{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T05:46:04Z","timestamp":1778391964275,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008636","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T00:00:00Z","timestamp":1614038400000}}],"reference-count":68,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004063","name":"Knut och Alice Wallenbergs Stiftelse","doi-asserted-by":"publisher","award":["Wallenberg Academy Fellows 2017.0221"],"award-info":[{"award-number":["Wallenberg Academy Fellows 2017.0221"]}],"id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union Horizon 2020 Research and Innovation programme under the Marie Sklodowska-Curie grant agreement","award":["713645"],"award-info":[{"award-number":["713645"]}]},{"name":"European Union Horizon 2020 Research and Innovation programme under the Marie Sklodowska-Curie grant agreement","award":["713645"],"award-info":[{"award-number":["713645"]}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Mechano-regulation during tendon healing, i.e. the relationship between mechanical stimuli and cellular response, has received more attention recently. However, the basic mechanobiological mechanisms governing tendon healing after a rupture are still not well-understood. Literature has reported spatial and temporal variations in the healing of ruptured tendon tissue. In this study, we explored a computational modeling approach to describe tendon healing. In particular, a novel 3D mechano-regulatory framework was developed to investigate spatio-temporal evolution of collagen content and orientation, and temporal evolution of tendon stiffness during early tendon healing. Based on an extensive literature search, two possible relationships were proposed to connect levels of mechanical stimuli to collagen production. Since literature remains unclear on strain-dependent collagen production at high levels of strain, the two investigated production laws explored the presence or absence of collagen production upon non-physiologically high levels of strain (&gt;15%). Implementation in a finite element framework, pointed to large spatial variations in strain magnitudes within the callus tissue, which resulted in predictions of distinct spatial distributions of collagen over time. The simulations showed that the magnitude of strain was highest in the tendon core along the central axis, and decreased towards the outer periphery. Consequently, decreased levels of collagen production for high levels of tensile strain were shown to accurately predict the experimentally observed delayed collagen production in the tendon core. In addition, our healing framework predicted evolution of collagen orientation towards alignment with the tendon axis and the overall predicted tendon stiffness agreed well with experimental data. In this study, we explored the capability of a numerical model to describe spatial and temporal variations in tendon healing and we identified that understanding mechano-regulated collagen production can play a key role in explaining heterogeneities observed during tendon healing.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008636","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T02:00:41Z","timestamp":1612836041000},"page":"e1008636","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["A numerical framework for mechano-regulated tendon healing\u2014Simulation of early regeneration of the Achilles tendon"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0381-3616","authenticated-orcid":true,"given":"Thomas","family":"Notermans","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9684-6902","authenticated-orcid":true,"given":"Petri","family":"Tanska","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3486-7855","authenticated-orcid":true,"given":"Rami K.","family":"Korhonen","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5751-3737","authenticated-orcid":true,"given":"Hanifeh","family":"Khayyeri","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9690-8907","authenticated-orcid":true,"given":"Hanna","family":"Isaksson","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2021,2,8]]},"reference":[{"key":"pcbi.1008636.ref001","article-title":"Tendon injury and repair\u2013a perspective on the basic mechanisms of tendon disease and future clinical therapy","author":"JG Snedeker","year":"2017","journal-title":"Acta biomaterialia"},{"key":"pcbi.1008636.ref002","doi-asserted-by":"crossref","first-page":"591","DOI":"10.2147\/DDDT.S154660","article-title":"Tendinopathy: injury, repair, and current exploration. Drug design","volume":"12","author":"K Lipman","year":"2018","journal-title":"development and therapy"},{"issue":"5","key":"pcbi.1008636.ref003","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1093\/jmicro\/dfs057","article-title":"The role of collagen arrangement change during tendon healing demonstrated by scanning electron microscopy","volume":"61","author":"K Sasaki","year":"2012","journal-title":"Journal of electron microscopy"},{"issue":"10","key":"pcbi.1008636.ref004","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1093\/ptj\/69.10.816","article-title":"Inflammation, cellularity, and fibrillogenesis in regenerating tendon: implications for tendon rehabilitation","volume":"69","author":"CS Enwemeka","year":"1989","journal-title":"Physical therapy"},{"issue":"6","key":"pcbi.1008636.ref005","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1046\/j.1524-475X.1999.00518.x","article-title":"Matrix remodeling in healing rabbit Achilles tendon","volume":"7","author":"GK Reddy","year":"1999","journal-title":"Wound Repair and Regeneration"},{"issue":"2","key":"pcbi.1008636.ref006","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1152\/japplphysiol.91563.2008","article-title":"Rat Achilles tendon healing: mechanical loading and gene expression","volume":"107","author":"P Eliasson","year":"2009","journal-title":"Journal of applied physiology"},{"issue":"2","key":"pcbi.1008636.ref007","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1152\/japplphysiol.00414.2009","article-title":"Tissue memory in healing tendons: short loading episodes stimulate healing","volume":"107","author":"T Andersson","year":"2009","journal-title":"Journal of applied physiology"},{"issue":"7","key":"pcbi.1008636.ref008","doi-asserted-by":"crossref","first-page":"e0201211","DOI":"10.1371\/journal.pone.0201211","article-title":"Different mechanisms activated by mild versus strong loading in rat Achilles tendon healing","volume":"13","author":"M Hammerman","year":"2018","journal-title":"PloS one"},{"issue":"12","key":"pcbi.1008636.ref009","doi-asserted-by":"crossref","first-page":"2172","DOI":"10.1002\/jor.23253","article-title":"Nonsurgical treatment and early return to activity leads to improved Achilles tendon fatigue mechanics and functional outcomes during early healing in an animal model","volume":"34","author":"BR Freedman","year":"2016","journal-title":"Journal of Orthopaedic Research"},{"key":"pcbi.1008636.ref010","article-title":"Effects of Immobilization Angle on Tendon Healing after Achilles Rupture in a Rat Model","author":"CD Hillin","year":"2019","journal-title":"Journal of Orthopaedic Research"},{"issue":"12","key":"pcbi.1008636.ref011","doi-asserted-by":"crossref","first-page":"e0236681","DOI":"10.1371\/journal.pone.0236681","article-title":"Diminishing effects of mechanical loading over time during rat Achilles tendon healing","volume":"15","author":"H Khayyeri","year":"2020","journal-title":"PLoS ONE"},{"key":"pcbi.1008636.ref012","first-page":"0363546518822836","article-title":"Application of a Purified Protein From Natural Latex and the Influence of Suture Type on Achilles Tendon Repair in Rats","author":"DP Cury","year":"2019","journal-title":"The American journal of sports medicine"},{"key":"pcbi.1008636.ref013","article-title":"Scleraxis-Lineage Cell Depletion Improves Tendon Healing","author":"KT Best","year":"2020","journal-title":"bioRxiv"},{"issue":"12","key":"pcbi.1008636.ref014","doi-asserted-by":"crossref","first-page":"e1006652","DOI":"10.1371\/journal.pcbi.1006652","article-title":"Multiscale computational model of Achilles tendon wound healing: Untangling the effects of repair and loading","volume":"14","author":"K Chen","year":"2018","journal-title":"PLoS computational biology"},{"key":"pcbi.1008636.ref015","first-page":"1","article-title":"Potential strain-dependent mechanisms defining matrix alignment in healing tendons","author":"WJ Richardson","year":"2018","journal-title":"Biomechanics and modeling in mechanobiology"},{"issue":"3","key":"pcbi.1008636.ref016","doi-asserted-by":"crossref","first-page":"e59944","DOI":"10.1371\/journal.pone.0059944","article-title":"The paratenon contributes to scleraxis-expressing cells during patellar tendon healing","volume":"8","author":"NA Dyment","year":"2013","journal-title":"PloS one"},{"issue":"1","key":"pcbi.1008636.ref017","first-page":"1","article-title":"Deletion of NFKB1 enhances canonical NF-\u03baB signaling and increases macrophage and myofibroblast content during tendon healing","volume":"9","author":"KT Best","year":"2019","journal-title":"Scientific reports"},{"issue":"4","key":"pcbi.1008636.ref018","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1006\/jmcc.1996.0347","article-title":"Mechanical load enhances the stimulatory effect of serum growth factors on cardiac fibroblast procollagen synthesis","volume":"29","author":"RP Butt","year":"1997","journal-title":"Journal of molecular and cellular cardiology"},{"issue":"4","key":"pcbi.1008636.ref019","doi-asserted-by":"crossref","first-page":"e0153926","DOI":"10.1371\/journal.pone.0153926","article-title":"Mechanical strain causes adaptive change in bronchial fibroblasts enhancing profibrotic and inflammatory responses","volume":"11","author":"W Manuyakorn","year":"2016","journal-title":"PloS one"},{"issue":"4","key":"pcbi.1008636.ref020","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.cardiores.2003.12.018","article-title":"Differential roles of extracellular signal-regulated kinase 1\/2 and p38MAPK in mechanical load-induced procollagen \u03b11 (I) gene expression in cardiac fibroblasts","volume":"61","author":"J Papakrivopoulou","year":"2004","journal-title":"Cardiovascular research"},{"issue":"5","key":"pcbi.1008636.ref021","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1080\/03008200902836081","article-title":"Cyclical cell stretching of skin-derived fibroblasts downregulates connective tissue growth factor (CTGF) production","volume":"50","author":"Y Kanazawa","year":"2009","journal-title":"Connective tissue research"},{"issue":"2","key":"pcbi.1008636.ref022","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1006\/excr.1999.4618","article-title":"Mechanical load enhances procollagen processing in dermal fibroblasts by regulating levels of procollagen C-proteinase","volume":"252","author":"M Parsons","year":"1999","journal-title":"Experimental cell research"},{"issue":"10","key":"pcbi.1008636.ref023","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1006\/jmcc.1999.1017","article-title":"Differential responses of adult cardiac fibroblasts to in vitro biaxial strain patterns","volume":"31","author":"AA Lee","year":"1999","journal-title":"Journal of molecular and cellular cardiology"},{"key":"pcbi.1008636.ref024","first-page":"2016","article-title":"Effects of mechanical stretch on cell proliferation and matrix formation of mesenchymal stem cell and anterior cruciate ligament fibroblast","author":"L Sun","year":"2016","journal-title":"Stem cells international"},{"issue":"11","key":"pcbi.1008636.ref025","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.joca.2006.05.006","article-title":"Prediction of collagen orientation in articular cartilage by a collagen remodeling algorithm","volume":"14","author":"W Wilson","year":"2006","journal-title":"Osteoarthritis and Cartilage"},{"key":"pcbi.1008636.ref026","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.jmbbm.2016.04.007","article-title":"Comparison of structural anisotropic soft tissue models for simulating Achilles tendon tensile behaviour","volume":"61","author":"H Khayyeri","year":"2016","journal-title":"Journal of the mechanical behavior of biomedical materials"},{"issue":"1","key":"pcbi.1008636.ref027","doi-asserted-by":"crossref","first-page":"13067","DOI":"10.1038\/s41598-017-13107-7","article-title":"Achilles tendon compositional and structural properties are altered after unloading by botox","volume":"7","author":"H Khayyeri","year":"2017","journal-title":"Scientific reports"},{"key":"pcbi.1008636.ref028","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.jmbbm.2019.04.041","article-title":"Understanding how reduced loading affects Achilles tendon mechanical properties using a fibre-reinforced poro-visco-hyper-elastic model","volume":"96","author":"T Notermans","year":"2019","journal-title":"Journal of the mechanical behavior of biomedical materials"},{"issue":"3","key":"pcbi.1008636.ref029","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S0021-9290(03)00267-7","article-title":"Stresses in the local collagen network of articular cartilage: a poroviscoelastic fibril-reinforced finite element study","volume":"37","author":"W Wilson","year":"2004","journal-title":"Journal of biomechanics"},{"issue":"3","key":"pcbi.1008636.ref030","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1007\/s10237-017-0986-3","article-title":"A computational algorithm to simulate disorganization of collagen network in injured articular cartilage","volume":"17","author":"P Tanska","year":"2018","journal-title":"Biomechanics and Modeling in Mechanobiology"},{"issue":"3","key":"pcbi.1008636.ref031","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/0014-4886(87)90226-3","article-title":"Mechanical properties of rat skeletal muscle after hind limb suspension","volume":"96","author":"AM Winiarski","year":"1987","journal-title":"Experimental neurology"},{"issue":"18","key":"pcbi.1008636.ref032","doi-asserted-by":"crossref","first-page":"jeb203554","DOI":"10.1242\/jeb.203554","article-title":"Rat bone properties and their relationship to gait during growth","volume":"222","author":"H Song","year":"2019","journal-title":"Journal of Experimental Biology"},{"issue":"1","key":"pcbi.1008636.ref033","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1152\/jappl.2000.88.1.203","article-title":"Mechanical strain increases type I collagen expression in pulmonary fibroblasts in vitro","volume":"88","author":"EC Breen","year":"2000","journal-title":"Journal of applied physiology"},{"key":"pcbi.1008636.ref034","doi-asserted-by":"crossref","first-page":"21112","DOI":"10.1038\/srep21112","article-title":"Mechanical stretching stimulates collagen synthesis via down-regulating SO 2\/AAT1 pathway","volume":"6","author":"J Liu","year":"2016","journal-title":"Scientific reports"},{"issue":"3","key":"pcbi.1008636.ref035","article-title":"Determination of optimal cyclic uniaxial stretches for stem cell-to-tenocyte differentiation under a wide range of mechanical stretch conditions by evaluating gene expression and protein synthesis levels","volume":"15","author":"Y Morita","year":"2013","journal-title":"Acta of bioengineering and biomechanics"},{"key":"pcbi.1008636.ref036","article-title":"Uniaxial Cyclic Tensile Stretching at 8% Strain Exclusively Promotes Tenogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stromal Cells","volume":"2019","author":"HY Nam","year":"2019","journal-title":"Stem cells international"},{"issue":"1","key":"pcbi.1008636.ref037","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1080\/03008200490278124","article-title":"Compression and tension: differential effects on matrix accumulation by periodontal ligament fibroblasts in vitro","volume":"45","author":"Y He","year":"2004","journal-title":"Connective tissue research"},{"issue":"3","key":"pcbi.1008636.ref038","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/jcp.20034","article-title":"Influence of the extracellular matrix on the regulation of cardiac fibroblast behavior by mechanical stretch","volume":"200","author":"J Atance","year":"2004","journal-title":"Journal of cellular physiology"},{"issue":"5","key":"pcbi.1008636.ref039","first-page":"613","article-title":"Tenocyte response to cyclical strain and transforming growth factor beta is dependent upon age and site of origin","volume":"41","author":"S Goodman","year":"2004","journal-title":"Biorheology"},{"issue":"8","key":"pcbi.1008636.ref040","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/j.jhsa.2008.04.019","article-title":"Optimization of flexor tendon tissue engineering with a cyclic strain bioreactor","volume":"33","author":"J Riboh","year":"2008","journal-title":"The Journal of hand surgery"},{"issue":"1","key":"pcbi.1008636.ref041","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1186\/1471-2474-15-386","article-title":"Enhanced collagen type I synthesis by human tenocytes subjected to periodic in vitro mechanical stimulation","volume":"15","author":"E Huisman","year":"2014","journal-title":"BMC musculoskeletal disorders"},{"issue":"2","key":"pcbi.1008636.ref042","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1016\/j.bbrc.2005.08.102","article-title":"Cyclic tensile strain upregulates collagen synthesis in isolated tendon fascicles","volume":"336","author":"HR Screen","year":"2005","journal-title":"Biochemical and biophysical research communications"},{"issue":"7","key":"pcbi.1008636.ref043","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/jor.22624","article-title":"Changes in macrophage phenotype and induction of epithelial-to-mesenchymal transition genes following acute Achilles tenotomy and repair","volume":"32","author":"KB Sugg","year":"2014","journal-title":"Journal of Orthopaedic Research"},{"issue":"10","key":"pcbi.1008636.ref044","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1002\/jor.21427","article-title":"Treatment with rhBMP12 or rhBMP13 increase the rate and the quality of rat Achilles tendon repair","volume":"29","author":"SA Jelinsky","year":"2011","journal-title":"Journal of Orthopaedic Research"},{"issue":"2","key":"pcbi.1008636.ref045","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1002\/jor.21220","article-title":"Scleraxis expression is coordinately regulated in a murine model of patellar tendon injury","volume":"29","author":"A Scott","year":"2011","journal-title":"Journal of Orthopaedic Research"},{"issue":"2","key":"pcbi.1008636.ref046","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1007\/s00776-014-0684-2","article-title":"Expression of tenocyte lineage-related factors in regenerated tissue at sites of tendon defect","volume":"20","author":"T Omachi","year":"2015","journal-title":"Journal of Orthopaedic Science"},{"issue":"3","key":"pcbi.1008636.ref047","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1002\/jor.20067","article-title":"Characteristics of the rat supraspinatus tendon during tendon-to-bone healing after acute injury","volume":"24","author":"LM Galatz","year":"2006","journal-title":"Journal of Orthopaedic Research"},{"issue":"1","key":"pcbi.1008636.ref048","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jbiomech.2004.11.009","article-title":"Tendon healing in interleukin-4 and interleukin-6 knockout mice","volume":"39","author":"TW Lin","year":"2006","journal-title":"Journal of biomechanics"},{"issue":"3","key":"pcbi.1008636.ref049","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1007\/s10439-012-0689-y","article-title":"Temporal healing in rat achilles tendon: ultrasound correlations","volume":"41","author":"CS Chamberlain","year":"2013","journal-title":"Annals of biomedical engineering"},{"issue":"9","key":"pcbi.1008636.ref050","doi-asserted-by":"crossref","first-page":"2028","DOI":"10.1016\/j.jbiomech.2013.10.054","article-title":"Biomechanical and structural response of healing Achilles tendon to fatigue loading following acute injury","volume":"47","author":"BR Freedman","year":"2014","journal-title":"Journal of biomechanics"},{"key":"pcbi.1008636.ref051","doi-asserted-by":"crossref","first-page":"94","DOI":"10.22203\/eCM.v023a07","article-title":"Improvement of tendon repair using muscle grafts transduced with TGF-\u03b21 cDNA","volume":"23","author":"M Majewski","year":"2012","journal-title":"European cells & materials"},{"issue":"10","key":"pcbi.1008636.ref052","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1177\/107110070502601008","article-title":"Exogenously administered substance P and neutral endopeptidase inhibitors stimulate fibroblast proliferation, angiogenesis and collagen organization during Achilles tendon healing","volume":"26","author":"P Burssens","year":"2005","journal-title":"Foot & ankle international"},{"issue":"8","key":"pcbi.1008636.ref053","doi-asserted-by":"crossref","first-page":"e12470","DOI":"10.1371\/journal.pone.0012470","article-title":"Stretch-induced stress fiber remodeling and the activations of JNK and ERK depend on mechanical strain rate, but not FAK","volume":"5","author":"H-J Hsu","year":"2010","journal-title":"PloS one"},{"issue":"7","key":"pcbi.1008636.ref054","doi-asserted-by":"crossref","first-page":"3470","DOI":"10.1529\/biophysj.107.128611","article-title":"Two characteristic regimes in frequency-dependent dynamic reorientation of fibroblasts on cyclically stretched substrates","volume":"95","author":"S Jungbauer","year":"2008","journal-title":"Biophysical journal"},{"issue":"1, 2, 3","key":"pcbi.1008636.ref055","first-page":"361","article-title":"Development of a technique to determine strains in tendons using the cell nuclei","volume":"40","author":"H Screen","year":"2003","journal-title":"Biorheology"},{"issue":"4","key":"pcbi.1008636.ref056","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/nmat4520","article-title":"Microstructural heterogeneity directs micromechanics and mechanobiology in native and engineered fibrocartilage","volume":"15","author":"WM Han","year":"2016","journal-title":"Nature materials"},{"issue":"1","key":"pcbi.1008636.ref057","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jbiomech.2005.10.032","article-title":"Comparison of cellular strain with applied substrate strain in vitro","volume":"40","author":"ME Wall","year":"2007","journal-title":"Journal of biomechanics"},{"issue":"2","key":"pcbi.1008636.ref058","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.fcl.2005.01.013","article-title":"Achilles tendon disorders: etiology and epidemiology","volume":"10","author":"TA J\u00e4rvinen","year":"2005","journal-title":"Foot and ankle clinics"},{"issue":"11","key":"pcbi.1008636.ref059","doi-asserted-by":"crossref","first-page":"1961","DOI":"10.1007\/s10439-007-9375-x","article-title":"Increased proteolysis of collagen in an in vitro tensile overload tendon model","volume":"35","author":"TL Willett","year":"2007","journal-title":"Annals of biomedical engineering"},{"issue":"2","key":"pcbi.1008636.ref060","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1067\/mse.2000.101962","article-title":"Neer Award 1999: Overuse activity injures the supraspinatus tendon in an animal model: A histologic and biomechanical study","volume":"9","author":"L Soslowsky","year":"2000","journal-title":"Journal of Shoulder and Elbow Surgery"},{"issue":"5","key":"pcbi.1008636.ref061","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/jor.21046","article-title":"Mechanobiological response of tendon stem cells: implications of tendon homeostasis and pathogenesis of tendinopathy","volume":"28","author":"J Zhang","year":"2010","journal-title":"Journal of orthopaedic research"},{"issue":"2","key":"pcbi.1008636.ref062","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/jor.20962","article-title":"Production of PGE2 increases in tendons subjected to repetitive mechanical loading and induces differentiation of tendon stem cells into non-tenocytes","volume":"28","author":"J Zhang","year":"2010","journal-title":"Journal of Orthopaedic Research"},{"key":"pcbi.1008636.ref063","article-title":"Tendon tissue microdamage and the limits of intrinsic repair","author":"T Stauber","year":"2019","journal-title":"Matrix Biology"},{"issue":"1","key":"pcbi.1008636.ref064","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1152\/japplphysiol.00741.2013","article-title":"Microtrauma stimulates rat Achilles tendon healing via an early gene expression pattern similar to mechanical loading","volume":"116","author":"M Hammerman","year":"2013","journal-title":"Journal of applied physiology"},{"key":"pcbi.1008636.ref065","doi-asserted-by":"crossref","first-page":"330","DOI":"10.3389\/fphys.2015.00330","article-title":"Tendon vasculature in health and disease","volume":"6","author":"H Tempfer","year":"2015","journal-title":"Frontiers in physiology"},{"issue":"4","key":"pcbi.1008636.ref066","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1097\/00000658-195104000-00019","article-title":"Utilization of scar tissue in bridging tendon defects","volume":"133","author":"WP Whalen","year":"1951","journal-title":"Annals of surgery"},{"key":"pcbi.1008636.ref067","first-page":"fj. 201900130RR","article-title":"Scleraxis lineage cells contribute to organized bridging tissue during tendon healing and identify a subpopulation of resident tendon cells","author":"KT Best","year":"2019","journal-title":"The FASEB Journal"},{"key":"pcbi.1008636.ref068","doi-asserted-by":"crossref","first-page":"45238","DOI":"10.1038\/srep45238","article-title":"Novel model of tendon regeneration reveals distinct cell mechanisms underlying regenerative and fibrotic tendon healing","volume":"7","author":"K Howell","year":"2017","journal-title":"Scientific reports"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1008636","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T00:00:00Z","timestamp":1614038400000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008636","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T18:53:39Z","timestamp":1697828019000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1008636"}},"subtitle":[],"editor":[{"given":"Megan","family":"Killian","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2021,2,8]]},"references-count":68,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2,8]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1008636","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1008636","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,8]]}}}