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Collagen-binding basic fibroblast growth factor improves functional remodeling of scarred endometrium in uterine infertile women: a pilot study

  • Peipei Jiang
  • Xiaoqiu Tang
  • Huiyan Wang
  • Chenyan Dai
  • Jing Su
  • Hui Zhu
  • Minmin Song
  • Jingyu Liu
  • Ziqing Nan
  • Tong Ru
  • Yaling Li
  • Jingmei Wang
  • Jun Yang
  • Bing Chen
  • Jianwu DaiEmail author
  • Yali HuEmail author
Research Paper
  • 6 Downloads

Abstract

Intrauterine adhesion (IUA) is a common cause of uterine infertility and one of the most severe clinical features is endometrial fibrosis namely endometrial scarring for which there are few cures currently. Blocked angiogenesis is the main pathological change in the scarred endometrium. The fibroblast growth factor 2 (bFGF), a member of FGF family, is usually applied to promote healing of refractory ulcer and contributes to angiogenesis of tissues. In this study, the sustained-release system of bFGF 100 µg was administrated around scarred endometrium guiding by ultrasound every 4 weeks in 18 patients (2–4 times). Results showed that after treatment, the menstrual blood volume, endometrial thickness and the scarred endometrial area were improved. Histological study showed blood vessel density increased obviously. Three patients (3/18) achieved pregnancy over 20 gestational weeks. Therefore, administrating the bFGF surrounding scarred endometrium may provide a new therapeutic approach for the patients with endometrial fibrosis.

Keywords

intrauterine adhesion CBD-bFGF endometrial scarring uterine infertility thin endometrium endometrial reconstruction 

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Notes

Acknowledgements

We thank Yaling Li and her nursing team for assistance in patient care, and thank the patients for their trust and willingness to participate in this clinical trial. This work was supported by The Strategic Priority Research Program of the Chinese Academy of Sciences (XDA01030505), Jiangsu Provincial Key Medical Center (YXZXB2016004), Key Research and Development Program of Jiangsu Province (BE2016612), National Natural Science Foundation of China (81771526), Excellent Youth Natural Science Foundation of Jiangsu Province (BK20170051), and Six Talent Peaks Projects in Jiangsu Province (WSW-074).

Compliance and ethicsThe author(s) declare that they have no conflict of interest. All procedures performed in studies involving human participants were in accordance with the ethical standards of Ethics Committee of Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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References

  1. AAGL Elevating Gynecologic Surgery. (2017). AAGL practice report: practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE). Gynecol Surg 14, 6.CrossRefGoogle Scholar
  2. Akita, S., Akino, K., Imaizumi, T., and Hirano, A. (2008). Basic fibroblast growth factor accelerates and improves second-degree burn wound healing. Wound Repair Regen 16, 635–641.CrossRefGoogle Scholar
  3. American College of Obstetricians and Gynecologists. (2014). ACOG Practice Bulletin No.142: Cerclage for the management of cervical insufficiency. Obstet Gynecol 123, 372–379.CrossRefGoogle Scholar
  4. Andrades, J.A., Wu, L.T., Hall, F.L., Nimni, M.E., and Becerra, J. (2001). Engineering, expression, and renaturation of a collagen-targeted human bFGF fusion protein. Growth Factors 18, 261–275.CrossRefGoogle Scholar
  5. Asherman, J.G. (1948). Amenorrhoea traumatica (atretica). J Obstet Gynaecol Br Emp 55, 23–30.CrossRefGoogle Scholar
  6. Asherman, J.G. (1950). Traumatic intra-uterine adhesions. J Obstet Gynaecol Br Emp 57, 892–896.CrossRefGoogle Scholar
  7. ACOG Committee on Practice Bulletins. (2006). ACOG Practice Bulletin No. 74. Antibiotic prophylaxis for gynecologic procedures. Obstet Gynecol 108, 225–234.CrossRefGoogle Scholar
  8. Beenken, A., and Mohammadi, M. (2009). The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8, 235–253.CrossRefGoogle Scholar
  9. Bush, M.A., Samara, E., Whitehouse, M.J., Yoshizawa, C., Novicki, D.L., Pike, M., Laham, R.J., Simons, M., and Chronos, N.A. (2001). Pharmacokinetics and pharmacodynamics of recombinant FGF-2 in a phase I trial in coronary artery disease. J Clin Pharmacol 41, 378–385.CrossRefGoogle Scholar
  10. Capella-Allouc, S., Morsad, F., Rongieres-Bertrand, C., Taylor, S., and Fernandez, H. (1999). Hysteroscopic treatment of severe Asherman’s syndrome and subsequent fertility. Hum Reprod 14, 1230–1233.CrossRefGoogle Scholar
  11. Carmeliet, P. (2000). VEGF gene therapy: stimulating angiogenesis or angioma-genesis? Nat Med 6, 1102–1103.CrossRefGoogle Scholar
  12. Chu, H., and Wang, Y. (2012). Therapeutic angiogenesis: controlled delivery of angiogenic factors. Ther Deliv 3, 693–714.CrossRefGoogle Scholar
  13. Deans, R., and Abbott, J. (2010). Review of intrauterine adhesions. J Minim Invasive Gynecol 17, 555–569.CrossRefGoogle Scholar
  14. Eppler, S.M., Combs, D.L., Henry, T.D., Lopez, J.J., Ellis, S.G., Yi, J.H., Annex, B.H., McCluskey, E.R., and Zioncheck, T.F. (2002). A targetmediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clin Pharmacol Ther 72, 20–32.CrossRefGoogle Scholar
  15. Fan, X., Krieg, S., Kuo, C.J., Wiegand, S.J., Rabinovitch, M., Druzin, M.L., Brenner, R.M., Giudice, L.C., and Nayak, N.R. (2008). VEGF blockade inhibits angiogenesis and reepithelialization of endometrium. FASEB J 22, 3571–3580.CrossRefGoogle Scholar
  16. Fujita, M., Ishihara, M., Simizu, M., Obara, K., Ishizuka, T., Saito, Y., Yura, H., Morimoto, Y., Takase, B., Matsui, T., et al. (2004). Vascularization in vivo caused by the controlled release of fibroblast growth factor-2 from an injectable chitosan/non-anticoagulant heparin hydrogel. Biomaterials 25, 699–706.CrossRefGoogle Scholar
  17. Gannon, B.J., Carati, C.J., and Verco, C.J. (1997). Endometrial perfusion across the normal human menstrual cycle assessed by laser Doppler fluxmetry. Hum Reprod 12, 132–139.CrossRefGoogle Scholar
  18. Gargett, C., and Rogers, P. (2001). Human endometrial angiogenesis. Reproduction 121, 181–186.CrossRefGoogle Scholar
  19. Gaudry, M., Bregerie, O., Andrieu, V., El Benna, J., Pocidalo, M.A., and Hakim, J. (1997). Intracellular pool of vascular endothelial growth factor in human neutrophils. Blood 90, 4153–4161.Google Scholar
  20. Girling, J.E., and Rogers, P.A.W. (2005). Recent advances in endometrial angiogenesis research. Angiogenesis 8, 89–99.CrossRefGoogle Scholar
  21. Gurtner, G.C., Werner, S., Barrandon, Y., and Longaker, M.T. (2008). Wound repair and regeneration. Nature 453, 314–321.CrossRefGoogle Scholar
  22. Hashimoto, T., Koyama, H., Miyata, T., Hosaka, A., Tabata, Y., Takato, T., and Nagawa, H. (2009). Selective and sustained delivery of basic fibroblast growth factor (bFGF) for treatment of peripheral arterial disease: results of a phase I trial. Eur J Vasc Endovasc Surg 38, 71–75.CrossRefGoogle Scholar
  23. Hato, N., Nota, J., Komobuchi, H., Teraoka, M., Yamada, H., Gyo, K., Yanagihara, N., and Tabata, Y. (2012). Facial nerve decompression surgery using bFGF-impregnated biodegradable gelatin hydrogel in patients with Bell palsy. Otolaryngol Head Neck Surg 146, 641–646.CrossRefGoogle Scholar
  24. Healy, M.W., Schexnayder, B., Connell, M.T., Terry, N., DeCherney, A.H., Csokmay, J.M., Yauger, B.J., and Hill, M.J. (2016). Intrauterine adhesion prevention after hysteroscopy: a systematic review and meta-analysis. Am J Obstet Gynecol 215, 267–275.e7.CrossRefGoogle Scholar
  25. Hirano, S., Mizuta, M., Kaneko, M., Tateya, I., Kanemaru, S.I., and Ito, J. (2013). Regenerative phonosurgical treatments for vocal fold scar and sulcus with basic fibroblast growth factor. Laryngoscope 123, 2749–2755.CrossRefGoogle Scholar
  26. Jiang, X.W., Zhang, Y., Zhang, H., Lu, K., Yang, S.K., and Sun, G.L. (2013). Double-blind, randomized, controlled clinical trial of the effects of diosmectite and basic fibroblast growth factor paste on the treatment of minor recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Rad 116, 570–575.CrossRefGoogle Scholar
  27. Kanazawa, T., Komazawa, D., Indo, K., Akagi, Y., Lee, Y., Nakamura, K., Matsushima, K., Kunieda, C., Misawa, K., Nishino, H., et al. (2015). Single injection of basic fibroblast growth factor to treat severe vocal fold lesions and vocal fold paralysis. Laryngoscope 125, E338–E344.CrossRefGoogle Scholar
  28. Kawaguchi, H., Oka, H., Jingushi, S., Izumi, T., Fukunaga, M., Sato, K., Matsushita, T., Nakamura, K., and Nakamura, K. (2010). A local application of recombinant human fibroblast growth factor 2 for tibial shaft fractures: A randomized, placebo-controlled trial. J Bone Miner Res 25, 2735–2743.CrossRefGoogle Scholar
  29. Khurana, R., and Simons, M. (2003). Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease. Trends Cardiovasc Med 13, 116–122.CrossRefGoogle Scholar
  30. Kumagai, M., Marui, A., Tabata, Y., Takeda, T., Yamamoto, M., Yonezawa, A., Tanaka, S., Yanagi, S., Ito-Ihara, T., Ikeda, T., et al. (2016). Safety and efficacy of sustained release of basic fibroblast growth factor using gelatin hydrogel in patients with critical limb ischemia. Heart Vessels 31, 713–721.CrossRefGoogle Scholar
  31. Li, Q., Tao, L., Chen, B., Ren, H., Hou, X., Zhou, S., Zhou, J., Sun, X., Dai, J., and Ding, Y. (2012). Extrahepatic bile duct regeneration in pigs using collagen scaffolds loaded with human collagen-binding bFGF. Biomaterials 33, 4298–4308.CrossRefGoogle Scholar
  32. Li, X.’., Sun, H., Lin, N., Hou, X., Wang, J., Zhou, B., Xu, P., Xiao, Z., Chen, B., Dai, J., et al. (2011). Regeneration of uterine horns in rats by collagen scaffolds loaded with collagen-binding human basic fibroblast growth factor. Biomaterials 32, 8172–8181.CrossRefGoogle Scholar
  33. Li, X., Wang, C., Xiao, J., McKeehan, W.L., and Wang, F. (2016). Fibroblast growth factors, old kids on the new block. Semin Cell Dev Biol 53, 155–167.CrossRefGoogle Scholar
  34. Lu, J., Zhu, H., Zhu, X., Tang, X., Wang, H., and Hu, Y. (2017). Logistic regression analysis of the risk factors of severe intrauterine adhesion recurrence (in Chinese). J Pract Obstet Gynecol 33, 751–754.Google Scholar
  35. Ma, F., Xiao, Z., Chen, B., Hou, X., Dai, J., and Xu, R. (2014). Linear ordered collagen scaffolds loaded with collagen-binding basic fibroblast growth factor facilitate recovery of sciatic nerve injury in rats. Tissue Eng Part A 20, 1253–1262.CrossRefGoogle Scholar
  36. March, C.M. (2011a). Asherman’s syndrome. Semin Reprod Med 29, 083–094.CrossRefGoogle Scholar
  37. March, C.M. (2011b). Management of Asherman’s syndrome. Reprod Biomed Online 23, 63–76.CrossRefGoogle Scholar
  38. Murayama, T., Tepper, O.M., Silver, M., Ma, H., Losordo, D.W., Isner, J. M., Asahara, T., and Kalla, C. (2002). Determination of bone marrow-derived endothelial progenitor cell significance in angiogenic growth factor-induced neovascularization in vivo. Exp Hematol 30, 967–972.CrossRefGoogle Scholar
  39. Nakamichi, M., Akishima-Fukasawa, Y., Fujisawa, C., Mikami, T., Onishi, K., and Akasaka, Y. (2016). Basic fibroblast growth factor induces angiogenic properties of fibrocytes to stimulate vascular formation during wound healing. Am J Pathol 186, 3203–3216.CrossRefGoogle Scholar
  40. Nunes, Q.M., Li, Y., Sun, C., Kinnunen, T.K., and Fernig, D.G. (2016). Fibroblast growth factors as tissue repair and regeneration therapeutics. PeerJ 4, e1535.CrossRefGoogle Scholar
  41. Ono, I., Akasaka, Y., Kikuchi, R., Sakemoto, A., Kamiya, T., Yamashita, T., and Jimbow, K. (2007). Basic fibroblast growth factor reduces scar formation in acute incisional wounds. Wound Repair Regen 15, 617–623.CrossRefGoogle Scholar
  42. Pabuçcu, R., Atay, V., Orhon, E., Urman, B., and Ergün, A. (1997). Hysteroscopic treatment of intrauterine adhesions is safe and effective in the restoration of normal menstruation and fertility. Fertil Steril 68, 1141–1143.CrossRefGoogle Scholar
  43. Rafii, S., and Lyden, D. (2003). Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 9, 702–712.CrossRefGoogle Scholar
  44. Rehman, J., Li, J., Orschell, C.M., and March, K.L. (2003). Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation 107, 1164–1169.CrossRefGoogle Scholar
  45. Risau, W. (1997). Mechanisms of angiogenesis. Nature 386, 671–674.CrossRefGoogle Scholar
  46. Rogers, P.A.W., and Gargett, C.E. (1998). Endometrial angiogenesis. Angiogenesis 2, 287–294.CrossRefGoogle Scholar
  47. Schenker, J.G., and Margalioth, E.J. (1982). Intrauterine adhesions: an updated appraisal. Fertil Steril 37, 593–610.CrossRefGoogle Scholar
  48. Shi, C., Chen, W., Chen, B., Shan, T., Jia, W., Hou, X., Li, L., Ye, G., and Dai, J. (2017). Bladder regeneration in a canine model using a bladder acellular matrix loaded with a collagen-binding bFGF. Biomater Sci 5, 2427–2436.CrossRefGoogle Scholar
  49. Shi, C., Chen, W., Zhao, Y., Chen, B., Xiao, Z., Wei, Z., Hou, X., Tang, J., Wang, Z., and Dai, J. (2011). Regeneration of full-thickness abdominal wall defects in rats using collagen scaffolds loaded with collagen-binding basic fibroblast growth factor. Biomaterials 32, 753–759.CrossRefGoogle Scholar
  50. Shi, Q., Gao, W., Han, X.L., Zhu, X.S., Sun, J., Xie, F., Hou, X.L., Yang, H. L., Dai, J.W., and Chen, L. (2014). Collagen scaffolds modified with collagen-binding bFGF promotes the neural regeneration in a rat hemisected spinal cord injury model. Sci China Life Sci 57, 232–240.CrossRefGoogle Scholar
  51. Silva, E.A., and Mooney, D.J. (2007). Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis. J Thromb Haemost 5, 590–598.CrossRefGoogle Scholar
  52. Smith, S.K. (2001). Regulation of angiogenesis in the endometrium. Trends Endocrinol Metab 12, 147–151.CrossRefGoogle Scholar
  53. Squires, C.H., Childs, J., Eisenberg, S.P., Polverini, P.J., and Sommer, A. (1988). Production and characterization of human basic fibroblast growth factor from Escherichia coli. J Biol Chem 263, 16297–16302.Google Scholar
  54. Tabata, Y., and Ikada, Y. (1999). Vascularization effect of basic fibroblast growth factor released from gelatin hydrogels with different biodegradabilities. Biomaterials 20, 2169–2175.CrossRefGoogle Scholar
  55. Taichman, N.S., Young, S., Cruchley, A.T., Taylor, P., and Paleolog, E. (1997). Human neutrophils secrete vascular endothelial growth factor. J Leukoc Biol 62, 397–400.CrossRefGoogle Scholar
  56. Tang, H., Jia, W., Hou, X., Zhao, Y., Huan, Y., Chen, W., Yu, W., Ou Zhu, M.M., Ye, G., Chen, B., et al. (2018). Collagen scaffolds tethered with bFGF promote corpus spongiosum regeneration in a beagle model. Biomed Mater 13, 031001.CrossRefGoogle Scholar
  57. Uchi, H., Igarashi, A., Urabe, K., Koga, T., Nakayama, J., Kawamori, R., Tamaki, K., Hirakata, H., Ohura, T., and Furue, M. (2009). Clinical efficacy of basic fibroblast growth factor (bFGF) for diabetic ulcer. Eur J Dermatol 19, 461–468.Google Scholar
  58. Virag, J.A.I., Rolle, M.L., Reece, J., Hardouin, S., Feigl, E.O., and Murry, C.E. (2007). Fibroblast growth factor-2 regulates myocardial infarct repair. Am J Pathol 171, 1431–1440.CrossRefGoogle Scholar
  59. Wamsteker, K., and De Block, S. (1998). Diagnostic hysteroscopy: Technique and documentation. In Endoscopic Surgery for Gynaecologists. Sutton, C., and Diamond, M., eds. (London: Saunders), pp. 511–524.Google Scholar
  60. Wei, P., Chen, X.L., Song, X.X., Han, C.S., and Liu, Y.X. (2004). VEGF, bFGF, and their receptors in the endometrium of rhesus monkey during menstrual cycle and early pregnancy. Mol Reprod Dev 68, 456–462.CrossRefGoogle Scholar
  61. Yang, J.H., Chen, C.D., Chen, S.U., Yang, Y.S., and Chen, M.J. (2016). The influence of the location and extent of intrauterine adhesions on recurrence after hysteroscopic adhesiolysis. BJOG 123, 618–623.CrossRefGoogle Scholar
  62. Yu, D., Wong, Y.M., Cheong, Y., Xia, E., and Li, T.C. (2008). Asherman syndrome—one century later. Fertil Steril 89, 759–779.CrossRefGoogle Scholar
  63. Zhang, D., Huang, Z., Sun, P., Huang, H., Zhang, Y., Dai, J., Liu, J., and Shi, Q. (2017). Acceleration of healing of traumatic tympanic membrane perforation in rats by implanted collagen membrane integrated with collagen-binding basic fibroblast growth factor. Tissue Eng Part A 23, 20–29.CrossRefGoogle Scholar
  64. Zhang, J., Ding, L., Zhao, Y., Sun, W., Chen, B., Lin, H., Wang, X., Zhang, L., Xu, B., and Dai, J. (2009). Collagen-targeting vascular endothelial growth factor improves cardiac performance after myocardial infarction. Circulation 119, 1776–1784.CrossRefGoogle Scholar
  65. Zhao, G., Cao, Y., Zhu, X., Tang, X., Ding, L., Sun, H., Li, J., Li, X., Dai, C., Ru, T., et al. (2017). Transplantation of collagen scaffold with autologous bone marrow mononuclear cells promotes functional endometrium reconstruction via downregulating ΔNp63 expression in Asherman’s syndrome. Sci China Life Sci 60, 404–416.CrossRefGoogle Scholar
  66. Zhao, W., Chen, B., Li, X., Lin, H., Sun, W., Zhao, Y., Wang, B., Zhao, Y., Han, Q., and Dai, J. (2007). Vascularization and cellularization of collagen scaffolds incorporated with two different collagen-targeting human basic fibroblast growth factors. J Biomed Mater Res 82A, 630–636.CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Peipei Jiang
    • 1
  • Xiaoqiu Tang
    • 1
  • Huiyan Wang
    • 1
  • Chenyan Dai
    • 1
  • Jing Su
    • 1
  • Hui Zhu
    • 1
  • Minmin Song
    • 1
  • Jingyu Liu
    • 2
  • Ziqing Nan
    • 3
  • Tong Ru
    • 1
  • Yaling Li
    • 1
  • Jingmei Wang
    • 4
  • Jun Yang
    • 4
  • Bing Chen
    • 5
  • Jianwu Dai
    • 5
    Email author
  • Yali Hu
    • 1
    Email author
  1. 1.Department of Obstetrics and GynecologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
  2. 2.Center for Reproductive Medicine, Department of Obstetrics and GynecologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
  3. 3.Nanjing Drum Tower HospitalChinese Academy of Medical Science & Peking Union Medical CollageNanjingChina
  4. 4.Department of PathologyThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
  5. 5.Institute of Genetics and Developmental BiologyChinese Academy of SciencesBeijingChina

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