General Thoracic and Cardiovascular Surgery

, Volume 66, Issue 11, pp 641–647 | Cite as

Sustained release of basic fibroblast growth factor using gelatin hydrogel improved left ventricular function through the alteration of collagen subtype in a rat chronic myocardial infarction model

  • Zipeng Li
  • Hidetoshi MasumotoEmail author
  • Jun-ichiro Jo
  • Kazuhiro Yamazaki
  • Tadashi Ikeda
  • Yasuhiko Tabata
  • Kenji Minatoya
Original Article



Chronic myocardial infarction (CMI) tends to be resistant to treatments possibly due to extensive solid fibrotic scar, hypoxia mediated by poorly vascularized environment, and/or inflammation and apoptosis. Here we aimed to testify the therapeutic effects of sustained release of basic fibroblast growth factor (bFGF) using gelatin hydrogel (GH) in a rat chronic MI model and to elucidate the therapeutic mechanism including the alteration of extracellular matrix component.


CMI model rats are prepared by the permanent ligation of proximal left anterior descending coronary artery. After 4 weeks, GH sheets (GHSs) with bFGF (100 µg) (bFGF group) or with phosphate-buffered saline (Vehicle group) were implanted to the CMI models to evaluate the effect of bFGF–GHS on chronic scar tissue. Sham operation group was also prepared (n = 5 for each).


4 weeks after implantation, bFGF–GHS significantly improved cardiac contractile function (fractional shortening: 21.8 ± 1.1 vs 21.5 ± 1.3 vs 29.7 ± 1.8%; P < 0.001/fractional area change: 33.0 ± 1.4 vs 34.1 ± 2.3 vs 40.6 ± 1.8%; P < 0.001) (Sham vs Vehicle vs bFGF) accompanied with neovascularization. Immunohistochemical studies revealed that bFGF–GHS increased collagen III/I ratio indicating the alteration of solid scar tissue. Quantitative RT-PCR results showed a decrease of collagen I mRNA expression within border MI zone.


The implantation of bFGF–GHS altered the collagen subtype of the fibrotic scar more suitable for tissue repair. The treatment of sustained-release bFGF may be promising for ischemic heart disease through chronic pathology.


Basic fibroblast growth factor Gelatin hydrogel Ischemic heart disease Drug delivery system Collagen 



This work was supported by grants from Japan Agency for Medical Research and development (AMED) (to KM), and Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (to HM) (#25462137). We thank Shuichi Miyake (Kyoto Univ.) for the excellent technical support.

Compliance with ethical standards

Conflict of interest

The authors have declared that no conflict of interest exists.


  1. 1.
    Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135:e146–603.CrossRefGoogle Scholar
  2. 2.
    Chamuleau SAJ, van der Naald M, Climent AM, Kraaijeveld AO, Wever KE, Duncker DJ, et al. Translational Research in cardiovascular repair: a call for a paradigm shift. Circ Res. 2018;122:310–8.CrossRefGoogle Scholar
  3. 3.
    Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX, et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA. 2012;307:1717–26.CrossRefGoogle Scholar
  4. 4.
    Traverse JH, Henry TD, Pepine CJ, Willerson JT, Zhao DX, Ellis SG, et al. Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA. 2012;308:2380–9.CrossRefGoogle Scholar
  5. 5.
    Menasche P, Vanneaux V. Stem cells for the treatment of heart failure. Curr Res Transl Med. 2016;64:97–106.CrossRefGoogle Scholar
  6. 6.
    Gospodarowicz D, Ferrara N, Schweigerer L, Neufeld G. Structural characterization and biological functions of fibroblast growth factor. Endocr Rev. 1987;8:95–114.CrossRefGoogle Scholar
  7. 7.
    Garbern JC, Minami E, Stayton PS, Murry CE. Delivery of basic fibroblast growth factor with a pH-responsive, injectable hydrogel to improve angiogenesis in infarcted myocardium. Biomaterials. 2011;32:2407–16.CrossRefGoogle Scholar
  8. 8.
    Takehara N, Tsutsumi Y, Tateishi K, Ogata T, Tanaka H, Ueyama T, et al. Controlled delivery of basic fibroblast growth factor promotes human cardiosphere-derived cell engraftment to enhance cardiac repair for chronic myocardial infarction. J Am Coll Cardiol. 2008;52:1858–65.CrossRefGoogle Scholar
  9. 9.
    Rosenblatt-Velin N, Lepore MG, Cartoni C, Beermann F, Pedrazzini T. FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes. J Clin Invest. 2005;115:1724–33.CrossRefGoogle Scholar
  10. 10.
    Tabata Y, Nagano A, Ikada Y. Biodegradation of hydrogel carrier incorporating fibroblast growth factor. Tissue Eng. 1999;5:127–38.CrossRefGoogle Scholar
  11. 11.
    Nakajima H, Sakakibara Y, Tambara K, Iwakura A, Doi K, Marui A, et al. Therapeutic angiogenesis by the controlled release of basic fibroblast growth factor for ischemic limb and heart injury: toward safety and minimal invasiveness. J Artif Organs. 2004;7:58–61.CrossRefGoogle Scholar
  12. 12.
    Iwakura A, Fujita M, Kataoka K, Tambara K, Sakakibara Y, Komeda M, et al. Intramyocardial sustained delivery of basic fibroblast growth factor improves angiogenesis and ventricular function in a rat infarct model. Heart Vessels. 2003;18:93–9.CrossRefGoogle Scholar
  13. 13.
    Matsuo T, Masumoto H, Tajima S, Ikuno T, Katayama S, Minakata K, et al. Efficient long-term survival of cell grafts after myocardial infarction with thick viable cardiac tissue entirely from pluripotent stem cells. Sci Rep. 2015;5:16842.CrossRefGoogle Scholar
  14. 14.
    Kabuto Y, Morihara T, Sukenari T, Kida Y, Oda R, Arai Y, et al. Stimulation of rotator cuff repair by sustained release of bone morphogenetic protein-7 using a gelatin hydrogel sheet. Tissue Eng Part A. 2015;21:2025–33.CrossRefGoogle Scholar
  15. 15.
    Tabata Y, Hijikata S, Muniruzzaman M, Ikada Y. Neovascularization effect of biodegradable gelatin microspheres incorporating basic fibroblast growth factor. J Biomater Sci Polym Ed. 1999;10:79–94.CrossRefGoogle Scholar
  16. 16.
    Ozeki M, Ishii T, Hirano Y, Tabata Y. Controlled release of hepatocyte growth factor from gelatin hydrogels based on hydrogel degradation. J Drug Target. 2001;9:461–71.CrossRefGoogle Scholar
  17. 17.
    Tabata Y, Nagano A, Muniruzzaman M, Ikada Y. In vitro sorption and desorption of basic fibroblast growth factor from biodegradable hydrogels. Biomaterials. 1998;19:1781–9.CrossRefGoogle Scholar
  18. 18.
    Tabata Y, Ikada Y. Vascularization effect of basic fibroblast growth factor released from gelatin hydrogels with different biodegradabilities. Biomaterials. 1999;20:2169–75.CrossRefGoogle Scholar
  19. 19.
    Masumoto H, Ikuno T, Takeda M, Fukushima H, Marui A, Katayama S, et al. Human iPS cell-engineered cardiac tissue sheets with cardiomyocytes and vascular cells for cardiac regeneration. Sci Rep. 2014;4:6716.CrossRefGoogle Scholar
  20. 20.
    Tambara K, Premaratne GU, Sakaguchi G, Kanemitsu N, Lin X, Nakajima H, et al. Administration of control-released hepatocyte growth factor enhances the efficacy of skeletal myoblast transplantation in rat infarcted hearts by greatly increasing both quantity and quality of the graft. Circulation. 2005;112:I129–34.PubMedGoogle Scholar
  21. 21.
    Kumagai M, Minakata K, Masumoto H, Yamamoto M, Yonezawa A, Ikeda T, et al. A therapeutic angiogenesis of sustained release of basic fibroblast growth factor using biodegradable gelatin hydrogel sheets in a canine chronic myocardial infarction model. Heart Vessels (in press).Google Scholar
  22. 22.
    Masumoto H, Matsuo T, Yamamizu K, Uosaki H, Narazaki G, Katayama S, et al. Pluripotent stem cell-engineered cell sheets reassembled with defined cardiovascular populations ameliorate reduction in infarct heart function through cardiomyocyte-mediated neovascularization. Stem Cells. 2012;30:1196–205.CrossRefGoogle Scholar
  23. 23.
    Sakakibara Y, Tambara K, Lu F, Nishina T, Sakaguchi G, Nagaya N, et al. Combined procedure of surgical repair and cell transplantation for left ventricular aneurysm: an experimental study. Circulation. 2002;106:I193-7.PubMedGoogle Scholar
  24. 24.
    Manjunatha BS, Agrawal A, Shah V. Histopathological evaluation of collagen fibers using picrosirius red stain and polarizing microscopy in oral squamous cell carcinoma. J Cancer Res Ther. 2015;11:272–6.CrossRefGoogle Scholar
  25. 25.
    Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.CrossRefGoogle Scholar
  26. 26.
    Nelson TJ, Martinez-Fernandez A, Yamada S, Perez-Terzic C, Ikeda Y, Terzic A. Repair of acute myocardial infarction by human stemness factors induced pluripotent stem cells. Circulation. 2009;120:408–16.CrossRefGoogle Scholar
  27. 27.
    Shiba Y, Gomibuchi T, Seto T, Wada Y, Ichimura H, Tanaka Y, et al. Allogeneic transplantation of iPS cell-derived cardiomyocytes regenerates primate hearts. Nature. 2016;538:388–91.CrossRefGoogle Scholar
  28. 28.
    Shiba Y, Filice D, Fernandes S, Minami E, Dupras SK, Biber BV, et al. Electrical integration of human embryonic stem cell-derived cardiomyocytes in a Guinea pig chronic infarct model. J Cardiovasc Pharmacol Ther. 2014;19:368–81.CrossRefGoogle Scholar
  29. 29.
    Gerbin KA, Murry CE. The winding road to regenerating the human heart. Cardiovasc Pathol. 2015;24:133–40.CrossRefGoogle Scholar
  30. 30.
    Ikada Y, Tabata Y. Protein release from gelatin matrices. Adv Drug Deliv Rev. 1998;31:287–301.CrossRefGoogle Scholar
  31. 31.
    Kumagai M, Marui A, Tabata Y, Takeda T, Yamamoto M, Yonezawa A, et al. Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia. Heart Vessels. 2016;31:713–21.CrossRefGoogle Scholar
  32. 32.
    Jugdutt BI. Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways. Curr Drug Targets Cardiovasc Haematol Disord. 2003;3:1–30.CrossRefGoogle Scholar
  33. 33.
    Medugorac I, Jacob R. Characterisation of left ventricular collagen in the rat. Cardiovasc Res. 1983;17:15–21.CrossRefGoogle Scholar
  34. 34.
    Gonzalez-Santamaria J, Villalba M, Busnadiego O, Lopez-Olaneta MM, Sandoval P, Snabel J, et al. Matrix cross-linking lysyl oxidases are induced in response to myocardial infarction and promote cardiac dysfunction. Cardiovasc Res. 2016;109:67–78.CrossRefGoogle Scholar
  35. 35.
    Montes GS, Junqueira LC. Biology of collagen. Rev Can Biol Exp. 1982;41:143–56.PubMedGoogle Scholar
  36. 36.
    Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol. 2018;9:419.CrossRefGoogle Scholar

Copyright information

© The Japanese Association for Thoracic Surgery 2018

Authors and Affiliations

  • Zipeng Li
    • 1
  • Hidetoshi Masumoto
    • 1
  • Jun-ichiro Jo
    • 2
  • Kazuhiro Yamazaki
    • 1
  • Tadashi Ikeda
    • 1
  • Yasuhiko Tabata
    • 2
  • Kenji Minatoya
    • 1
  1. 1.Department of Cardiovascular Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
  2. 2.Department of BiomaterialsInstitute for Frontier Life and Medical Sciences, Kyoto UniversityKyotoJapan

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