{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T19:13:48Z","timestamp":1791314028687,"version":"4.3.1"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,5,18]],"date-time":"2016-05-18T00:00:00Z","timestamp":1463529600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,5,18]],"date-time":"2016-05-18T00:00:00Z","timestamp":1463529600000},"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>In orthopedic surgery, large amount of diseased or injured bone routinely needs to be replaced. Autografts are mainly used but their availability is limited. Commercially available bone substitutes allow bone ingrowth but lack the capacity to induce bone formation. Thus, off-the-shelf osteoinductive bone substitutes that can replace bone grafts are required. We tested the carrier properties of a biphasic, calcium sulphate and hydroxyapatite ceramic material, containing a combination of recombinant human bone morphogenic protein-2 (rhBMP-2) to induce bone and zoledronic acid (ZA) to delay early resorption. <jats:italic>In-vitro<\/jats:italic>, the biphasic material released 90% of rhBMP-2 and 10% of ZA in the first week. No major changes were found in the surface structure using scanning electron microscopy (SEM) or in the mechanical properties after adding rhBMP-2 or ZA. <jats:italic>In-vivo<\/jats:italic> bone formation was studied in an abdominal muscle pouch model in rats (n\u2009=\u20096\/group). The mineralized volume was significantly higher when the biphasic material was combined with both rhBMP-2 and ZA (21.4\u2009\u00b1\u20095.5\u2009mm<jats:sup>3<\/jats:sup>) as compared to rhBMP-2 alone (10.9\u2009\u00b1\u20092.1\u2009mm<jats:sup>3<\/jats:sup>) when analyzed using micro computed tomography (\u03bc-CT) (p\u2009&lt;\u20090.01). In the clinical setting, the biphasic material combined with both rhBMP-2 and ZA can potentially regenerate large volumes of bone.<\/jats:p>","DOI":"10.1038\/srep26033","type":"journal-article","created":{"date-parts":[[2016,5,18]],"date-time":"2016-05-18T10:15:03Z","timestamp":1463566503000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["A Biphasic Calcium Sulphate\/Hydroxyapatite Carrier Containing Bone Morphogenic Protein-2 and Zoledronic Acid Generates Bone"],"prefix":"10.1038","volume":"6","author":[{"given":"Deepak Bushan","family":"Raina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Isaksson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Hettwer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashok","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Lidgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"T\u00e4gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,5,18]]},"reference":[{"key":"BFsrep26033_CR1","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1615\/CritRevBiomedEng.v40.i5.10","volume":"40","author":"AR Amini","year":"2012","unstructured":"Amini, A. R., Laurencin, C. T. & Nukavarapu, S. P. Bone tissue engineering: recent advances and challenges. Crit. Rev. Biomed. Eng. 40, 363\u2013408 (2012).","journal-title":"Crit. Rev. Biomed. Eng."},{"key":"BFsrep26033_CR2","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1302\/2046-3758.33.2000296","volume":"3","author":"L Lidgren","year":"2014","unstructured":"Lidgren, L., Gomez-Barrena, E. N., Duda, G., Puhl, W. & Carr, A. European musculoskeletal health and mobility in Horizon 2020: Setting priorities for musculoskeletal research and innovation. Bone Joint Res. 3, 48\u201350 (2014).","journal-title":"Bone Joint Res."},{"key":"BFsrep26033_CR3","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1097\/00003086-199608000-00037","volume":"329","author":"ED Arrington","year":"1996","unstructured":"Arrington, E. D., Smith, W. J., Chambers, H. G., Bucknell, A. L. & Davino, N. A. Complications of iliac crest bone graft harvesting. Clin. Orthop. Rel. Res. 329, 300\u2013309 (1996).","journal-title":"Clin. Orthop. Rel. Res."},{"key":"BFsrep26033_CR4","doi-asserted-by":"publisher","first-page":"S20","DOI":"10.1016\/j.injury.2005.07.029","volume":"36","author":"PV Giannoudis","year":"2005","unstructured":"Giannoudis, P. V., Dinopoulos, H. & Tsiridis, E. Bone substitutes: an update. Injury 36, S20\u2013S27 (2005).","journal-title":"Injury"},{"key":"BFsrep26033_CR5","first-page":"217","volume":"50","author":"BD Boyan","year":"2006","unstructured":"Boyan, B. D., Ranly, D. M. & Schwartz, Z. Use of Growth Factors to Modify Osteoinductivity of Demineralized Bone Allografts: Lessons for Tissue Engineering of Bone. Dent. Clin. 50, 217\u2013228 (2006).","journal-title":"Dent. Clin."},{"key":"BFsrep26033_CR6","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1902\/jop.1996.67.9.918","volume":"67","author":"Z Schwartz","year":"1996","unstructured":"Schwartz, Z. et al. Ability of commercial demineralized freeze-dried bone allograft to induce new bone formation. J. Periodontol. 67, 918\u2013926 (1996).","journal-title":"J. Periodontol."},{"key":"BFsrep26033_CR7","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1902\/jop.1998.69.4.470","volume":"69","author":"Z Schwartz","year":"1998","unstructured":"Schwartz, Z. et al. Ability of commercial demineralized freeze-dried bone allograft to induce new bone formation is dependent on donor age but not gender. J. Periodontol. 69, 470\u2013478 (1998).","journal-title":"J. Periodontol."},{"key":"BFsrep26033_CR8","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1111\/cid.12118","volume":"17","author":"L Wei","year":"2013","unstructured":"Wei, L., Miron, R. J., Shi, B. & Zhang, Y. Osteoinductive and osteopromotive variability among different demineralized bone allografts. Clin. Implant Dent. Rel. Res. 17, 533\u2013542 (2013).","journal-title":"Clin. Implant Dent. Rel. Res."},{"key":"BFsrep26033_CR9","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.2106\/00004623-199511000-00017","volume":"77","author":"WW Tomford","year":"1995","unstructured":"Tomford, W. W. Transmission of disease through transplantation of musculoskeletal allografts. J. Bone Joint Surg. 77, 1742\u20131754 (1995).","journal-title":"J. Bone Joint Surg."},{"key":"BFsrep26033_CR10","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1002\/term.5","volume":"1","author":"P Habibovic","year":"2007","unstructured":"Habibovic, P. & de Groot, K. Osteoinductive biomaterials\u2014properties and relevance in bone repair. J. Tissue Eng. Regen. Med. 1, 25\u201332 (2007).","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"BFsrep26033_CR11","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1186\/1749-799X-9-18","volume":"9","author":"A Oryan","year":"2014","unstructured":"Oryan, A., Alidadi, S., Moshiri, A. & Maffulli, N. Bone regenerative medicine: classic options, novel strategies and future directions. J. Orthop. Surg. Res. 9, 1749\u20131799 (2014).","journal-title":"J. Orthop. Surg. Res."},{"key":"BFsrep26033_CR12","doi-asserted-by":"crossref","unstructured":"Blackwood, K. A., Bock, N., Dargaville, T. R. & Ann Woodruff, M. Scaffolds for growth factor delivery as applied to bone tissue engineering. Int. J. Polym. Sci. 2012, 25 Pages (2012).","DOI":"10.1155\/2012\/174942"},{"key":"BFsrep26033_CR13","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nmat2441","volume":"8","author":"ES Place","year":"2009","unstructured":"Place, E. S., Evans, N. D. & Stevens, M. M. Complexity in biomaterials for tissue engineering. Nat. Mater. 8, 457\u2013470 (2009).","journal-title":"Nat. Mater."},{"key":"BFsrep26033_CR14","doi-asserted-by":"publisher","first-page":"2529","DOI":"10.1016\/S0142-9612(00)00121-6","volume":"21","author":"DW Hutmacher","year":"2000","unstructured":"Hutmacher, D. W. Scaffolds in tissue engineering bone and cartilage. Biomaterials 21, 2529\u20132543 (2000).","journal-title":"Biomaterials"},{"key":"BFsrep26033_CR15","doi-asserted-by":"publisher","first-page":"2391","DOI":"10.1089\/ten.tea.2009.0206","volume":"16","author":"BB Mandal","year":"2010","unstructured":"Mandal, B. B., Das, S., Choudhury, K. & Kundu, S. C. Implication of silk film RGD availability and surface roughness on cytoskeletal organization and proliferation of primary rat bone marrow cells. Tissue Eng. A 16, 2391\u20132403 (2010).","journal-title":"Tissue Eng. A"},{"key":"BFsrep26033_CR16","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1002\/jor.22815","volume":"33","author":"P Bosemark","year":"2015","unstructured":"Bosemark, P., Perdikouri, C., Pelkonen, M., Isaksson, H. & T\u00e4gil, M. The Masquelet Induced Membrane Technique with BMP and a Synthetic Scaffold Can Heal a Rat Femoral Critical Size Defect. J. Orthop. Res. 33, 488\u2013495 (2015).","journal-title":"J. Orthop. Res."},{"key":"BFsrep26033_CR17","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1002\/(SICI)1097-4636(199612)32:4<505::AID-JBM2>3.0.CO;2-V","volume":"32","author":"TJ Gao","year":"1996","unstructured":"Gao, T. J. et al. Enhanced healing of segmental tibial defects in sheep by a composite bone substitute composed of tricalcium phosphate cylinder, bone morphogenetic protein and type IV collagen. J. Biomed. Mater. Res. 32, 505\u2013512 (1996).","journal-title":"J. Biomed. Mater. Res."},{"key":"BFsrep26033_CR18","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1002\/(SICI)1097-4636(19980905)41:3<359::AID-JBM3>3.0.CO;2-B","volume":"41","author":"JA Koempel","year":"1998","unstructured":"Koempel, J. A., Patt, B. S., O\u2019Grady, K., Wozney, J. & Toriumi, D. M. The effect of recombinant human bone morphogenetic protein-2 on the integration of porous hydroxyapatite implants with bone. J. Biomed. Mater. Res. 41, 359\u2013363 (1998).","journal-title":"J. Biomed. Mater. Res."},{"key":"BFsrep26033_CR19","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.11607\/jomi.3708","volume":"29","author":"J Caball\u00e9-Serrano","year":"2013","unstructured":"Caball\u00e9-Serrano, J., Bosshardt, D. D., Buser, D. & Gruber, R. Proteomic Analysis of Porcine Bone-Conditioned Medium. Int. J. Oral Maxillofac. Implants 29, 1208\u20131215 (2013).","journal-title":"Int. J. Oral Maxillofac. Implants"},{"key":"BFsrep26033_CR20","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/j.bone.2013.06.030","volume":"56","author":"N Mathavan","year":"2013","unstructured":"Mathavan, N., Bosemark, P., Isaksson, H. & T\u00e4gil, M. Investigating the synergistic efficacy of BMP-7 and zoledronate on bone allografts using an open rat osteotomy model. Bone 56, 440\u2013448 (2013).","journal-title":"Bone"},{"key":"BFsrep26033_CR21","doi-asserted-by":"publisher","first-page":"228","DOI":"10.3109\/17453674.2011.566138","volume":"82","author":"O Belfrage","year":"2011","unstructured":"Belfrage, O., Flivik, G., Sundberg, M., Kesteris, U. & T\u00e4gil, M. Local treatment of cancellous bone grafts with BMP-7 and zoledronate increases both the bone formation rate and bone density: a bone chamber study in rats. Acta Orthop. 82, 228\u2013233 (2011).","journal-title":"Acta Orthop."},{"key":"BFsrep26033_CR22","doi-asserted-by":"publisher","first-page":"2654","DOI":"10.1097\/00007632-200212010-00004","volume":"27","author":"R Johnsson","year":"2002","unstructured":"Johnsson, R., Str\u00f6mqvist, B. & Aspenberg, P. Randomized Radiostereometric Study Comparing Osteogenic Protein-1 (BMP-7) and Autograft Bone in Human Noninstrumented Posterolateral Lumbar Fusion: 2002 Volvo Award in Clinical Studies. Spine 27, 2654\u20132661 (2002).","journal-title":"Spine"},{"key":"BFsrep26033_CR23","doi-asserted-by":"publisher","first-page":"S151","DOI":"10.2106\/00004623-200100022-00013","volume":"83","author":"GE Friedlaender","year":"2001","unstructured":"Friedlaender, G. E. et al. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J. Bone Joint Surg. 83, S151\u2013S158 (2001).","journal-title":"J. Bone Joint Surg."},{"key":"BFsrep26033_CR24","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/S8756-3282(00)00358-6","volume":"27","author":"H Kaneko","year":"2000","unstructured":"Kaneko, H. et al. Direct stimulation of osteoclastic bone resorption by bone morphogenetic protein (BMP)-2 and expression of BMP receptors in mature osteoclasts. Bone 27, 479\u2013486 (2000).","journal-title":"Bone"},{"key":"BFsrep26033_CR25","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/S8756-3282(99)00121-0","volume":"25","author":"H Yasuda","year":"1999","unstructured":"Yasuda, H. et al. A novel molecular mechanism modulating osteoclast differentiation and function. Bone 25, 109\u2013113 (1999).","journal-title":"Bone"},{"key":"BFsrep26033_CR26","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/ar134","volume":"3","author":"EM Gravallese","year":"2001","unstructured":"Gravallese, E. M., Galson, D. L., Goldring, S. R. & Auron, P. E. The role of TNF-receptor family members and other TRAF-dependent receptors in bone resorption. Arthritis Res. 3, 6\u201312 (2001).","journal-title":"Arthritis Res."},{"key":"BFsrep26033_CR27","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1007\/s00198-007-0441-x","volume":"18","author":"P Giannoudis","year":"2007","unstructured":"Giannoudis, P., Kanakaris, N. & Einhorn, T. Interaction of bone morphogenetic proteins with cells of the osteoclast lineage: review of the existing evidence. Osteoporos. Int. 18, 1565\u20131581 (2007).","journal-title":"Osteoporos. Int."},{"key":"BFsrep26033_CR28","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1002\/jbmr.5650101008","volume":"10","author":"DE Hughes","year":"1995","unstructured":"Hughes, D. E. et al. Bisphosphonates promote apoptosis in murine osteoclasts in vitro and in vivo. J. Bone Miner. Res. 10, 1478\u20131487 (1995).","journal-title":"J. Bone Miner. Res."},{"key":"BFsrep26033_CR29","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.bone.2010.11.008","volume":"49","author":"MJ Rogers","year":"2011","unstructured":"Rogers, M. J., Crockett, J. C., Coxon, F. P. & M\u00f6nkk\u00f6nen, J. Biochemical and molecular mechanisms of action of bisphosphonates. Bone 49, 34\u201341 (2011).","journal-title":"Bone"},{"key":"BFsrep26033_CR30","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1016\/j.bone.2005.05.003","volume":"38","author":"GH Nancollas","year":"2006","unstructured":"Nancollas, G. H. et al. Novel insights into actions of bisphosphonates on bone: Differences in interactions with hydroxyapatite. Bone 38, 617\u2013627 (2006).","journal-title":"Bone"},{"key":"BFsrep26033_CR31","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1210\/jc.2004-0952","volume":"90","author":"CV Odvina","year":"2005","unstructured":"Odvina, C. V. et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J. Clin. Endocrinol. Metabol. 90, 1294\u20131301 (2005).","journal-title":"J. Clin. Endocrinol. Metabol."},{"key":"BFsrep26033_CR32","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.joms.2004.02.004","volume":"62","author":"SL Ruggiero","year":"2004","unstructured":"Ruggiero, S. L., Mehrotra, B., Rosenberg, T. J. & Engroff, S. L. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J. Oral Maxillofac. Surg. 62, 527\u2013534 (2004).","journal-title":"J. Oral Maxillofac. Surg."},{"key":"BFsrep26033_CR33","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.1056\/NEJMra022308","volume":"349","author":"J-T Chang","year":"2003","unstructured":"Chang, J.-T., Green, J. & Beitz, J. Renal Failure with the Use of Zoledronic Acid. New Eng. J. Med. 349, 1676\u20131679 (2003).","journal-title":"New Eng. J. Med."},{"key":"BFsrep26033_CR34","first-page":"475","volume":"5","author":"IJ Diel","year":"2007","unstructured":"Diel, I. J., Bergner, R. & Grotz, K. Adverse effects of bisphosphonates: current issues. J. Support. Oncol. 5, 475\u2013482 (2007).","journal-title":"J. Support. Oncol."},{"key":"BFsrep26033_CR35","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/0142-9612(96)85763-2","volume":"17","author":"JO Hollinger","year":"1996","unstructured":"Hollinger, J. O. & Leong, K. Poly (\u03b1-hydroxy acids): carriers for bone morphogenetic proteins. Biomaterials 17, 187\u2013194 (1996).","journal-title":"Biomaterials"},{"key":"BFsrep26033_CR36","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1097\/00007632-200104150-00017","volume":"26","author":"A Minamide","year":"2001","unstructured":"Minamide, A., Kawakami, M., Hashizume, H., Sakata, R. & Tamaki, T. Evaluation of carriers of bone morphogenetic protein for spinal fusion. Spine 26, 933\u2013939 (2001).","journal-title":"Spine"},{"key":"BFsrep26033_CR37","doi-asserted-by":"publisher","first-page":"S95","DOI":"10.1097\/00003086-199910001-00010","volume":"367","author":"SR Winn","year":"1999","unstructured":"Winn, S. R., Uludag, H. & Hollinger, J. O. Carrier Systems for Bone Morphogenetic Proteins. Clin. Orthop. Rel. Res. 367, S95\u2013S106 (1999).","journal-title":"Clin. Orthop. Rel. Res."},{"key":"BFsrep26033_CR38","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.jconrel.2012.08.004","volume":"162","author":"M Kisiel","year":"2012","unstructured":"Kisiel, M. et al. Critical assessment of rhBMP-2 mediated bone induction: An in vitro and in vivo evaluation. J. Control. Rel. 162, 646\u2013653 (2012).","journal-title":"J. Control. Rel."},{"key":"BFsrep26033_CR39","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/S0939-6411(98)00017-4","volume":"45","author":"W Friess","year":"1998","unstructured":"Friess, W. Collagen \u2013 biomaterial for drug delivery1. Eur. J. Pharm. Biopharm. 45, 113\u2013136 (1998).","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"BFsrep26033_CR40","first-page":"1013","volume":"25","author":"S Stenfelt","year":"2014","unstructured":"Stenfelt, S. et al. Pre-incubation of chemically crosslinked hyaluronan-based hydrogels, loaded with BMP-2 and hydroxyapatite and its effect on ectopic bone formation. J. Mater. Sci: Mater. Med. 25, 1013\u20131023 (2014).","journal-title":"J. Mater. Sci: Mater. Med."},{"key":"BFsrep26033_CR41","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.jconrel.2015.03.028","volume":"207","author":"E Quinlan","year":"2015","unstructured":"Quinlan, E., Thompson, E. M., Matsiko, A., O\u2019Brien, F. J. & L\u00f3pez-Noriega, A. Long-term controlled delivery of rhBMP-2 from collagen\u2013hydroxyapatite scaffolds for superior bone tissue regeneration. J. Control. Rel. 207, 112\u2013119 (2015).","journal-title":"J. Control. Rel."},{"key":"BFsrep26033_CR42","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1098\/rsif.2004.0009","volume":"2","author":"J-S Wang","year":"2005","unstructured":"Wang, J.-S. et al. In vitro and in vivo biological responses to a novel radiopacifying agent for bone cement. J. Royal Soc. Interface 2, 71\u201378 (2005).","journal-title":"J. Royal Soc. Interface"},{"key":"BFsrep26033_CR43","first-page":"399","volume":"14","author":"M Nilsson","year":"2003","unstructured":"Nilsson, M., Wielanek, L., Wang, J. S., Tanner, K. E. & Lidgren, L. Factors influencing the compressive strength of an injectable calcium sulfate\u2013hydroxyapatite cement. J. Mater. Sci: Mater. Med. 14, 399\u2013404 (2003).","journal-title":"J. Mater. Sci: Mater. Med."},{"key":"BFsrep26033_CR44","unstructured":"Karlsson, V., Nilsson, M. & Lid\u00e9n, E. Inventors; Bone Support AB, assignee. Preparation of bone cement compositions. European Patent EP2353619 A1. 2011 Aug 10."},{"key":"BFsrep26033_CR45","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1126\/science.150.3698.893","volume":"150","author":"MR Urist","year":"1965","unstructured":"Urist, M. R. Bone: Formation by Autoinduction. Science 150, 893\u2013899 (1965).","journal-title":"Science"},{"key":"BFsrep26033_CR46","doi-asserted-by":"publisher","first-page":"1613","DOI":"10.1016\/j.addr.2003.08.010","volume":"55","author":"M Geiger","year":"2003","unstructured":"Geiger, M., Li, R. H. & Friess, W. Collagen sponges for bone regeneration with rhBMP-2. Adv. Drug Del. Rev. 55, 1613\u20131629 (2003).","journal-title":"Adv. Drug Del. Rev."},{"key":"BFsrep26033_CR47","doi-asserted-by":"publisher","first-page":"98","DOI":"10.22203\/eCM.v027a08","volume":"27","author":"N Yu","year":"2014","unstructured":"Yu, N. et al. Spatial control of bone formation using a porous polymer scaffold co-delivering anabolic rhBMP-2 and anti-resorptive agents. Eur. Cell. Mater. 27, 98\u2013109 (2014).","journal-title":"Eur. Cell. Mater."},{"key":"BFsrep26033_CR48","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1186\/1471-2474-13-240","volume":"13","author":"O Belfrage","year":"2012","unstructured":"Belfrage, O., Isaksson, H. & T\u00e4gil, M. Local treatment of a bone graft by soaking in zoledronic acid inhibits bone resorption and bone formation. A bone chamber study in rats. BMC Musculoskelet. Disord. 13, 240 (2012).","journal-title":"BMC Musculoskelet. Disord."},{"key":"BFsrep26033_CR49","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1016\/j.cellbi.2007.02.004","volume":"31","author":"OH Ozturk","year":"2007","unstructured":"Ozturk, O. H. et al. Cisplatin cytotoxicity is enhanced with zoledronic acid in A549 lung cancer cell line: Preliminary results of an in vitro study. Cell Biol. Int. 31, 1069\u20131071 (2007).","journal-title":"Cell Biol. Int."},{"key":"BFsrep26033_CR50","doi-asserted-by":"publisher","first-page":"2250","DOI":"10.1016\/j.actbio.2014.01.016","volume":"10","author":"CM Murphy","year":"2014","unstructured":"Murphy, C. M. et al. A collagen\u2013hydroxyapatite scaffold allows for binding and co-delivery of recombinant bone morphogenetic proteins and bisphosphonates. Acta Biomater. 10, 2250\u20132258 (2014).","journal-title":"Acta Biomater."},{"key":"BFsrep26033_CR51","doi-asserted-by":"crossref","first-page":"561","DOI":"10.3928\/01477447-20100625-15","volume":"33","author":"Z Jindong","year":"2010","unstructured":"Jindong, Z. et al. Evaluation of a novel osteoporotic drug delivery system in vitro: alendronate-loaded calcium phosphate cement. Orthopedics 33, 561 (2010).","journal-title":"Orthopedics"},{"key":"BFsrep26033_CR52","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1002\/jor.20481","volume":"26","author":"A Schindeler","year":"2008","unstructured":"Schindeler, A. et al. Modeling bone morphogenetic protein and bisphosphonate combination therapy in wild\u2010type and Nf1 haploinsufficient mice. J. Orthop. Res. 26, 65\u201374 (2008).","journal-title":"J. Orthop. Res."},{"key":"BFsrep26033_CR53","doi-asserted-by":"publisher","first-page":"1537","DOI":"10.2106\/JBJS.L.01483","volume":"95","author":"EJ Carragee","year":"2013","unstructured":"Carragee, E. J. et al. Cancer risk after use of recombinant bone morphogenetic protein-2 for spinal arthrodesis. J. Bone Joint Surg. 95, 1537\u20131545 (2013).","journal-title":"J. Bone Joint Surg."},{"key":"BFsrep26033_CR54","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.1359\/JBMR.050712","volume":"20","author":"DG Little","year":"2005","unstructured":"Little, D. G., McDonald, M., Bransford, R., Godfrey, C. B. & Amanat, N. Manipulation of the Anabolic and Catabolic Responses With OP\u20101 and Zoledronic Acid in a Rat Critical Defect Model. J.Bone Miner. Res. 20, 2044\u20132052 (2005).","journal-title":"J.Bone Miner. Res."},{"key":"BFsrep26033_CR55","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1002\/jor.1100070415","volume":"7","author":"H Ohgushi","year":"1989","unstructured":"Ohgushi, H., Goldberg, V. M. & Caplan, A. I. Heterotopic osteogenesis in porous ceramics induced by marrow cells. J. Orthop. Res. 7, 568\u2013578 (1989).","journal-title":"J. Orthop. Res."},{"key":"BFsrep26033_CR56","doi-asserted-by":"publisher","first-page":"1854","DOI":"10.1359\/jbmr.2003.18.10.1854","volume":"18","author":"Y Nakamura","year":"2003","unstructured":"Nakamura, Y. et al. Temporal and Spatial Expression Profiles of BMP Receptors and Noggin During BMP\u20102\u2010Induced Ectopic Bone Formation. J. Bone Miner. Res. 18, 1854\u20131862 (2003).","journal-title":"J. Bone Miner. Res."},{"key":"BFsrep26033_CR57","doi-asserted-by":"publisher","first-page":"272","DOI":"10.7150\/ijbs.2929","volume":"8","author":"G Chen","year":"2012","unstructured":"Chen, G., Deng, C. & Li, Y.-P. TGF-beta and BMP signaling in osteoblast differentiation and bone formation. Int. J. Biol. Sci. 8, 272\u2013288 (2012).","journal-title":"Int. J. Biol. Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep26033","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep26033.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep26033.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T15:08:38Z","timestamp":1672844918000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep26033"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,5,18]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,9,19]]}},"alternative-id":["BFsrep26033"],"URL":"https:\/\/doi.org\/10.1038\/srep26033","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,5,18]]},"assertion":[{"value":"5 November 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 April 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 May 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Prof. Lars Lidgren is a board member of Bonesupport AB, Lund, Sweden and Orthocell, Australia. None of the other authors declare any conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"26033"}}