Table 2.

Summary of tendon injury models

Injured Tendon Characteristics	Model Characteristics	Model Outcomes	References
Overuse injury	Downhill running in rats	Induced overuse injury in the supraspinatus	Soslowsky 2000 [107] Archaumbault 2006 [108]
	Bipedal downhill running in rats	Reduced stiffness and tensile strength; localized disintegration of collagen bundles	Ng 2011 [109]
	Uphill running in rats	Achilles tendons adapted to loading; no observable pathology	Heinemeier 2012 [110] Dirks 2013 [111]
Transection/Acute injury	Neonatal and adult mouse Achilles tendons	Regeneration observed in neonates, but not adults	Howell 2017 [112]
	Mouse supraspinatus tendons with full and partial transections	Different cell populations involved in healing of full versus partial injury; distinct cell lineages participate in healing response	Moser 2018 [113] Yoshida 2016 [114]
	Rat Achilles tendon partial transection repaired with scaffolds	Cells in scaffolds expressed mohawk during repair	Otabe 2015 [32]
	Mouse Achilles tendon full transections repaired with MSC sheets overexpressing mohawk	Mohawk-overexpressing MSC sheets resulted in increased collagen fibril diameter, visible crimp, increased stiffness, elastic modulus, maximum force and stress, and energy absorbed	Liu 2015 [31]
	Canine digital flexor tendons	Following injury, IL-1β upregulated 4000-fold, MMP-13 upregulated 24,000-fold	Manning 2014 [115]
IL-1β treatment	E15 and P7 mouse tendon cells treated with IL-1β	Higher expression of IL-6, TNFα, COX2, MMP-3 and MMP-13 in P7 compared to E15	Li 2019 [116]
	Human patellar tendon fibroblasts treated with IL-1β and strain	IL-1β and 8% strain upregulated MMP-1, COX2, and PGE2; IL-1β and 4% strain downregulated expression of MMP-1, COX2, and PGE2 compared to 8% strain	Yang 2005 [117]
	Adult and fetal equine tendon cells, and equine embryonic stem cells treated with IL-1β	Adult and fetal tendon cells upregulated MMP-1, −2, −3, −8, −9, and − 13, tenascin-C, Sox9, and downregulated scleraxis and COMP, compared to embryonic stem cells	McClellan 2019 [118]
Genetic knockouts	Tenomodulin knockout mice with transected and repaired Achilles tendons	Downregulation of Col I, tenascin-C, thrombospondin 2, and TGFβ1; upregulation of scleraxis, COMP, and proteoglycan 4	Lin 2017 [119]
	GDF-5 knockout mice subjected to Achilles tendon injury	Delayed healing and increased adipocytes in knockouts	Chhabra 2003 [120]
	Decorin-null and biglycan-null mice subjected to full thickness, partial width patellar tendon injury in adult and aged groups	Smaller diameter collagen fibrils, decreased cell density, and altered cell shape and collagen alignment in knockouts; biglycan influenced early healing, decorin influenced late healing	Dunkman 2014 [121] Dunkman 2014 [122]
Chronic Injury/Induced Tendinopathy	Transection or Botox-unloading of rat Achilles tendon	Irreversible loss of scleraxis expression with transection; partial loss and return of scleraxis with Botox	Maeda 2011 [123]
	Immediate or delayed repair of rat rotator cuff injury	Delayed repair had worse outcomes than immediate repair	Killian 2014 [124]
	TGFβ1 injection to rat Achilles	Warburg pathway, hypoxic, angiogenic, and glycolytic metabolism gene activation	Sikes 2018 [125]
	Collagenase injection in rat Achilles tendon	Increased IL-6 and MMP-9 in senescence-accelerated rats compared to senescence-resistant rats	Ueda 2019 [126]
	Carrageenan injection in rat patellar tendon; treatment with IL-1 receptor antagonist	Carrageenan decreased tendon length, and increased MMP activity and inflammation. Inflammation absent with IL-1 receptor antagonist	Berkoff 2016 [127]
Ex vivo Loading	Stress deprivation in rat tail tendons	Increased MMP-13 expression	Arnoczky 2007 [128]
	Stress deprivation in rat tail tendons	Stress deprivation decreased TIMP/MMP ratio; loading increased TIMP/MMP ratio	Gardner 2008 [129]
	Fatigue loading of rat flexor digitorum longus tendon loaded at low (6.0–7.0%), moderate (8.5–9.5%), and high (11.0–12.0%) tensile strain	Isolated fiber deformations at low strain; fiber dissociation and localized rupture, decreased stiffness, and increased hysteresis at high strain	Fung 2009 [130]
	Equine flexor and extensor tendon cells subjected to 10% biaxial cyclic loading	Collagen synthesis, proliferation, COMP expression as a function of tendon type	Goodman 2004 [131]
	Equine superficial digital flexor tendon fascicles cyclically loaded from 2–12% uniaxial strain and 1800 cycles	Increased expression of IL-6, COX2, C1, C2, and MMP-13	Thorpe 2015 [132]
	Bovine deep digital flexor tendons cyclically loaded from 1 to 10% strain	Collagen fiber disruption, kinks, and interfascicular network damage, and expression of IL-6, COX2, MMP-1, 3, and 13	Spiesz 2015 [48]
	Mouse patellar tendon cells isolated from 3-week old mohawk knockouts and subjected to 4% cyclic tensile loading	Increased chondrogenic gene expression (Col II, Aggrecan, COMP)	Suzuki 2016 [47]
Computational models	Cell- and tissue-level responses to strain simulated via Hill functions	Tissue-level response similar at low and high strain conditions	Mehdizadeh 2017 [133]
	Hill-type equations of human Achilles-soleus unit	Proteolytic damage leads to collagen fiber shortening; mechanical damage lengthens fibers	Young 2016 [134]
	Regression model of healing	Multiple differential predictors of early development and early developmental healing; however, no differential predictors of late development and late developmental healing	Ansorge 2012 [135]
	2D FEA simulation of “jumper’s knee” in Patellar tendon	Highest localized strain predicted successfully	Lavagnino 2008 [136]
	Agent-based model of collagen fibril alignment with applications in tendon loading during healing	Peak collagen alignment occurs at lower strain level than peak deposition; peak deposition occurs above damage threshhold	Richardson 2018 [137]
	Multiscale OpenSim model of cellular responses to various loading parameters	Single set of cellular response curves explained tendon behavior observed in several different experiments	Chen 2018 [138]
	Empirical model of patellar tendon response to aging and injury	Effects of aging and injury on patellar tendon mechanical properties predicted by damage models	Buckley 2013 [139]
	Empirical model of Achilles tendon response to decorin and biglycan knockout in aging mice	Model predicted changes in dynamic modulus resulting from decorin and biglycan knockout	Gordon 2015 [140]