{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T23:58:46Z","timestamp":1779235126187,"version":"3.51.4"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,5,12]],"date-time":"2016-05-12T00:00:00Z","timestamp":1463011200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,5,12]],"date-time":"2016-05-12T00:00:00Z","timestamp":1463011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Many strategies, including various growth factors and gene transfer, have been used to augment healing after anterior cruciate ligament (ACL) reconstruction. The biological environment regulated by the growth factors during the stage of tendon-bone healing was considered important in controlling the integrating process. The purpose of this study was to evaluate the effects of bone marrow-derived mesenchymal stem cells (BMSCs) genetically modified with bone morphogenetic protein 2 (BMP2) and basic fibroblast growth factor (bFGF) on healing after ACL reconstruction. BMSCs were infected with an adenoviral vector encoding BMP2 (AdBMP2) or bFGF (AdbFGF). Then, the infected BMSCs were surgically implanted into the tendon-bone interface. At 12 weeks postoperatively, the formation of abundant cartilage-like cells, smaller tibial bone tunnel and significantly higher ultimate load and stiffness levels, through histological analysis, micro-computed tomography and biomechanical testing, were observed. In addition, the AdBMP2-plus-AdbFGF group had the smallest bone tunnel and the best mechanical properties among all the groups. The addition of BMP2 or bFGF by gene transfer resulted in better cellularity, new bone formation and higher mechanical property, which contributed to the healing process after ACL reconstruction. Furthermore, the co-application of these two genes was more powerful and efficient than either single gene therapy.<\/jats:p>","DOI":"10.1038\/srep25940","type":"journal-article","created":{"date-parts":[[2016,5,12]],"date-time":"2016-05-12T10:19:38Z","timestamp":1463048378000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":49,"title":["Enhancement of tendon-to-bone healing after anterior cruciate ligament reconstruction using bone marrow-derived mesenchymal stem cells genetically modified with bFGF\/BMP2"],"prefix":"10.1038","volume":"6","author":[{"given":"Biao","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong-Jian","family":"Qi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qu-Bo","family":"Ni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng-Qi","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liao-Bin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,5,12]]},"reference":[{"key":"BFsrep25940_CR1","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1136\/ard.2003.008136","volume":"63","author":"A von Porat","year":"2004","unstructured":"von Porat, A., Roos, E. M. & Roos, H. High prevalence of osteoarthritis 14 years after an anterior cruciate ligament tear in male soccer players: a study of radiographic and patient relevant outcomes. Ann Rheum Dis 63, 269\u2013273 (2004).","journal-title":"Ann Rheum Dis"},{"key":"BFsrep25940_CR2","first-page":"143","volume":"13","author":"VK Goradia","year":"2000","unstructured":"Goradia, V. K., Rochat, M. C., Grana, W. A., Rohrer, M. D. & Prasad, H. S. Tendon-to-bone healing of a semitendinosus tendon autograft used for ACL reconstruction in a sheep model. Am J Knee Surg 13, 143\u2013151 (2000).","journal-title":"Am J Knee Surg"},{"key":"BFsrep25940_CR3","doi-asserted-by":"publisher","first-page":"620","DOI":"10.1177\/03635465010290051501","volume":"29","author":"CD Papageorgiou","year":"2001","unstructured":"Papageorgiou, C. D., Ma, C. B., Abramowitch, S. D., Clineff, T. D. & Woo, S. L. A multidisciplinary study of the healing of an intraarticular anterior cruciate ligament graft in a goat model. Am J Sports Med 29, 620\u2013626 (2001).","journal-title":"Am J Sports Med"},{"key":"BFsrep25940_CR4","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1177\/036354658701500306","volume":"15","author":"M Kurosaka","year":"1987","unstructured":"Kurosaka, M., Yoshiya, S. & Andrish, J. T. A biomechanical comparison of different surgical techniques of graft fixation in anterior cruciate ligament reconstruction. Am J Sports Med 15, 225\u2013229 (1987).","journal-title":"Am J Sports Med"},{"key":"BFsrep25940_CR5","doi-asserted-by":"publisher","first-page":"1756","DOI":"10.1177\/0363546507307396","volume":"35","author":"LS Lohmander","year":"2007","unstructured":"Lohmander, L. S., Englund, P. M., Dahl, L. L. & Roos, E. M. The long-term consequence of anterior cruciate ligament and meniscus injuries: osteoarthritis. Am J Sports Med 35, 1756\u20131769 (2007).","journal-title":"Am J Sports Med"},{"key":"BFsrep25940_CR6","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1177\/0363546509338827","volume":"37","author":"BE Oiestad","year":"2009","unstructured":"Oiestad, B. E., Engebretsen, L., Storheim, K. & Risberg, M. A. Knee osteoarthritis after anterior cruciate ligament injury: a systematic review. Am J Sports Med 37, 1434\u20131443 (2009).","journal-title":"Am J Sports Med"},{"key":"BFsrep25940_CR7","doi-asserted-by":"publisher","first-page":"3145","DOI":"10.1002\/art.20589","volume":"50","author":"LS Lohmander","year":"2004","unstructured":"Lohmander, L. S., Ostenberg, A., Englund, M. & Roos, H. High prevalence of knee osteoarthritis, pain and functional limitations in female soccer players twelve years after anterior cruciate ligament injury. Arthritis Rheum 50, 3145\u20133152 (2004).","journal-title":"Arthritis Rheum"},{"key":"BFsrep25940_CR8","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1007\/s00167-003-0482-4","volume":"12","author":"C Lattermann","year":"2004","unstructured":"Lattermann, C. et al. Gene transfer to the tendon-bone insertion site. Knee Surg Sports Traumatol Arthrosc 12, 510\u2013515 (2004).","journal-title":"Knee Surg Sports Traumatol Arthrosc"},{"key":"BFsrep25940_CR9","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1530\/REP-11-0277","volume":"143","author":"KJ Woad","year":"2012","unstructured":"Woad, K. J. et al. Fibroblast growth factor 2 is a key determinant of vascular sprouting during bovine luteal angiogenesis. Reproduction 143, 35\u201343 (2012).","journal-title":"Reproduction"},{"key":"BFsrep25940_CR10","doi-asserted-by":"publisher","first-page":"40575","DOI":"10.1074\/jbc.M111.274910","volume":"286","author":"Y Fei","year":"2011","unstructured":"Fei, Y., Xiao, L., Doetschman, T., Coffin, D. J. & Hurley, M. M. Fibroblast growth factor 2 stimulation of osteoblast differentiation and bone formation is mediated by modulation of the Wnt signaling pathway. J Biol Chem 286, 40575\u201340583 (2011).","journal-title":"J Biol Chem"},{"key":"BFsrep25940_CR11","doi-asserted-by":"publisher","first-page":"2751","DOI":"10.1016\/j.actbio.2009.12.045","volume":"6","author":"H Tsurushima","year":"2010","unstructured":"Tsurushima, H. et al. Enhanced bone formation using hydroxyapatite ceramic coated with fibroblast growth factor-2. Acta Biomater 6, 2751\u20132759 (2010).","journal-title":"Acta Biomater"},{"key":"BFsrep25940_CR12","first-page":"545","volume":"27","author":"M Chen","year":"2011","unstructured":"Chen, M. et al. Roles of exogenously regulated bFGF expression in angiogenesis and bone regeneration in rat calvarial defects. Int J Mol Med 27, 545\u2013553 (2011).","journal-title":"Int J Mol Med"},{"key":"BFsrep25940_CR13","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1016\/j.arthro.2009.11.014","volume":"26","author":"CJ Wang","year":"2010","unstructured":"Wang, C. J. et al. pCMV-BMP-2-transfected cell-mediated gene therapy in anterior cruciate ligament reconstruction in rabbits. Arthroscopy 26, 968\u2013976 (2010).","journal-title":"Arthroscopy"},{"key":"BFsrep25940_CR14","doi-asserted-by":"publisher","first-page":"13605","DOI":"10.3390\/ijms131013605","volume":"13","author":"Y Dong","year":"2012","unstructured":"Dong, Y., Zhang, Q., Li, Y., Jiang, J. & Chen, S. Enhancement of tendon-bone healing for anterior cruciate ligament (ACL) reconstruction using bone marrow-derived mesenchymal stem cells infected with BMP-2. Int J Mol Sci 13, 13605\u201313620 (2012).","journal-title":"Int J Mol Sci"},{"key":"BFsrep25940_CR15","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s00776-006-1088-8","volume":"12","author":"T Kohno","year":"2007","unstructured":"Kohno, T. et al. Immunohistochemical demonstration of growth factors at the tendon-bone interface in anterior cruciate ligament reconstruction using a rabbit model. J Orthop Sci 12, 67\u201373 (2007).","journal-title":"J Orthop Sci"},{"key":"BFsrep25940_CR16","doi-asserted-by":"publisher","first-page":"684","DOI":"10.3858\/emm.2010.42.10.067","volume":"42","author":"B Chen","year":"2010","unstructured":"Chen, B., Qin, J., Wang, H., Magdalou, J. & Chen, L. Effects of adenovirus-mediated bFGF, IL-1Ra and IGF-1 gene transfer on human osteoarthritic chondrocytes and osteoarthritis in rabbits. Exp Mol Med 42, 684\u2013695 (2010).","journal-title":"Exp Mol Med"},{"key":"BFsrep25940_CR17","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/s002640000199","volume":"25","author":"MJ Park","year":"2001","unstructured":"Park, M. J., Lee, M. C. & Seong, S. C. A comparative study of the healing of tendon autograft and tendon-bone autograft using patellar tendon in rabbits. Int Orthop 25, 35\u201339 (2001).","journal-title":"Int Orthop"},{"key":"BFsrep25940_CR18","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1002\/bdrc.20049","volume":"75","author":"S Tozer","year":"2005","unstructured":"Tozer, S. & Duprez, D. Tendon and ligament: development, repair and disease. Birth Defects Res C Embryo Today 75, 226\u2013236 (2005).","journal-title":"Birth Defects Res C Embryo Today"},{"key":"BFsrep25940_CR19","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1111\/wrr.12129","volume":"22","author":"JB Tang","year":"2014","unstructured":"Tang, J. B., Chen, C. H., Zhou, Y. L., McKeever, C. & Liu, P. Y. Regulatory effects of introduction of an exogenous FGF2 gene on other growth factor genes in a healing tendon. Wound Repair Regen 22, 111\u2013118 (2014).","journal-title":"Wound Repair Regen"},{"key":"BFsrep25940_CR20","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1089\/ten.tea.2010.0413","volume":"17","author":"AF Steinert","year":"2011","unstructured":"Steinert, A. F. et al. Mesenchymal stem cell characteristics of human anterior cruciate ligament outgrowth cells. Tissue Eng Part A 17, 1375\u20131388 (2011).","journal-title":"Tissue Eng Part A"},{"key":"BFsrep25940_CR21","doi-asserted-by":"publisher","first-page":"505","DOI":"10.3109\/14653241003709652","volume":"12","author":"M Haddad-Weber","year":"2010","unstructured":"Haddad-Weber, M. et al. BMP12 and BMP13 gene transfer induce ligamentogenic differentiation in mesenchymal progenitor and anterior cruciate ligament cells. Cytotherapy 12, 505\u2013513 (2010).","journal-title":"Cytotherapy"},{"key":"BFsrep25940_CR22","doi-asserted-by":"publisher","first-page":"5476","DOI":"10.1016\/j.biomaterials.2013.04.013","volume":"34","author":"Y Mifune","year":"2013","unstructured":"Mifune, Y. et al. Tendon graft revitalization using adult anterior cruciate ligament (ACL)-derived CD34\u2009+\u2009cell sheets for ACL reconstruction. Biomaterials 34, 5476\u20135487 (2013).","journal-title":"Biomaterials"},{"key":"BFsrep25940_CR23","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.2106\/00004623-200207000-00005","volume":"84-A","author":"V Martinek","year":"2002","unstructured":"Martinek, V. et al. Enhancement of tendon-bone integration of anterior cruciate ligament grafts with bone morphogenetic protein-2 gene transfer: a histological and biomechanical study. J Bone Joint Surg Am 84-A, 1123\u20131131 (2002).","journal-title":"J Bone Joint Surg Am"},{"key":"BFsrep25940_CR24","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1177\/0363546508316282","volume":"36","author":"K Sasaki","year":"2008","unstructured":"Sasaki, K. et al. Enhancement of tendon-bone osteointegration of anterior cruciate ligament graft using granulocyte colony-stimulating factor. Am J Sports Med 36, 1519\u20131527 (2008).","journal-title":"Am J Sports Med"},{"key":"BFsrep25940_CR25","doi-asserted-by":"publisher","first-page":"19073","DOI":"10.1038\/srep19073","volume":"6","author":"X Zhang","year":"2016","unstructured":"Zhang, X. et al. Runx2-Modified Adipose-Derived Stem Cells Promote Tendon Graft Integration in Anterior Cruciate Ligament Reconstruction. Sci Rep 6, 19073 (2016).","journal-title":"Sci Rep"},{"key":"BFsrep25940_CR26","doi-asserted-by":"publisher","first-page":"e0125900","DOI":"10.1371\/journal.pone.0125900","volume":"10","author":"F Bi","year":"2015","unstructured":"Bi, F., Shi, Z., Liu, A., Guo, P. & Yan, S. Anterior cruciate ligament reconstruction in a rabbit model using silk-collagen scaffold and comparison with autograft. PLoS One 10, e0125900 (2015).","journal-title":"PLoS One"},{"key":"BFsrep25940_CR27","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1002\/term.532","volume":"7","author":"LC Rose","year":"2013","unstructured":"Rose, L. C. et al. Effect of basic fibroblast growth factor in mouse embryonic stem cell culture and osteogenic differentiation. J Tissue Eng Regen Med 7, 371\u2013382 (2013).","journal-title":"J Tissue Eng Regen Med"},{"key":"BFsrep25940_CR28","doi-asserted-by":"publisher","first-page":"1531","DOI":"10.1007\/s10856-014-5185-5","volume":"25","author":"H Hikiji","year":"2014","unstructured":"Hikiji, H. et al. An in vivo murine model for screening cranial bone regenerative materials: testing of a novel synthetic collagen gel. J Mater Sci Mater Med 25, 1531\u20131538 (2014).","journal-title":"J Mater Sci Mater Med"},{"key":"BFsrep25940_CR29","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/j.mce.2011.10.018","volume":"349","author":"MC Kuhn","year":"2012","unstructured":"Kuhn, M. C. et al. Adipocyte-secreted factors increase osteoblast proliferation and the OPG\/RANKL ratio to influence osteoclast formation. Mol Cell Endocrinol 349, 180\u2013188 (2012).","journal-title":"Mol Cell Endocrinol"},{"key":"BFsrep25940_CR30","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1007\/s00774-013-0538-6","volume":"32","author":"P Li","year":"2014","unstructured":"Li, P. et al. Synergistic and sequential effects of BMP-2, bFGF and VEGF on osteogenic differentiation of rat osteoblasts. J Bone Miner Metab 32, 627\u2013635 (2014).","journal-title":"J Bone Miner Metab"},{"key":"BFsrep25940_CR31","doi-asserted-by":"publisher","first-page":"1924","DOI":"10.1177\/0363546515585314","volume":"43","author":"S Dong","year":"2015","unstructured":"Dong, S. et al. Decellularized Versus Fresh-Frozen Allografts in Anterior Cruciate Ligament Reconstruction: An In Vitro Study in a Rabbit Model. Am J Sports Med 43, 1924\u20131934 (2015).","journal-title":"Am J Sports Med"},{"key":"BFsrep25940_CR32","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1111\/j.1600-0501.2010.01976.x","volume":"22","author":"L Wang","year":"2011","unstructured":"Wang, L. et al. Repair of bone defects around dental implants with bone morphogenetic protein\/fibroblast growth factor-loaded porous calcium phosphate cement: a pilot study in a canine model. Clin Oral Implants Res 22, 173\u2013181 (2011).","journal-title":"Clin Oral Implants Res"},{"key":"BFsrep25940_CR33","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.tripleo.2006.01.019","volume":"103","author":"S Alam","year":"2007","unstructured":"Alam, S. et al. Expression of bone morphogenetic protein 2 and fibroblast growth factor 2 during bone regeneration using different implant materials as an onlay bone graft in rabbit mandibles. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 103, 16\u201326 (2007).","journal-title":"Oral Surg Oral Med Oral Pathol Oral Radiol Endod"},{"key":"BFsrep25940_CR34","doi-asserted-by":"publisher","first-page":"750","DOI":"10.1111\/j.1600-0501.2012.02481.x","volume":"24","author":"FG Draenert","year":"2013","unstructured":"Draenert, F. G., Nonnenmacher, A. L., Kammerer, P. W., Goldschmitt, J. & Wagner, W. BMP-2 and bFGF release and in vitro effect on human osteoblasts after adsorption to bone grafts and biomaterials. Clin Oral Implants Res 24, 750\u2013757 (2013).","journal-title":"Clin Oral Implants Res"},{"key":"BFsrep25940_CR35","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.bbrc.2011.02.015","volume":"406","author":"X Wei","year":"2011","unstructured":"Wei, X. et al. Local administration of TGFbeta-1\/VEGF165 gene-transduced bone mesenchymal stem cells for Achilles allograft replacement of the anterior cruciate ligament in rabbits. Biochem Biophys Res Commun 406, 204\u2013210 (2011).","journal-title":"Biochem Biophys Res Commun"},{"key":"BFsrep25940_CR36","first-page":"81","volume":"22","author":"Y Deng","year":"2012","unstructured":"Deng, Y. et al. Effect of nicotine on chondrogenic differentiation of rat bone marrow mesenchymal stem cells in alginate bead culture. Biomed Mater Eng 22, 81\u201387 (2012).","journal-title":"Biomed Mater Eng"},{"key":"BFsrep25940_CR37","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1016\/S0749-8063(04)00653-X","volume":"20","author":"JK Lim","year":"2004","unstructured":"Lim, J. K. et al. Enhancement of tendon graft osteointegration using mesenchymal stem cells in a rabbit model of anterior cruciate ligament reconstruction. Arthroscopy 20, 899\u2013910 (2004).","journal-title":"Arthroscopy"},{"key":"BFsrep25940_CR38","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1177\/0095399703258682","volume":"32","author":"HW Ouyang","year":"2004","unstructured":"Ouyang, H. W. Use of Bone Marrow Stromal Cells for Tendon Graft-to-Bone Healing: Histological and Immunohistochemical Studies in a Rabbit Model. Am J Sports Med 32, 321\u2013327 (2004).","journal-title":"Am J Sports Med"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep25940","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep25940.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep25940.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T15:19:07Z","timestamp":1672845547000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep25940"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,12]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,9,19]]}},"alternative-id":["BFsrep25940"],"URL":"https:\/\/doi.org\/10.1038\/srep25940","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,12]]},"assertion":[{"value":"2 February 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 April 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 May 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"25940"}}