Table 1.

Summary of developmental tendon models

Developing Tendon Characteristics	Model Characteristics	Model Outcomes	References
High cell density and low collagen content (Ansorge 2011) [26] (Chaplin 1975) [27] (Richardson 2007) [28] (Schiele 2015) [29]	Self-assembled cellular fibers	Upregulated expression of scleraxis and tenomodulin with loading; potential for scaffold-free, cellular self-assembly for single tendon fibers	Mubyana 2018 [34] Schiele 2013 [35]
	Embryonic tendon cells in fibrin gels	Upregulated tendon genes and collagen synthesis; improved tendon formation in fibrin gel vs collagen gel models	Kalson 2010 [36] Kapacee 2010 [33] Yeung 2015 [37] Breidenbach 2015 [38]
Cell-cell junction proteins (Cadherin-11 & N-Cadherin) (Richardson 2007) [28]	Chick tendon explants, fibroblasts, and mouse MSCs	Possible regulators of early tendon tissue formation; N-cadherin and cadherin-11 levels decreased with tenogenic induction	Richardson 2007 [28] Schiele 2013 [35] Theodossiou 2019 [39]
TGFβ2&3 (Pryce 2009) [21] (Kuo 2008) [30]	Mouse embryonic tendon progenitor cells and fibroblasts, and MSCs	TGFβ2 increased scleraxis and tenomodulin expression	Pryce 2009 [21] Brown 2014 [40] Brown 2015 [41] Havis 2014 [42] Havis 2016 [43] Chien 2018 [44]
	Mouse MSCs	TGFβ2 increased scleraxis and tenomodulin production; decreased N-cadherin and cadherin−11 production	Theodossiou 2019 [39]
	Human BM-MNCs and MSCs in fibrin gels	TGFβ3 increased collagen fibril synthesis, and upregulated TGFβ3, Col I, and Smad2	Kapacee 2010 [33]
Scleraxis and mohawk (Schweitzer 2001) [18] (Liu 2015) [31] (Otabe 2015) [32] (Shukunami 2018) [33]	Scleraxis knockdown in equine embryonic stem cells, and fetal and adult tendon cells	Decreased expression of Col I, COMP, and Sox9, and reduced cell survival in embryonic stem cells and fetal tendon cells with scleraxis knockdown; adult tendon cells unaffected	Bavin 2017 [45]
	Scleraxis knockout in mice, and scleraxis knockdown in isolated rat tendon cells	Decreased or absent tenomodulin expression at P1 in scleraxis −/− mice; tenomodulin expression reduced to 17% of control by scleraxis knockdown in rat tendon cells	Shukunami 2018 [46]
	Mohawk knockout in rats via CRISPR/Cas9	Heterotropic mineralization of Achilles tendons and tendon hypoplasia in 3 and 4-week-old rats; increased expression of Col II, Runx2, Aggrecan, COMP, and osteopontin in patellar tendon cells	Suzuki 2016 [47]
	Overexpression of mohawk and scleraxis in mouse MSCs and cell sheets	Increased expression of Col I, biglycan, Col III, Col V, Col XIV, decorin, fibromodulin, tenascin C, tenomodulin, and scleraxis via binding to the TGFβ2 promoter	Liu 2015 [31]
	Overexpression of mohawk in human and mouse bone marrow-derived MSCs	Increased expression of Col I, tenomodulin, tenascin C, tenascin XB, scleraxis	Otabe 2015 [32]
	Overexpression of scleraxis in human MSCs in a silk-collagen scaffold	Increased expression of tenogenic genes, cell alignment, and fibril diameter	Chen 2014 [48]
FGF4 (Edom-Vovard 2002) [49] (Brent 2005) [50] (Havis 2014) [42]	Mouse MSCs and chick limb explants	Species-specific scleraxis expression: decreased in mouse or increased in chick	Havis 2014 [42] Havis 2016 [43]
	Mouse embryonic tendon progenitor cells and MSCs	No changes or decreased scleraxis expression	Brown 2014 [40] Brown 2015 [41]
BMPs (Lorda-Diez 2014) [38] (Liu 2015) [31] (Otabe 2015) [32]	Chick progenitor mesodermal cells	Transient gene expression determines response to BMP isoforms	Lorda Diez 2014 [54]
	Human bone marrow-derived MSCs	BMP-12 increased mohawk, scleraxis, Col I, tenascin XB, and decorin expression	Otabe 2015 [32]
LOX and Mechanical Stimuli (Marturano 2013) [51] (Pan 2018) [52]	Embryonic chick tendon and limb explants	Paralysis decreased elastic modulus and LOX, hypermotility increased LOX and elastic modulus, LOX inhibition decreased elastic modulus	Pan 2018 [55]
Lengthening/slow stretching (Hamburger & Hamilton 1951) [53]	Embryonic chick tendon cells in fibrin gels stretched 2 mm/day	Increased collagen fibril diameter, packing volume, and stiffness	Kalson 2011 [56]
Elastic modulus (Marturano 2013) [51]	RGD-functionalized alginate gels with embryonic-mimicking elastic modulus	Scleraxis, Col XII, and Col I gene expression regulated by elastic modulus	Marturano 2016 [57]
Progressive mineralization of tendon to bone attachment (Thomopoulos 2010) [12]	FEA model of cell- and tissue-level stress concentrations	Cell-level stresses much higher than tissue-level stresses; higher stresses may drive enthesis formation	Liu 2014 [58]