pages: 2309-4990
  • DOI: 10.1177/2309499019887997
  • Peer Reviewed
• [Journal Article] Systemic Effect of LIPUS on B-TCP-(tri-calcium-phosphate) Ceramic Discs Subcutaneously Implanted in the Dorsal Aspect of Rat (2019)
  • Author(s): Hidaka K, Mikuni-Takagaki Y, Fujita M, Seki A, Ito Y, Kumagai K, Takeuchi R
  • Journal Title: Journal of Orthopaedic Trauma Volume: 33S2 Issue: 10 Pages: S2-S2
  • DOI: 10.1097/01.bot.0000602540.27662.b1
  • Peer Reviewed
• [Journal Article] Low-Intensity Pulsed Ultrasound Prevents Development of Bisphosphonate-Related Osteonecrosis of the Jaw-Like Pathophysiology in a Rat Model. (2019)
  • Author(s): Kouki Hidaka, Yuko Mikuni-Takagaki, Satoko Wada-Takahashi, Makiko Saita, Ryota Kawamata, Takenori Sato, Akira Kawata, Chihiro Miyamoto, Yojiro Maehata, Hirotaka Watabe, Nobuyuki Tani-Ishii, Nobushiro Hamada, Shun-suke Takahashi, Shinji Deguchi, Ryohei Takeuchi
  • Journal Title: Ultrasound Med Biol. Volume: 45 Issue: 7 Pages: 1-12
  • DOI: 10.1016/j.ultrasmedbio.2019.02.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Medication Related Osteonecrosis of the Jaw: Basic Research and Clinical Practice for Prevention and Treatment by Ultrasound/Laser Pulsation (2018)
  • Author(s): Yuko Mikuni-Takagaki, Kouki Hidaka, Shinichiro Kuroshima
  • Journal Title: J Orthop Trauma Volume: 32 Issue: 7 Pages: S3-S3
  • DOI: 10.1097/01.bot.0000542214.31778.55
  • Peer Reviewed
• [Presentation] 膝周囲骨切り術の利点と欠点そしてピットフォール (2021)
  • Author(s): 竹内良平
  • Organizer: 島根整形外科医学会講演
  • Invited
• [Presentation] 膝関節周囲骨切り術の歴史と未来 (2021)
  • Author(s): 竹内良平
  • Organizer: お茶の水運動器疾患セミナー
  • Invited
• [Presentation] 膝骨切り術に関する世界の現状と展望 (2021)
  • Author(s): 竹内良平
  • Organizer: 第37回膝関節フォーラム
  • Invited
• [Presentation] 並体結合（parabiosis）ラットの背部皮下に埋植したβ-TCPディスクに及ぼす低出力超音波パルスLIPUSの全身性効果 (2020)
  • Author(s): 高垣裕子，日髙恒輝，大谷茉衣子，河田 亮，竹内良平
  • Organizer: 第55回神奈川歯科大学学会総会
• [Presentation] 皮下に埋植したβ-TCPディスクへの低出力超音波パルス(LIPUS)照射による全身性の骨再生効果 (2019)
  • Author(s): 高垣裕子, 日髙恒輝, 藤田茉衣子, 関あずさ, 伊藤由広, 熊谷研, 竹内良平
  • Organizer: 第37回日本骨代謝学会学術集会
• [Presentation] ラットの背部皮下に埋植したβ-TCPディスクに及ぼすLIPUSの全身性効果Systemic Effect of LIPUS on b-TCP-(tri-calcium-phosphate) ceramic discs subcutaneously implanted in the dorsal aspect of rat. (2019)
  • Author(s): 日髙恒輝，高垣裕子，藤田茉衣子，関あずさ，伊藤由広，熊谷 研，竹内良平：
  • Organizer: 第22回超音波骨折治療研究会
  • Int'l Joint Research
• [Presentation] Low-intensity Pulsed Ultrasound (LIPUS) Prevents Development of BRONJ-like Pathophysiology in Rat Alveolar Bone Defect Induced by Tooth Removal after Alendronate and Porphyromonas Gingivalis Challenges. (2018)
  • Author(s): Hidaka K, Mikuni-Takagaki Y, Wada-Takahashi S, Saita M, Kawamata R, Sato T, Kawata A, Miyamoto C, Maehata,Y, Watabe H, Tani-Ishii N, Hamada N, Takahashi S-S, Deguchi S, Takeuchi, R
  • Organizer: American Soc Bone Miner Res 2018 Annual Meeting, Montreal, Canada
  • Int'l Joint Research
• [Presentation] 物理的刺激を利用した薬剤関連顎骨壊死MRONJの臨床・基礎研究の現状と予防・治療戦略 (2018)
  • Author(s): 高垣裕子，日髙恒輝，黒嶋伸一郎，竹内良平，岩渕博史
  • Organizer: 第21回超音波骨折治療研究会
• [Presentation] アップデートシンポジウム US6-3 非侵襲的な力学的刺激を用いたステージ0 BRONJ病態進展の予防 (2017)
  • Author(s): 日髙恒輝，竹内良平，高垣裕子
  • Organizer: 第59回歯科基礎医学会学術大会
  • Invited
• [Presentation] Therapeutic ultrasound prevents delayed healing of socket, possibly BRONJ, humorally. (2017)
  • Author(s): Hidaka K, Miyamoto C, Wada-Takahashi1 S, Kawamata R,Kawata A, Maehata Y, Saita M, Sato T, Watabe H, Tani-Ishii N, Takahashi S-S, Hamada N, Deguchi S, Mikuni-Takagaki Y, Takeuchi R
  • Organizer: CED-IADR/NOF Oral Health Research Congress 2017
  • Int'l Joint Research