Tomorrow's Vascular Surgery Induced by World's Longest Tissue-engineered Vascular Grafts

• Project/Area Number: 19H04447
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 90110:Biomedical engineering-related
• Research Institution: Oita University
• Principal Investigator: Nakayama Yasuhide 大分大学, 医学部, 客員研究員 (50250262)
• Co-Investigator(Kenkyū-buntansha): 穴井 博文 大分大学, 医学部, 教授 (20291544) ; 寺澤 武 旭川医科大学, 医学部, 講師 (20815401) ; 岩井 良輔 岡山理科大学, フロンティア理工学研究所, 講師 (60611481) ; 宮本 伸二 大分大学, 医学部, 教授 (70253797) ; 西邑 隆徳 北海道大学, 農学研究院, 教授 (10237729)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2021: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2020: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
• Keywords: バイオチューブ / 生体内組織形成術 / 再生医療 / 組織工学 / 血管 / 移植 / 動物実験 / 人工血管 / 重症下肢虚血 / バスキュラーアクセス

Outline of Research at the Start

重症下肢虚血(CLI)患者に対して年間数万人の足切断が行われている。また、30万人以上の透析患者の約半数が毎年のようにバスキュラーアクセス(VA)血管トラブルを繰り返し、数ヶ月毎に狭窄を頻回に繰り返す例も少なく無い。一方、組織工学的手法による5mm 以下の小口径人工血管の開発例は近年多い。しかし、数十cm を超える長さは実現できず、臨床ニーズに根ざしているとは言えない。50cm以上の長い小口径組織工学人工血管の製造法を確立させ、動物移植実験によってCLI 用の動脈バイパス血管やAV 用のシャント血管としての長期信頼性を確かめ、異種移植の可能性も見出し、透析分野での臨床応用をめざす。

Outline of Final Research Achievements

There are no small-diameter, long artificial vascular grafts that can be used for below-knee bypass surgery. We have developed tissue-engineered vascular grafts called Biotube using a completely autologous approach called in-body tissue architecture (iBTA). Molds were subcutaneously embedded into goats for predetermined periods (one, two, or three months). All Makers produced Biotubes as designed in all periods. All Biotubes obtained had an inner diameter of 4 mm and a length over 50 cm with wall thickness of 0.6 mm. All Biotubes did not kink when completely bent and did not leak without any deformation under a water pressure of 200 mmHg. Their burst strength was ca. 2500 mmHg. This study confirmed that Biotubes have properties comparable to arteries; hence, we will start an investigator-initiated clinical trial in near future after obtaining the results of another implantation study.

Academic Significance and Societal Importance of the Research Achievements

膝下でのバイパス術に使用可能な細く長い人工血管は存在しない。自家静脈を使うバイパス術では、採取しても脆くて使えない、あるいは既に他手術で使われている場合には実施できない。年間約１万人が足切断に至り、その後１年の死亡率は25％と生命に直結する。本研究において、皮下に1ヶ月間型を埋植するだけで長さ50cm以上の小口径人工血管を開発できた。経済性、汎用性に優れているため、医療費の大幅な低減をもたらせると考えられる。また、移植後速やかに自己再生が起こることが確認できたため、小児患者に対して再手術の必要の無い、成長する移植体を提供する社会貢献も期待できる。

Research Products

• [Journal Article] Application of Biosheets as Right Ventricular Outflow Tract Repair Materials in a Rat Model (2022)
  • Author(s): Takeshi Mizuno , Ryosuke Iwai, Takeshi Moriwaki, Yasuhide Nakayama
  • Journal Title: Front Vet Sci Volume: 9 Pages: 837319-837319
  • DOI: 10.3389/fvets.2022.837319
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Method for Urinary Tract Reconstruction in Transplanted Embryonic Kidneys Using the Hybrid Stent: A Pig Study (2022)
  • Author(s): Kenji Matsui, Satomi Iwai, Hiroshi Sasaki, Tsuyoshi Takamura, Yoshitaka Kinoshita, Yatsumu Saito, Toshinari Fujimoto, Yasuhide Nakayama, Yohei Suzuki, Hitomi Matsunari, Hiroshi Nagashima, Eiji Kobayashi, Takashi Yokoo
  • Journal Title: Transplant Direct Volume: 8 Issue: 3 Pages: e1293-e1293
  • DOI: 10.1097/txd.0000000000001293
  • Peer Reviewed / Open Access
• [Journal Article] Acute Phase Pilot Evaluation of Small Diameter Long iBTA Induced Vascular Graft "Biotube" in a Goat Model (2022)
  • Author(s): Ryuji Higashita , Yasuhide Nakayama, Yasuyuki Shiraishi, Ryosuke Iwai, Yusuke Inoue, Akihiro Yamada , Takesi Terazawa, Tsutomu Tajikawa, Manami Miyazaki, Mamiko Ohara, Tadashi Umeno, Keitaro Okamoto, Tomonori Oie, Tomoyuki Yambe, Shinji Miyamoto
  • Journal Title: EJVES Vasc Forum Volume: 54 Pages: 27-35
  • DOI: 10.1016/j.ejvsvf.2022.01.004
  • Peer Reviewed / Open Access
• [Journal Article] Aortic valve neocuspidization with in-body tissue-engineered autologous membranes: preliminary results in a long-term goat model (2021)
  • Author(s): Kawashima Takayuki、Umeno Tadashi、Terazawa Takeshi、Wada Tomoyuki、Shuto Takashi、Nishida Haruto、Anai Hirofumi、Nakayama Yasuhide、Miyamoto Shinji
  • Journal Title: Interactive CardioVascular and Thoracic Surgery Volume: - Issue: 6 Pages: 969-977
  • DOI: 10.1093/icvts/ivab015
  • Peer Reviewed
• [Journal Article] Initial 3-year results of first human use of an in-body tissue-engineered autologous “Biotube” vascular graft for hemodialysis (2020)
  • Author(s): Nakayama Yasuhide、Kaneko Yoshiyuki、Okumura Noriko、Terazawa Takeshi
  • Journal Title: The Journal of Vascular Access Volume: 21 Issue: 1 Pages: 110-115
  • DOI: 10.1177/1129729819852550
  • Peer Reviewed
• [Journal Article] Mechanical characterization of an in-body tissue-engineered autologous collagenous sheet for application as an aortic valve reconstruction material. (2019)
  • Author(s): Terazawa T, Takayuki Kawashima T, Tadashi Umeno T, Wada T, Ozaki S, Miyamoto S, Nakayama Y.
  • Journal Title: Journal of Biomechanics（J Biomech. ） Volume: 99 Pages: 109528-109528
  • DOI: 10.1016/j.jbiomech.2019.109528
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 再生医療の常識を「破壊する」発想から生まれた技術とは？ (2019)
  • Author(s): 中山泰秀
  • Organizer: 第20回 Tonomachi Cafe
  • Invited
• [Presentation] 厚生労働省の先駆け審査指定を受けたバイオチューブ作製用の鋳型とは？ (2019)
  • Author(s): 中山泰秀
  • Organizer: 第23回日本アクセス研究会
  • Invited
• [Presentation] 先駆け審査指定を受けたバイオチューブ作製用鋳型とは？ (2019)
  • Author(s): 中山泰秀
  • Organizer: 第17回医療機器フォーラム
  • Invited