{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T15:02:07Z","timestamp":1793199727711,"version":"4.5.0"},"reference-count":53,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T00:00:00Z","timestamp":1618963200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T00:00:00Z","timestamp":1618963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"ETH Postdoctoral Fellowship Program\/MSCA-COFUND","award":["FEL-25_15-1"],"award-info":[{"award-number":["FEL-25_15-1"]}]},{"name":"ERC Advanced MechAGE","award":["ERC-2016-ADG-741883"],"award-info":[{"award-number":["ERC-2016-ADG-741883"]}]},{"DOI":"10.13039\/100011102","name":"Seventh Framework Programme","doi-asserted-by":"publisher","award":["FP7-NMP-2012-262948"],"award-info":[{"award-number":["FP7-NMP-2012-262948"]}],"id":[{"id":"10.13039\/100011102","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Thorough preclinical evaluation of functionalized biomaterials for treatment of large bone defects is essential prior to clinical application. Using in vivo micro-computed tomography (micro-CT) and mouse femoral defect models with different defect sizes, we were able to detect spatio-temporal healing patterns indicative of physiological and impaired healing in three defect sub-volumes and the adjacent cortex. The time-lapsed in vivo micro-CT-based approach was then applied to evaluate the bone regeneration potential of functionalized biomaterials using collagen and bone morphogenetic protein (BMP-2). Both collagen and BMP-2 treatment led to distinct changes in bone turnover in the different healing phases. Despite increased periosteal bone formation, 87.5% of the defects treated with collagen scaffolds resulted in non-unions. Additional BMP-2 application significantly accelerated the healing process and increased the union rate to 100%. This study further shows potential of time-lapsed in vivo micro-CT for capturing spatio-temporal deviations preceding non-union formation and how this can be prevented by application of functionalized biomaterials. This study therefore supports the application of longitudinal in vivo micro-CT for discrimination of normal and disturbed healing patterns and for the spatio-temporal characterization of the bone regeneration capacity of functionalized biomaterials.<\/jats:p>","DOI":"10.1038\/s41598-021-87788-6","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T06:44:41Z","timestamp":1618987481000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Spatio-temporal characterization of fracture healing patterns and assessment of biomaterials by time-lapsed in vivo micro-computed tomography"],"prefix":"10.1038","volume":"11","author":[{"given":"Esther","family":"Wehrle","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duncan C.","family":"Tourolle n\u00e9 Betts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisela A.","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Floreani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malavika H.","family":"Nambiar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryant J.","family":"Schroeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,4,21]]},"reference":[{"issue":"Suppl 1","key":"87788_CR1","doi-asserted-by":"publisher","first-page":"S90","DOI":"10.1016\/j.injury.2007.02.014","volume":"38","author":"P Giannoudis","year":"2007","unstructured":"Giannoudis, P., Tzioupis, C., Almalki, T. & Buckley, R. Fracture healing in osteoporotic fractures: is it really different? A basic science perspective. Injury 38(Suppl 1), S90-99. https:\/\/doi.org\/10.1016\/j.injury.2007.02.014 (2007).","journal-title":"Injury"},{"key":"87788_CR2","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/S0020-1383(03)00247-X","volume":"35","author":"AA Syed","year":"2004","unstructured":"Syed, A. A., Agarwal, M., Giannoudis, P. V., Matthews, S. J. E. & Smith, R. M. Distal femoral fractures: long-term outcome following stabilisation with the LISS. Injury Int. J. Care Injured 35, 599\u2013607. https:\/\/doi.org\/10.1016\/S0020-1383(03)00247-X (2004).","journal-title":"Injury Int. J. Care Injured"},{"key":"87788_CR3","doi-asserted-by":"publisher","first-page":"232","DOI":"10.1302\/2046-3758.73.Bjr-2017-0270.R1","volume":"7","author":"T Winkler","year":"2018","unstructured":"Winkler, T., Sass, F. A., Duda, G. N. & Schmidt-Bleek, K. A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering THE UNSOLVED CHALLENGE. Bone Joint Res. 7, 232\u2013243. https:\/\/doi.org\/10.1302\/2046-3758.73.Bjr-2017-0270.R1 (2018).","journal-title":"Bone Joint Res."},{"key":"87788_CR4","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1016\/j.msec.2019.01.061","volume":"97","author":"A Przekora","year":"2019","unstructured":"Przekora, A. The summary of the most important cell-biomaterial interactions that need to be considered during in vitro biocompatibility testing of bone scaffolds for tissue engineering applications. Mater. Sci. Eng. C Mater. 97, 1036\u20131051. https:\/\/doi.org\/10.1016\/j.msec.2019.01.061 (2019).","journal-title":"Mater. Sci. Eng. C Mater."},{"key":"87788_CR5","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/S1369-7021(08)70086-5","volume":"11","author":"MM Stevens","year":"2008","unstructured":"Stevens, M. M. Biomaterials for bone tissue engineering. Mater. Today 11, 18\u201325. https:\/\/doi.org\/10.1016\/S1369-7021(08)70086-5 (2008).","journal-title":"Mater. Today"},{"key":"87788_CR6","doi-asserted-by":"publisher","first-page":"312","DOI":"10.22203\/eCM.v031a20","volume":"31","author":"G Hulsart-Billstrom","year":"2016","unstructured":"Hulsart-Billstrom, G. et al. A surprisingly poor correlation between in vitro and in vivo testing of biomaterials for bone regeneration: results of a multicentre analysis. Eur. Cells Mater. 31, 312\u2013322. https:\/\/doi.org\/10.22203\/eCM.v031a20 (2016).","journal-title":"Eur. Cells Mater."},{"key":"87788_CR7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.22203\/eCM.v013a01","volume":"13","author":"AI Pearce","year":"2007","unstructured":"Pearce, A. I., Richards, R. G., Milz, S., Schneider, E. & Pearce, S. G. Animal models for implant biomaterial research in bone: a review. Eur. Cells Mater. 13, 1\u201310 (2007).","journal-title":"Eur. Cells Mater."},{"key":"87788_CR8","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.bone.2014.07.010","volume":"70","author":"M Peric","year":"2015","unstructured":"Peric, M. et al. The rational use of animal models in the evaluation of novel bone regenerative therapies. Bone 70, 73\u201386. https:\/\/doi.org\/10.1016\/j.bone.2014.07.010 (2015).","journal-title":"Bone"},{"key":"87788_CR9","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1258\/la.2010.010085","volume":"45","author":"PS Gomes","year":"2011","unstructured":"Gomes, P. S. & Fernandes, M. H. Rodent models in bone-related research: the relevance of calvarial defects in the assessment of bone regeneration strategies. Lab. Anim. UK 45, 14\u201324. https:\/\/doi.org\/10.1258\/la.2010.010085 (2011).","journal-title":"Lab. Anim. UK"},{"key":"87788_CR10","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.bone.2013.02.002","volume":"55","author":"JS Harris","year":"2013","unstructured":"Harris, J. S., Bemenderfer, T. B., Wessel, A. R. & Kacena, M. A. A review of mouse critical size defect models in weight bearing bones. Bone 55, 241\u2013247. https:\/\/doi.org\/10.1016\/j.bone.2013.02.002 (2013).","journal-title":"Bone"},{"key":"87788_CR11","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-85729-293-3_14","author":"JH Holstein","year":"2011","unstructured":"Holstein, J. H. et al. Mouse models for the study of fracture healing and bone regeneration. Osteoporos. Res.: Anim. Models https:\/\/doi.org\/10.1007\/978-0-85729-293-3_14 (2011).","journal-title":"Osteoporos. Res.: Anim. Models"},{"key":"87788_CR12","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1089\/ten.teb.2009.0224","volume":"16","author":"EA Horner","year":"2010","unstructured":"Horner, E. A. et al. Long bone defect models for tissue engineering applications: criteria for choice. Tissue Eng. Part B Rev. 16, 263\u2013271. https:\/\/doi.org\/10.1089\/ten.teb.2009.0224 (2010).","journal-title":"Tissue Eng. Part B Rev."},{"key":"87788_CR13","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/j.addr.2015.07.006","volume":"94","author":"M van Griensven","year":"2015","unstructured":"van Griensven, M. Preclinical testing of drug delivery systems to bone. Adv. Drug Deliv. Rev. 94, 151\u2013164. https:\/\/doi.org\/10.1016\/j.addr.2015.07.006 (2015).","journal-title":"Adv. Drug Deliv. Rev."},{"key":"87788_CR14","doi-asserted-by":"publisher","first-page":"5444","DOI":"10.1016\/j.biomaterials.2005.01.072","volume":"26","author":"O Gauthier","year":"2005","unstructured":"Gauthier, O. et al. In vivo bone regeneration with injectable calcium phosphate biomaterial: a three-dimensional micro-computed tomographic, biomechanical and SEM study. Biomaterials 26, 5444\u20135453. https:\/\/doi.org\/10.1016\/j.biomaterials.2005.01.072 (2005).","journal-title":"Biomaterials"},{"key":"87788_CR15","first-page":"35","volume":"8","author":"M Martino","year":"2014","unstructured":"Martino, M. et al. Growth factors engineered for super-affinity to extracellular matrix enhance tissue healing. J. Tissue Eng. Regen. Med. 8, 35\u201336 (2014).","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"87788_CR16","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1016\/j.bone.2006.04.019","volume":"39","author":"L Meinel","year":"2006","unstructured":"Meinel, L. et al. Silk based biomaterials to heal critical sized femur defects. Bone 39, 922\u2013931. https:\/\/doi.org\/10.1016\/j.bone.2006.04.019 (2006).","journal-title":"Bone"},{"key":"87788_CR17","doi-asserted-by":"publisher","first-page":"10238","DOI":"10.1038\/srep12391","volume":"5","author":"PS Lienemann","year":"2015","unstructured":"Lienemann, P. S. et al. Longitudinal in vivo evaluation of bone regeneration by combined measurement of multi-pinhole SPECT and micro-CT for tissue engineering. Sci. Rep. UK 5, 10238. https:\/\/doi.org\/10.1038\/srep12391 (2015).","journal-title":"Sci. Rep. UK"},{"key":"87788_CR18","doi-asserted-by":"publisher","first-page":"2479","DOI":"10.1016\/j.biomaterials.2007.01.017","volume":"28","author":"GH van Lenthe","year":"2007","unstructured":"van Lenthe, G. H. et al. Nondestructive micro-computed tomography for biological imaging and quantification of scaffold-bone interaction in vivo. Biomaterials 28, 2479\u20132490. https:\/\/doi.org\/10.1016\/j.biomaterials.2007.01.017 (2007).","journal-title":"Biomaterials"},{"key":"87788_CR19","doi-asserted-by":"publisher","first-page":"5241","DOI":"10.1016\/j.biomaterials.2011.03.063","volume":"32","author":"JD Boerckel","year":"2011","unstructured":"Boerckel, J. D. et al. Effects of protein dose and delivery system on BMP-mediated bone regeneration. Biomaterials 32, 5241\u20135251. https:\/\/doi.org\/10.1016\/j.biomaterials.2011.03.063 (2011).","journal-title":"Biomaterials"},{"key":"87788_CR20","doi-asserted-by":"publisher","first-page":"358","DOI":"10.22203\/eCM.v024a26","volume":"24","author":"M Mehta","year":"2012","unstructured":"Mehta, M., Checa, S., Lienau, J., Hutmacher, D. & Duda, G. N. In vivo tracking of segmental bone defect healing reveals that callus patterning is related to early mechanical stimuli. Eur. Cells Mater. 24, 358\u2013371. https:\/\/doi.org\/10.22203\/eCM.v024a26 (2012).","journal-title":"Eur. Cells Mater."},{"key":"87788_CR21","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1038\/s41598-020-57461-5","volume":"10","author":"DC Tourolle n\u00e9 Betts","year":"2020","unstructured":"Tourolle n\u00e9 Betts, D. C. et al. The association between mineralised tissue formation and the mechanical local in vivo environment: time-lapsed quantification of a mouse defect healing model. Sci. Rep. UK 10, 1100. https:\/\/doi.org\/10.1038\/s41598-020-57461-5 (2020).","journal-title":"Sci. Rep. UK"},{"key":"87788_CR22","doi-asserted-by":"publisher","first-page":"17445","DOI":"10.1038\/s41598-019-53822-x","volume":"9","author":"E Wehrle","year":"2019","unstructured":"Wehrle, E. et al. Evaluation of longitudinal time-lapsed in vivo micro-CT for monitoring fracture healing in mouse femur defect models. Sci. Rep. UK 9, 17445. https:\/\/doi.org\/10.1038\/s41598-019-53822-x (2019).","journal-title":"Sci. Rep. UK"},{"key":"87788_CR23","doi-asserted-by":"publisher","first-page":"E7","DOI":"10.1016\/j.jss.2012.06.039","volume":"181","author":"S Zwingenberger","year":"2013","unstructured":"Zwingenberger, S. et al. Establishment of a femoral critical-size bone defect model in immunodeficient mice. J. Surg. Res. 181, E7\u2013E14. https:\/\/doi.org\/10.1016\/j.jss.2012.06.039 (2013).","journal-title":"J. Surg. Res."},{"key":"87788_CR24","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.3801","author":"E Borgiani","year":"2019","unstructured":"Borgiani, E. et al. Age-related changes in the mechanical regulation of bone healing are explained by altered cellular mechanoresponse. J. Bone Miner. Res. https:\/\/doi.org\/10.1002\/jbmr.3801 (2019).","journal-title":"J. Bone Miner. Res."},{"key":"87788_CR25","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.procir.2017.04.032","volume":"65","author":"AA Al-Tamimi","year":"2017","unstructured":"Al-Tamimi, A. A., Peach, C., Fernandes, P. R., Cseke, A. & Bartolo, P. J. D. S. Topology optimization to reduce the stress shielding effect for orthopedic applications. Procedia CIRP 65, 202\u2013206. https:\/\/doi.org\/10.1016\/j.procir.2017.04.032 (2017).","journal-title":"Procedia CIRP"},{"key":"87788_CR26","doi-asserted-by":"publisher","DOI":"10.1097\/00003086-199012000-00022","author":"JD Bobyn","year":"1990","unstructured":"Bobyn, J. D. et al. The effect of stem stiffness on femoral bone resorption after canine porous-coated total hip arthroplasty. Clin. Orthop. Relat. Res. https:\/\/doi.org\/10.1097\/00003086-199012000-00022 (1990).","journal-title":"Clin. Orthop. Relat. Res."},{"key":"87788_CR27","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.bioactmat.2017.08.004","volume":"3","author":"DW Zhang","year":"2018","unstructured":"Zhang, D. W., Wu, X. W., Chen, J. D. & Lin, K. L. The development of collagen based composite scaffolds for bone regeneration. Bioact. Mater. 3, 129\u2013138. https:\/\/doi.org\/10.1016\/j.bioactmat.2017.08.004 (2018).","journal-title":"Bioact. Mater."},{"key":"87788_CR28","doi-asserted-by":"publisher","first-page":"3191","DOI":"10.1016\/j.actbio.2012.06.014","volume":"8","author":"AM Ferreira","year":"2012","unstructured":"Ferreira, A. M., Gentile, P., Chiono, V. & Ciardelli, G. Collagen for bone tissue regeneration. Acta Biomater. 8, 3191\u20133200. https:\/\/doi.org\/10.1016\/j.actbio.2012.06.014 (2012).","journal-title":"Acta Biomater."},{"key":"87788_CR29","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1002\/bip.20871","volume":"89","author":"J Glowacki","year":"2008","unstructured":"Glowacki, J. & Mizuno, S. Collagen scaffolds for tissue engineering. Biopolymers 89, 338\u2013344. https:\/\/doi.org\/10.1002\/bip.20871 (2008).","journal-title":"Biopolymers"},{"key":"87788_CR30","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1002\/jbm.b.33956","volume":"106","author":"J Hertweck","year":"2018","unstructured":"Hertweck, J. et al. CD34(+) cells seeded in collagen scaffolds promote bone formation in a mouse calvarial defect model. J. Biomed. Mater. Res. B Appl. Biomater. 106, 1505\u20131516. https:\/\/doi.org\/10.1002\/jbm.b.33956 (2018).","journal-title":"J. Biomed. Mater. Res. B Appl. Biomater."},{"key":"87788_CR31","doi-asserted-by":"publisher","DOI":"10.3390\/ma12193105","author":"K Stuckensen","year":"2019","unstructured":"Stuckensen, K. et al. Anisotropic cryostructured collagen scaffolds for efficient delivery of RhBMP-2 and enhanced bone regeneration. Materials (Basel) https:\/\/doi.org\/10.3390\/ma12193105 (2019).","journal-title":"Materials (Basel)"},{"key":"87788_CR32","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1016\/j.actbio.2015.05.015","volume":"23","author":"A Cipitria","year":"2015","unstructured":"Cipitria, A. et al. BMP delivery complements the guiding effect of scaffold architecture without altering bone microstructure in critical-sized long bone defects: a multiscale analysis. Acta Biomater. 23, 282\u2013294. https:\/\/doi.org\/10.1016\/j.actbio.2015.05.015 (2015).","journal-title":"Acta Biomater."},{"key":"87788_CR33","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.1016\/j.biomaterials.2005.10.039","volume":"27","author":"MR Sarkar","year":"2006","unstructured":"Sarkar, M. R. et al. Bone formation in a long bone defect model using a platelet-rich plasma-loaded collagen scaffold. Biomaterials 27, 1817\u20131823. https:\/\/doi.org\/10.1016\/j.biomaterials.2005.10.039 (2006).","journal-title":"Biomaterials"},{"key":"87788_CR34","doi-asserted-by":"publisher","first-page":"5474","DOI":"10.1016\/j.biomaterials.2005.02.002","volume":"26","author":"V Karageorgiou","year":"2005","unstructured":"Karageorgiou, V. & Kaplan, D. Porosity of 3D biomaterial scaffolds and osteogenesis. Biomaterials 26, 5474\u20135491. https:\/\/doi.org\/10.1016\/j.biomaterials.2005.02.002 (2005).","journal-title":"Biomaterials"},{"key":"87788_CR35","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/315397","author":"ZW Luo","year":"2015","unstructured":"Luo, Z. W. et al. Effect of pore size on the biodegradation rate of silk fibroin scaffolds. Adv. Mater. Sci. Eng. https:\/\/doi.org\/10.1155\/2015\/315397 (2015).","journal-title":"Adv. Mater. Sci. Eng."},{"key":"87788_CR36","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1016\/j.msec.2016.09.074","volume":"70","author":"H Begam","year":"2017","unstructured":"Begam, H., Nandi, S. K., Kundu, B. & Chanda, A. Strategies for delivering bone morphogenetic protein for bone healing. Mater. Sci. Eng. C Mater. 70, 856\u2013869. https:\/\/doi.org\/10.1016\/j.msec.2016.09.074 (2017).","journal-title":"Mater. Sci. Eng. C Mater."},{"key":"87788_CR37","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/nrendo.2016.12","volume":"12","author":"VS Salazar","year":"2016","unstructured":"Salazar, V. S., Gamer, L. W. & Rosen, V. BMP signalling in skeletal development, disease and repair. Nat. Rev. Endocrinol. 12, 203\u2013221. https:\/\/doi.org\/10.1038\/nrendo.2016.12 (2016).","journal-title":"Nat. Rev. Endocrinol."},{"key":"87788_CR38","doi-asserted-by":"publisher","first-page":"166","DOI":"10.22203\/eCM.v028a13","volume":"28","author":"D Gothard","year":"2014","unstructured":"Gothard, D. et al. Tissue engineered bone using select growth factors: a comprehensive review of animal studies and clinical translation studies in man. Eur. Cells Mater. 28, 166\u2013208. https:\/\/doi.org\/10.22203\/eCM.v028a13 (2014).","journal-title":"Eur. Cells Mater."},{"key":"87788_CR39","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/ten.teb.2015.0357","volume":"22","author":"AW James","year":"2016","unstructured":"James, A. W. et al. A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng. Part B Rev. 22, 284\u2013297. https:\/\/doi.org\/10.1089\/ten.teb.2015.0357 (2016).","journal-title":"Tissue Eng. Part B Rev."},{"key":"87788_CR40","doi-asserted-by":"publisher","first-page":"1862","DOI":"10.1097\/Brs.0000000000001126","volume":"40","author":"B Skovrlj","year":"2015","unstructured":"Skovrlj, B. et al. Association between BMP-2 and carcinogenicity. Spine 40, 1862\u20131871. https:\/\/doi.org\/10.1097\/Brs.0000000000001126 (2015).","journal-title":"Spine"},{"key":"87788_CR41","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1016\/j.spinee.2013.08.060","volume":"14","author":"CA Tannoury","year":"2014","unstructured":"Tannoury, C. A. & An, H. S. Complications with the use of bone morphogenetic protein 2 (BMP-2) in spine surgery. Spine J. 14, 552\u2013559. https:\/\/doi.org\/10.1016\/j.spinee.2013.08.060 (2014).","journal-title":"Spine J."},{"key":"87788_CR42","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.cytogfr.2015.11.006","volume":"27","author":"K Schmidt-Bleek","year":"2016","unstructured":"Schmidt-Bleek, K., Willie, B. M., Schwabe, P., Seemann, P. & Duda, G. N. BMPs in bone regeneration: Less is more effective, a paradigm-shift. Cytokine Growth Factor Rev. 27, 141\u2013148. https:\/\/doi.org\/10.1016\/j.cytogfr.2015.11.006 (2016).","journal-title":"Cytokine Growth Factor Rev."},{"key":"87788_CR43","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1002\/jbm.a.30728","volume":"78","author":"V Karageorgiou","year":"2006","unstructured":"Karageorgiou, V. et al. Porous silk fibroin 3-D scaffolds for delivery of bone morphogenetic protein-2 in vitro and in vivo. J. Biomed. Mater. Res. A 78, 324\u2013334. https:\/\/doi.org\/10.1002\/jbm.a.30728 (2006).","journal-title":"J. Biomed. Mater. Res. A"},{"key":"87788_CR44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.22203\/ecm.v027a01","volume":"27","author":"W Zhang","year":"2014","unstructured":"Zhang, W. et al. VEGF and BMP-2 promote bone regeneration by facilitating bone marrow stem cell homing and differentiation. Eur. Cell Mater. 27, 1\u201311. https:\/\/doi.org\/10.22203\/ecm.v027a01 (2014) (discussion 11\u201312).","journal-title":"Eur. Cell Mater."},{"key":"87788_CR45","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1002\/(sici)1097-4636(199824)43:4<356::aid-jbm3>3.0.co;2-7","volume":"43","author":"JO Hollinger","year":"1998","unstructured":"Hollinger, J. O. et al. Recombinant human bone morphogenetic protein-2 and collagen for bone regeneration. J. Biomed. Mater. Res. 43, 356\u2013364. https:\/\/doi.org\/10.1002\/(sici)1097-4636(199824)43:4%3c356::aid-jbm3%3e3.0.co;2-7 (1998).","journal-title":"J. Biomed. Mater. Res."},{"key":"87788_CR46","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aax2476","author":"S Herberg","year":"2019","unstructured":"Herberg, S. et al. Combinatorial morphogenetic and mechanical cues to mimic bone development for defect repair. Sci. Adv. https:\/\/doi.org\/10.1126\/sciadv.aax2476 (2019).","journal-title":"Sci. Adv."},{"key":"87788_CR47","doi-asserted-by":"publisher","DOI":"10.1177\/2041731419854586","author":"EA Fragogeorgi","year":"2019","unstructured":"Fragogeorgi, E. A. et al. In vivo imaging techniques for bone tissue engineering. J. Tissue Eng. https:\/\/doi.org\/10.1177\/2041731419854586 (2019).","journal-title":"J. Tissue Eng."},{"key":"87788_CR48","doi-asserted-by":"publisher","DOI":"10.3390\/mi10070474","author":"CJ Gil","year":"2019","unstructured":"Gil, C. J. et al. In vivo tracking of tissue engineered constructs. Micromach. Basel https:\/\/doi.org\/10.3390\/mi10070474 (2019).","journal-title":"Micromach. Basel"},{"key":"87788_CR49","doi-asserted-by":"publisher","first-page":"6570","DOI":"10.1039\/c4cs00014e","volume":"43","author":"K Li","year":"2014","unstructured":"Li, K. & Liu, B. Polymer-encapsulated organic nanoparticles for fluorescence and photoacoustic imaging. Chem. Soc. Rev. 43, 6570\u20136597. https:\/\/doi.org\/10.1039\/c4cs00014e (2014).","journal-title":"Chem. Soc. Rev."},{"key":"87788_CR50","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/j.msec.2017.05.142","volume":"80","author":"MK Mafina","year":"2017","unstructured":"Mafina, M. K., Sullivan, A. C. & Hing, K. A. Use of a fluorescent probe to monitor the enhanced affinity of rh-BMP-2 to silicated-calcium phosphate synthetic bone graft substitutes under competitive conditions. Mater. Sci. Eng. C Mater. 80, 207\u2013212. https:\/\/doi.org\/10.1016\/j.msec.2017.05.142 (2017).","journal-title":"Mater. Sci. Eng. C Mater."},{"key":"87788_CR51","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.jconrel.2018.07.012","volume":"285","author":"G Hulsart-Billstrom","year":"2018","unstructured":"Hulsart-Billstrom, G. et al. Non-invasive tri-modal visualisation via PET\/SPECT\/mu CT of recombinant human bone morphogenetic protein-2 retention and associated bone regeneration: a proof of concept. J. Control Release 285, 178\u2013186. https:\/\/doi.org\/10.1016\/j.jconrel.2018.07.012 (2018).","journal-title":"J. Control Release"},{"key":"87788_CR52","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1515\/cdbme-2016-0099","volume":"2","author":"C Taylor","year":"2016","unstructured":"Taylor, C., Scheuren, A., Tr\u00fcssel, A. & M\u00fcller, R. 3D local in vivo environment (LivE) imaging for single cell protein analysis of bone tissue. Curr. Direct. Biomed. Eng. 2, 449\u2013453 (2016).","journal-title":"Curr. Direct. Biomed. Eng."},{"key":"87788_CR53","first-page":"1526","volume":"44","author":"E Wehrle","year":"2019","unstructured":"Wehrle, E., Paul, G. R., Betts, D. C., Kuhn, G. A. & M\u00fcller, R. Individualized cyclic mechanical loading improves callus properties in novel femur fracture loading model as assessed by time-lapsed in vivo imaging and real-time micro-finite element analysis. Trans. Orthop. Res. Soc. 44, 1526 (2019).","journal-title":"Trans. Orthop. Res. Soc."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87788-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87788-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87788-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T02:02:31Z","timestamp":1670032951000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-87788-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,21]]},"references-count":53,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["87788"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-87788-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,21]]},"assertion":[{"value":"15 January 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8660"}}