{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T15:35:46Z","timestamp":1790696146019,"version":"4.1.0"},"reference-count":66,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T00:00:00Z","timestamp":1646092800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/V011235\/1"],"award-info":[{"award-number":["EP\/V011235\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/R003610\/1, BB\/R003610\/1"],"award-info":[{"award-number":["BB\/R003610\/1, BB\/R003610\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R025673\/1"],"award-info":[{"award-number":["MR\/R025673\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000271","name":"Science and Technology Facilities Council","doi-asserted-by":"publisher","award":["SM-18524-2"],"award-info":[{"award-number":["SM-18524-2"]}],"id":[{"id":"10.13039\/501100000271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Materials"],"abstract":"<jats:p>Fibrotic scarring is prevalent in a range of collagenous tissue disorders. Understanding the role of matrix biophysics in contributing to fibrotic progression is important to develop therapies, as well as to elucidate biological mechanisms. Here, we demonstrate how microfocus small-angle X-ray scattering (SAXS), with in situ mechanics and correlative imaging, can provide quantitative and position-resolved information on the fibrotic matrix nanostructure and its mechanical properties. We use as an example the case of keloid scarring in skin. SAXS mapping reveals heterogeneous gradients in collagen fibrillar concentration, fibril pre-strain (variations in D-period) and a new interfibrillar component likely linked to proteoglycans, indicating evidence of a complex 3D structure at the nanoscale. Furthermore, we demonstrate a proof-of-principle for a diffraction-contrast correlative imaging technique, incorporating, for the first time, DIC and SAXS, and providing an initial estimate for measuring spatially resolved fibrillar-level strain and reorientation in such heterogeneous tissues. By application of the method, we quantify (at the microscale) fibrillar reorientations, increases in fibrillar D-period variance, and increases in mean D-period under macroscopic tissue strains of ~20%. Our results open the opportunity of using synchrotron X-ray nanomechanical imaging as a quantitative tool to probe structure\u2013function relations in keloid and other fibrotic disorders in situ.<\/jats:p>","DOI":"10.3390\/ma15051836","type":"journal-article","created":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T21:25:14Z","timestamp":1646169914000},"page":"1836","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Investigating the Fibrillar Ultrastructure and Mechanics in Keloid Scars Using In Situ Synchrotron X-ray Nanomechanical Imaging"],"prefix":"10.3390","volume":"15","author":[{"given":"Yuezhou","family":"Zhang","sequence":"first","affiliation":[{"name":"Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dave","family":"Hollis","sequence":"additional","affiliation":[{"name":"LaVision UK, 2 Minton Place, Victoria Road, Bicester OX26 6QB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosie","family":"Ross","sequence":"additional","affiliation":[{"name":"Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7146-6885","authenticated-orcid":false,"given":"Tim","family":"Snow","sequence":"additional","affiliation":[{"name":"Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8783-1282","authenticated-orcid":false,"given":"Nick J.","family":"Terrill","sequence":"additional","affiliation":[{"name":"Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjie","family":"Lu","sequence":"additional","affiliation":[{"name":"Centre for Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 5PZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Connelly","sequence":"additional","affiliation":[{"name":"Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Tozzi","sequence":"additional","affiliation":[{"name":"School of Engineering, London South Bank University, London SE1 0AA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2201-8933","authenticated-orcid":false,"given":"Himadri S.","family":"Gupta","sequence":"additional","affiliation":[{"name":"Institute of Bioengineering and School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/s41584-019-0322-7","article-title":"Shared and distinct mechanisms of fibrosis","volume":"15","author":"Distler","year":"2019","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"113","DOI":"10.2119\/molmed.2009.00153","article-title":"Hypertrophic Scarring and Keloids: Pathomechanisms and Current and Emerging Treatment Strategies","volume":"17","author":"Gauglitz","year":"2011","journal-title":"Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1111\/exd.14243","article-title":"Keloid disorder: Fibroblast differentiation and gene expression profile in fibrotic skin diseases","volume":"30","author":"Macarak","year":"2021","journal-title":"Exp. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1007\/s11926-018-0710-z","article-title":"Matrix Stiffness: The Conductor of Organ Fibrosis","volume":"20","author":"Santos","year":"2018","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Aarabi, S., Longaker, M.T., and Gurtner, G.C. (2007). Hypertrophic Scar Formation Following Burns and Trauma: New Approaches to Treatment. PLoS Med., 4.","DOI":"10.1371\/journal.pmed.0040234"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/j.jss.2011.07.007","article-title":"A Review of the Role of Mechanical Forces in Cutaneous Wound Healing","volume":"171","author":"Agha","year":"2011","journal-title":"J. Surg. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108676","DOI":"10.1016\/j.abb.2020.108676","article-title":"Impaired collagen fibril assembly in keloids with enhanced expression of lumican and collagen V","volume":"697","author":"Zhou","year":"2020","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.matbio.2016.01.013","article-title":"Keloids: The paradigm of skin fibrosis\u2014Pathomechanisms and treatment","volume":"51","author":"Andrews","year":"2016","journal-title":"Matrix Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1097\/00006534-196912000-00006","article-title":"Keloids in Various Races A Review of 175 Cases","volume":"44","author":"Alhady","year":"1969","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1038\/ng.645","article-title":"A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population","volume":"42","author":"Nakashima","year":"2010","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2796","DOI":"10.1210\/me.2005-0303","article-title":"FOXL2 in the Pituitary: Molecular, Genetic, and Developmental Analysis","volume":"20","author":"Ellsworth","year":"2006","journal-title":"Mol. Endocrinol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1038\/sj.onc.1207412","article-title":"Regulation of the TGF\u03b2 signalling pathway by ubiquitin-mediated degradation","volume":"23","author":"Izzi","year":"2004","journal-title":"Oncogene"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1111\/j.1524-475X.2006.00193.x","article-title":"Prostaglandin E2 inhibition of keloid fibroblast migration, contraction, and transforming growth factor (TGF)-\u03b21-induced collagen synthesis","volume":"15","author":"Sandulache","year":"2007","journal-title":"Wound Repair Regen."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100016","DOI":"10.1016\/j.mbplus.2019.100016","article-title":"Cartilage-like composition of keloid scar extracellular matrix suggests fibroblast mis-differentiation in disease","volume":"4","author":"Woods","year":"2019","journal-title":"Matrix Biol. Plus"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/j.1524-475X.2012.00766.x","article-title":"The relationship between skin stretching\/contraction and pathologic scarring: The important role of mechanical forces in keloid generation","volume":"20","author":"Ogawa","year":"2012","journal-title":"Wound Repair Regen."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9728","DOI":"10.1021\/acsnano.7b00563","article-title":"The Secret Life of Collagen: Temporal Changes in Nanoscale Fibrillar Pre-Strain and Molecular Organization during Physiological Loading of Cartilage","volume":"11","author":"Inamdar","year":"2017","journal-title":"ACS Nano"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.actbio.2019.07.055","article-title":"Proteoglycan degradation mimics static compression by altering the natural gradients in fibrillar organisation in cartilage","volume":"97","author":"Inamdar","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.actbio.2019.02.053","article-title":"Compressive behaviour of uniaxially aligned individual mineralised collagen fibres at the micro- and nanoscale","volume":"89","author":"Groetsch","year":"2019","journal-title":"Acta Biomater."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jsb.2005.08.003","article-title":"Internal strains and stresses measured in cortical bone via high-energy X-ray diffraction","volume":"152","author":"Almer","year":"2005","journal-title":"J. Struct. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.matbio.2016.09.001","article-title":"Advanced glycation end-products: Mechanics of aged collagen from molecule to tissue","volume":"59","author":"Gautieri","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1006\/jsbi.1998.3966","article-title":"Fibrillar Structure and Mechanical Properties of Collagen","volume":"122","author":"Fratzl","year":"1998","journal-title":"J. Struct. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"103703","DOI":"10.1039\/C5RA21870E","article-title":"Collagen fibril strain, recruitment and orientation for pericardium under tension and the effect of cross links","volume":"5","author":"Kayed","year":"2015","journal-title":"RSC Adv."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"115111","DOI":"10.1016\/j.bone.2019.115111","article-title":"Reduction of fibrillar strain-rate sensitivity in steroid-induced osteoporosis linked to changes in mineralized fibrillar nanostructure","volume":"131","author":"Xi","year":"2020","journal-title":"Bone"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.actbio.2018.05.053","article-title":"Bone matrix development in steroid-induced osteoporosis is associated with a consistently reduced fibrillar stiffness linked to altered bone mineral quality","volume":"76","author":"Xi","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6649","DOI":"10.1038\/ncomms7649","article-title":"On the tear resistance of skin","volume":"6","author":"Yang","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_26","first-page":"349","article-title":"Nanostructure surveys of macroscopic specimens by small-angle scattering tensor tomography","volume":"527","author":"Liebi","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1016\/j.burns.2019.07.040","article-title":"Exploring the collagen nanostructure of dermal tissues after injury","volume":"45","author":"Tian","year":"2019","journal-title":"Burns"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s11033-018-4444-9","article-title":"Exploring nanoscale structure change of dermal tissues suffering injury by small angle X-ray scattering and transmission electron microscopy","volume":"46","author":"Jiang","year":"2018","journal-title":"Mol. Biol. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"FB1","DOI":"10.1116\/1.2955443","article-title":"From diffraction to imaging: New avenues in studying hierarchical biological tissues with X-ray microbeams","volume":"3","author":"Paris","year":"2008","journal-title":"Biointerphases"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1557\/JMR.2009.0064","article-title":"Digital image correlation shows localized deformation bands in inelastic loading of fibrolamellar bone","volume":"24","author":"Benecke","year":"2009","journal-title":"J. Mater. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"062001","DOI":"10.1088\/0957-0233\/20\/6\/062001","article-title":"Two-dimensional digital image correlation for in-plane displacement and strain measurement: A review","volume":"20","author":"Pan","year":"2009","journal-title":"Meas. Sci. Technol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1021\/acsbiomaterials.8b01044","article-title":"Full-Field Strain Analysis of Bone-Biomaterial Systems Produced by the Implantation of Osteoregenerative Biomaterials in an Ovine Model","volume":"5","author":"Bodey","year":"2019","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/23335432.2015.1117395","article-title":"The use of digital image correlation in the biomechanical area: A review","volume":"3","author":"Palanca","year":"2016","journal-title":"Int. Biomech."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"31","DOI":"10.3389\/fmats.2017.00031","article-title":"Precision of Digital Volume Correlation Approaches for Strain Analysis in Bone Imaged with Micro-Computed Tomography at Different Dimensional Levels","volume":"4","author":"Palanca","year":"2017","journal-title":"Front. Mater."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1111\/j.1524-4725.2008.34406.x","article-title":"Hypertrophic Scars and Keloids\u2014A Review of Their Pathophysiology, Risk Factors, and Therapeutic Management","volume":"35","author":"Wolfram","year":"2009","journal-title":"Dermatol. Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1107\/S1600577521002113","article-title":"I22: SAXS\/WAXS beamline at Diamond Light Source\u2014An overview of 10 years operation","volume":"28","author":"Smith","year":"2021","journal-title":"J. Synchrotron Radiat."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"17741","DOI":"10.1073\/pnas.0604237103","article-title":"Cooperative deformation of mineral and collagen in bone at the nanoscale","volume":"103","author":"Gupta","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1107\/S1600576717004708","article-title":"Processing two-dimensional X-ray diffraction and small-angle scattering data inDAWN 2","volume":"50","author":"Filik","year":"2017","journal-title":"J. Appl. Crystallogr."},{"key":"ref_39","unstructured":"Newville, M., Stensitzki, T., Allen, D.B., and Ingargiola, A. (2014). LMFIT: Non-Linear Least-Square Minimization and Curve-Fitting for Python. Astrophys. Source Code Libr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.actbio.2017.11.015","article-title":"The hierarchical response of human corneal collagen to load","volume":"65","author":"Bell","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1098\/rsif.2005.0100","article-title":"Nano measurements with micro-devices: Mechanical properties of hydrated collagen fibrils","volume":"3","author":"Eppell","year":"2005","journal-title":"J. R. Soc. Interface"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1038\/jid.2011.212","article-title":"Pushing Back: Wound Mechanotransduction in Repair and Regeneration","volume":"131","author":"Wong","year":"2011","journal-title":"J. Investig. Dermatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.jsb.2009.10.002","article-title":"In situ multi-level analysis of viscoelastic deformation mechanisms in tendon collagen","volume":"169","author":"Gupta","year":"2010","journal-title":"J. Struct. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/0022-2836(87)90228-2","article-title":"Structural dynamic of native tendon collagen","volume":"193","author":"Folkhard","year":"1987","journal-title":"J. Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"5942","DOI":"10.1038\/ncomms6942","article-title":"Osmotic pressure induced tensile forces in tendon collagen","volume":"6","author":"Masic","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9001","DOI":"10.1073\/pnas.0502718103","article-title":"Microfibrillar structure of type I collagen in situ","volume":"103","author":"Orgel","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S0968-4328(00)00042-1","article-title":"Collagen structure and functional implications","volume":"32","author":"Ottani","year":"2001","journal-title":"Micron"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1529\/biophysj.106.085704","article-title":"Collagen Fibrils: Nanoscale Ropes","volume":"92","author":"Bozec","year":"2007","journal-title":"Biophys. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.jmbbm.2015.03.010","article-title":"Osmotically driven tensile stress in collagen-based mineralized tissues","volume":"52","author":"Bertinetti","year":"2015","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Fratzl, P. (2008). Collagen: Structure and Mechanics, an Introduction, Springer.","DOI":"10.1007\/978-0-387-73906-9"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1107\/S205327331701614X","article-title":"Small-angle X-ray scattering tensor tomography: Model of the three-dimensional reciprocal-space map, reconstruction algorithm and angular sampling requirements","volume":"74","author":"Liebi","year":"2018","journal-title":"Acta Crystallogr. Sect. A Found. Adv."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"104854","DOI":"10.1016\/j.jmbbm.2021.104854","article-title":"D-band strain underestimates fibril strain for twisted collagen fibrils at low strains","volume":"124","author":"Leighton","year":"2021","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/j.1469-7793.1999.00307.x","article-title":"In vivo human tendon mechanical properties","volume":"521","author":"Maganaris","year":"1999","journal-title":"J. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1111\/j.1469-7998.1986.tb03609.x","article-title":"Mechanical properties of various mammalian tendons","volume":"209","author":"Bennett","year":"1986","journal-title":"J. Zool."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1177\/1350650112463307","article-title":"Contact modelling of human skin: What value to use for the modulus of elasticity?","volume":"227","author":"Masen","year":"2013","journal-title":"Proc. Inst. Mech. Eng. Part J J. Eng. Tribol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1016\/S0006-3495(00)76426-5","article-title":"Mineralized Collagen Fibrils: A Mechanical Model with a Staggered","volume":"79","author":"Fratzl","year":"2000","journal-title":"Biophys. J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/j.jmps.2011.06.005","article-title":"Mechanical model for staggered bio-structure","volume":"59","author":"Wagner","year":"2011","journal-title":"J. Mech. Phys. Solids"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.jmbbm.2013.03.020","article-title":"Intrafibrillar plasticity through mineral\/collagen sliding is the dominant mechanism for the extreme toughness of antler bone","volume":"28","author":"Gupta","year":"2013","journal-title":"J. Mech. Behav. Biomed. Mater."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1021\/nl103943u","article-title":"Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up","volume":"11","author":"Gautieri","year":"2011","journal-title":"Nano Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1098\/rstb.2001.1033","article-title":"Viscoelastic properties of collagen: Synchrotron radiation investigations and structural model","volume":"357","author":"Puxkandl","year":"2002","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/0021-9290(96)00024-3","article-title":"Elongation mechanism of collagen fibrils and force-strain relations of tendon at each level of structural hierarchy","volume":"29","author":"Sasaki","year":"1996","journal-title":"J. Biomech."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"E6362","DOI":"10.1073\/pnas.1609341113","article-title":"Interfibrillar stiffening of echinoderm mutable collagenous tissue demonstrated at the nanoscale","volume":"113","author":"Mo","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"eaao2189","DOI":"10.1126\/science.aao2189","article-title":"Fractal-like hierarchical organization of bone begins at the nanoscale","volume":"360","author":"Reznikov","year":"2018","journal-title":"Science"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"19178","DOI":"10.1073\/pnas.1201513109","article-title":"Dilatational band formation in bone","volume":"109","author":"Poundarik","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"14416","DOI":"10.1073\/pnas.1107966108","article-title":"Age-related changes in the plasticity and toughness of human cortical bone at multiple length scales","volume":"108","author":"Zimmermann","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1007\/BF00735574","article-title":"Synchrotronstrahl-Beugung bei der zeitaufgel\u00f6sten Analyse von Bewegungsabl\u00e4ufen auf biomolekularer Ebene","volume":"75","author":"Nemetschek","year":"1988","journal-title":"Naturwissenschaften"}],"container-title":["Materials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1996-1944\/15\/5\/1836\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:30:03Z","timestamp":1760135403000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1996-1944\/15\/5\/1836"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,1]]},"references-count":66,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["ma15051836"],"URL":"https:\/\/doi.org\/10.3390\/ma15051836","relation":{},"ISSN":["1996-1944"],"issn-type":[{"value":"1996-1944","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,1]]}}}