TABLE 1.

Summary of results and characteristics of the studies which investigated the effects of exogenous VEGF (or VEGF inhibitor) in tendon healing.

Study	Animal type	Models establish	Dosage	Mode of administration	Time post operation	Outcome	Conclusion
Kaux et al., 2014	Sprague–Dawley rats	Achilles tenotomy	VEGF: 100 ng	Single local injection	5, 15, 30 days	Ultimate tensile strength ↑ Mechanical stress values ↑ Type III collagen ↓	A local injection of VEGF-111 improved tensile strength in the early stage of healing.
Zhang et al., 2003	Sprague–Dawley rats	Achilles tenotomy and repair with plantaris preserved	VEGF: 100 μg (50 μg/ml)	Single local injection	4 days, 1, 2, 4 weeks	Tensile strength↑ TGF-β↑ IGF-1 n.a.	Administration of exogenous VEGF can significantly improve tensile strength in the early stage of healing.
Tang et al., 2016	White Leghorn chickens	FDP tenotomy and repair	VEGF: 2 × 109 viral particles	Injection of AAV2-VEGF vector	1, 2, 3, 4, 5, 6, 8, 12, 16 weeks	Type I collagen ↑ Type III collagen ↓ MMP1 ↓ TIMP ↑ PCNA ↑ Apoptosis index ↓ Tendon healing strength ↑	Delivery of VEGF genes through AAV2 vectors improved the tendon strength in the early and middle healing stages.
Mao et al., 2017	White Leghorn chickens	FDP tenotomy and repair	VEGF: 2 × 109 particles	Injection of AAV2-VEGF vector	4, 6, 8 weeks	Ultimate strength ↑ Gliding excursion n.a. Cellular apoptosis ↓ Type III collagen ↑ MMP2 ↑	AAV2-VEGF improved healing strength without aggravating adhesion formation after tendon injury.
Chen et al., 2012	New Zealand rabbits	ACL transection and reconstruction with allograft B-PT-B	VEGF: 5 μg/ml	Allograft B-PT-B was soaked in the VEGF/SH formulation.	2, 4, 8 weeks	Linear stiffness ↑ Ultimate failure load ↑ Blood vessel density ↑	VEGF/SH can enhance the effect of VEGF on revascularization and the biomechanical properties of grafts.
Riggin et al., 2020	Fischer rats	Achilles tenotomy	VEGF: 5 μg	Local injection on 3 consecutive days on either day 0–2 (early) or 4–6 (late)	3, 7, 14, 21, 28 days	Late Delivery: MCL ↑(at day 21), vascular size↑ (at day 7). Early Delivery: FA ↓ (at day 7), percent relaxation ↓ (at day 28)	Reducing the vascular response following injury impairs healing potential only at early time points but may improve healing potential at later time points when vascularity is increased.
			Anti-VEGF antibody (B20.4-1-1): 250 μg			Late Delivery: FA, CWFA and MCL (all ↓ at day 14 and ↑ at day 21) Vascular density ↓ (at day 14) Failure load ↓, Max stress ↓ (at day 14) Early Delivery: FA ↓, CWFA↓ (at day 7) Breaking force ↓, TNFα↑ (at day 3)
Kovac et al., 2018	Horses	7/3 horses with naturally occurring injuries of SDFTs/SLB desmopathy	NA	Plasmid DNA encoding VEGF164 and FGF2 genes	12 months period	Ultrasonographic examination ↑ Clinical observation ↑ (in eight out of 10 horses)	Plasmid DNA encoding VEGF164 and FGF2 is a novel treatment of naturally occurring tendinitis and desmitis in horses.
Yoshikawa et al., 2006b	Sheep	ACL excision and reconstruction with semitendinosus tendon graft	VEGF: 5 μg/mL	Semitendinosus tendon graft was soaked in a VEGF solution.	12 weeks	The number of newly formed vessels ↑ Infiltrative fibroblasts ↑ the anterior-posterior translation of the knee during an anterior-posterior force of ± 100N ↑ Linear stiffness ↓	Exogenous VEGF application for ACL reconstruction can induce an increase in knee laxity and a decrease in the stiffness of the grafted tendon at least temporarily after ACL reconstruction.
Hou et al., 2009	New Zealand White rabbits	Achilles tenotomy	NA	VEGF165 gene transduced BMSCs	1, 2, 4, 8 weeks	Type I collagen n.a. Type III collagen n.a. Vascular numbers ↑ Cross section area ↑ Elastic modulus ↓	VEGF deteriorated tendon properties via neovessel formation and destruction of the collagen network.
Dallaudière et al., 2013	Sprague–Dawley rats	Patellar and Achilles tendinosis (T +) induced by Collagenase 1®	Bevacizumab: 0.1 ml (2.5 mg)	Single local injection	6, 13 days	Clinical score ↑ Anteroposterior diameters ↓ Fibrillar disorganization ↓ Neovascularization. ↓	High dose mono-injection of bevacizumab in tendinosis accelerated tendon healing, with no local toxicity.
Tempfer et al., 2018	Lewis rats	Achilles tenotomy	Bevacizumab: 25 mg/ml	Local injection	14, 28 days	Cross sectional area ↓ Matrix organization ↑ Stiffness ↑ Young’s modulus ↑ Maximum load and stress ↑ Ankle joint angle in the pre-swing phase ↑	Anti-angiogenic treatment during early tendon healing is beneficial for tendon quality following injury.
Ju et al., 2006	Japanese White rabbits	In situ frozen-thawed ACL	VEGF: 30 μg	Single local injection	3, 6, 12 weeks	Microvessel density ↑ Cross-sectional areas n.a. Tensile failure n.a.	VEGF did not affect the mechanical properties of the in situ frozen-thawed ACL although promoted angiogenesis.
Thomopoulos et al., 2005	In vitro	Canine flexor tendon fibroblasts	VEGF: 20, 50, 100 ng/mL	VEGF added to the serum-free culture medium	1 day	In each concentration group, Cell proliferation n.a. Collagen production n.a.	VEGF had no effect on cell proliferation or collagen synthesis, however, on endothelial cells.

↑, significant increase; ↓, significant decrease.

n.a., not affected, NA, not applicable; AT, achilles tendon; MMP, matrix metalloproteinase; TGF-β, transforming growth factor-β; FDP, flexor digitorum profundus; PIP, proximal interphalangeal; AAV2, adeno-associated viral type-2; TIMP, tissue inhibitor of metalloproteinases; ACL, anterior cruciate ligament; B-PT-B, bone-patellar tendon-bone. SH, sodium hyaluronate; FA, fractional area; CWFA, color weighted fractional area; MCL, mean color level; TNFα, tumor necrosis factor-α; SDFT, superficial digital flexor tendon; SLB, suspensory ligament branch; PBS, phosphate buffered saline; BMSCs, bone marrow-derived mesenchymal stem cells.