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For example, insufficient early revascularization of the injured site can lead to delayed or non-healing. During sprouting, endothelial cells are known to be mechano-sensitive and respond to local mechanical stimuli. Endothelial cells interact and communicate mechanically with their surroundings, such as outer-vascular stromal cells, through cell-induced traction forces. In addition, external physiological loads act at the healing site, resulting in tissue deformations and impacting cellular arrangements. How these two distinct mechanical cues (cell-induced and external) impact angiogenesis and sprout patterning in early bone healing remains however largely unknown. Therefore, the aim of this study was to investigate the relative role of externally applied and cell-induced mechanical signals in driving sprout patterning at the onset of bone healing. To investigate cellular self-organisation in early bone healing, an <jats:italic>in silico<\/jats:italic> model accounting for the mechano-regulation of sprouting angiogenesis and stromal cell organization was developed. Computer model predictions were compared to <jats:italic>in vivo<\/jats:italic> experiments of a mouse osteotomy model stabilized with a rigid or a semirigid fixation system. We found that the magnitude and orientation of principal strains within the healing region can explain experimentally observed sprout patterning, under both fixation conditions. Furthermore, upon simulating the selective inhibition of either cell-induced or externally applied mechanical cues, external mechanical signals appear to overrule the mechanical communication acting on a cell-cell interaction level. Such findings illustrate the relevance of external mechanical signals over the local cell-mediated mechanical cues and could be used in the design of fracture treatment strategies for bone regeneration.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011647","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T18:46:37Z","timestamp":1699901197000},"page":"e1011647","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["External mechanical loading overrules cell-cell mechanical communication in sprouting angiogenesis during early bone regeneration"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5435-0554","authenticated-orcid":true,"given":"Chiara","family":"Dazzi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Mehl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mounir","family":"Benamar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Holger","family":"Gerhardt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Knaus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg N.","family":"Duda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1444-5858","authenticated-orcid":true,"given":"Sara","family":"Checa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,11,13]]},"reference":[{"issue":"6","key":"pcbi.1011647.ref001","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/nm0603-653","article-title":"Angiogenesis in health and disease","volume":"9","author":"P. 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J\u00f8rgensen","year":"1991","journal-title":"Bone"},{"issue":"8","key":"pcbi.1011647.ref049","first-page":"1625","article-title":"A model of angiogenesis in the mouse cornea","volume":"37","author":"BM Kenyon","year":"1996","journal-title":"Investigative Ophthalmology & Visual Science"},{"issue":"1","key":"pcbi.1011647.ref050","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s12195-010-0102-6","article-title":"Substrate Stiffness and Cell Area Predict Cellular Traction Stresses in Single Cells and Cells in Contact","volume":"3","author":"JP Califano","year":"2010","journal-title":"Cell Mol Bioeng"},{"issue":"1","key":"pcbi.1011647.ref051","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1007\/s12195-014-0360-9","article-title":"Probing the biophysical properties of primary breast tumor-derived fibroblasts","volume":"8","author":"TA Alcoser","year":"2015","journal-title":"Cell Mol 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Adv"},{"issue":"1","key":"pcbi.1011647.ref067","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.bone.2007.08.048","article-title":"Structural and cellular differences between metaphyseal and diaphyseal periosteum in different aged rats","volume":"42","author":"W Fan","year":"2008","journal-title":"Bone"},{"issue":"4","key":"pcbi.1011647.ref068","doi-asserted-by":"crossref","first-page":"048102","DOI":"10.1103\/PhysRevLett.88.048102","article-title":"Elastic interactions of cells","volume":"88","author":"US Schwarz","year":"2002","journal-title":"Phys Rev Lett"},{"key":"pcbi.1011647.ref069","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/978-1-59745-353-0_6","article-title":"Dynamic assessment of cell-matrix mechanical interactions in three-dimensional culture","volume":"370","author":"WM Petroll","year":"2007","journal-title":"Methods Mol Biol"},{"issue":"6","key":"pcbi.1011647.ref070","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1089\/ten.teb.2010.0176","article-title":"Growth Factor Interactions in Bone Regeneration","volume":"16","author":"DHR Kempen","year":"2010","journal-title":"Tissue Engineering Part B: Reviews"},{"issue":"19","key":"pcbi.1011647.ref071","doi-asserted-by":"crossref","DOI":"10.3390\/cancers13194987","article-title":"Mechanical Aspects of Angiogenesis","volume":"13","author":"M Kretschmer","year":"2021","journal-title":"Cancers (Basel)"},{"issue":"1","key":"pcbi.1011647.ref072","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10237-014-0581-9","article-title":"The emergence of extracellular matrix mechanics and cell traction forces as important regulators of cellular self-organization","volume":"14","author":"S Checa","year":"2015","journal-title":"Biomech Model Mechanobiol"},{"issue":"8","key":"pcbi.1011647.ref073","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1007\/s00590-019-02486-4","article-title":"Early versus delayed weight bearing after surgical fixation of distal femur fractures: a non-randomized comparative study","volume":"29","author":"P Consigliere","year":"2019","journal-title":"Eur J Orthop Surg Traumatol"},{"issue":"1","key":"pcbi.1011647.ref074","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s00068-018-1016-6","article-title":"Weight-bearing or non-weight-bearing after surgical treatment of ankle fractures: a multicenter randomized controlled trial","volume":"46","author":"DPJ Smeeing","year":"2020","journal-title":"European Journal of Trauma and Emergency Surgery"},{"key":"pcbi.1011647.ref075","unstructured":"Elfarnawany MH. Signal Processing Methods for Quantitative Power Doppler Microvascular Angiography. Electronic Thesis and Dissertation Repository2015."},{"issue":"2","key":"pcbi.1011647.ref076","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1093\/cvr\/cvn055","article-title":"Effect of mechanical boundary conditions on orientation of angiogenic microvessels","volume":"78","author":"L Krishnan","year":"2008","journal-title":"Cardiovasc Res"},{"key":"pcbi.1011647.ref077","first-page":"7","article-title":"YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development","author":"F Neto","year":"2018","journal-title":"Elife"},{"issue":"36","key":"pcbi.1011647.ref078","doi-asserted-by":"crossref","first-page":"15279","DOI":"10.1073\/pnas.0905891106","article-title":"Cyclic tensile strain triggers a sequence of autocrine and paracrine signaling to regulate angiogenic sprouting in human vascular cells","volume":"106","author":"YC Yung","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"pcbi.1011647.ref079","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1089\/ten.2006.0058","article-title":"Mechanical strain regulates endothelial cell patterning in vitro","volume":"13","author":"T Matsumoto","year":"2007","journal-title":"Tissue Eng"},{"issue":"12","key":"pcbi.1011647.ref080","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1038\/ncb1658","article-title":"Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells","volume":"9","author":"C Gaggioli","year":"2007","journal-title":"Nat Cell Biol"},{"issue":"9","key":"pcbi.1011647.ref081","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1002\/jbmr.3454","article-title":"Sclerostin Neutralizing Antibody Treatment Enhances Bone Formation but Does Not Rescue Mechanically Induced Delayed Healing","volume":"33","author":"B Kruck","year":"2018","journal-title":"J Bone Miner Res"},{"issue":"3","key":"pcbi.1011647.ref082","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1073\/pnas.1613855114","article-title":"Matrix stiffening promotes a tumor vasculature phenotype","volume":"114","author":"F Bordeleau","year":"2017","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"pcbi.1011647.ref083","first-page":"6933","article-title":"Evidence of a large-scale mechanosensing mechanism for cellular adaptation to substrate stiffness","volume":"109","author":"L Trichet","year":"2012","journal-title":"Proceedings of the National Academy of Sciences of the United States of America. 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