Stem cell therapies in tendon-bone healing

Table 2 Summary of pre-clinical studies using bone marrow mesenchymal stem cells

Ref.	Animal/model	Cell/cell number	Method of delivery	Control	Outcome measurement/timeline
Lim et al[52], 2004	Rabbit/Bilateral ACL reconstructions using hamstring tendon autografts	BMSC/3-4 × 106	Grafts were coated with BMSCs in a fibrin glue carrier	ACL reconstruction without BMSCs	Histology, biomechanics/2, 4, and 8 wk
Ouyang et al[53], 2004	Rabbit/The hallucis longus tendons were translated into calcaneal bone tunnels	BMSCs/× 107	BMSCs immobilized in fibrin glue were injected in the bone tunnel	Translation without BMSCs	Histology, immunohistochemistry/2, 4, and 6 wk
Soon et al[54], 2007	Rabbit/Bilateral ACL reconstructions using Achilles tendon allografts	BMSCs/4 × 106	Grafts were coated with BMSCs in a fibrin glue carrier	ACL reconstruction without BMSCs	Histology, biomechanics/2, 4, and 8 wk
Gulotta et al[60], 2009	Rat/Unilateral detachment and repair of the supraspinatus tendon	BMSC/× 106	BMSCs were pelleted down and mixed with fibrin sealant for implantation	Rotator cuff repair without BMSCs	Histology, biomechanics, cell tracking/2, 4 wk
Nourissat et al[57], 2010	Rat/Destructing the enthesis of the Achilles' tendon and attaching the tendon back to the calcaneum	BMSCs/4 × 106, chondrocytes/4 × 106	Cells were injected at the site of repair	Defect without cells	Histology, immunohistochemistry, biomechanics/15, 30, and 45 d
Li et al[56], 2011	Rat/The isolated flexor digitorum longus tendon were translated into tibia bone tunnels	BMSCs/5 × 106	BMSCs were injected into the tendon-bone interface	Translation without BMSCs	Biomechanics, cell tracking/2, 4, and 8 wk
Kida et al[16], 2013	Rat/Bilateral detachment and repair of the supraspinatus tendon	BMSCs/-	Drilling into the bone marrow was performed in the greater tuberosity	Rotator cuff repair without drilling	Histology, biomechanics, cell tracking/2, 4, and 8 wk
Kanazawa et al[61], 2014	Rabbit/Bilateral ACL reconstruction without a tibial bone tunnel using semitendinosus tendon autografts	BMSCs/× 106	BMSCs with the collagen sponge or a fibrin sealant were transplanted between the bottom of the grafted tendon and the bone pit of the tibia	ACL reconstruction without BMSCs	Histology, immunohistochemistry/4 and 8 wk
Teng et al[62], 2016	Rabbit/Unilateral ACL reconstructions using hamstring tendon autografts	BMSCs/× 107	Graft wrapped with PRP and BMSCs in fibrin glue and secured to the periosteum by surgical	ACL reconstruction without BMSCs	Histology, biomechanics, RT-PCR, micro-CT scan/4 and 8 wk
Degen et al[58], 2016	Rat/Unilateral detachment and transosseous repair of the supraspinatus tendon	Human BMSCs/106	BMSCs placed at the tendon-bone interface with fibrin glue	Rotator cuff repair without BMSCs	Histology, biomechanics/2 and 4 wk
Setiawati et al[64], 2017	Rabbit/Unilateral ACL reconstructions using semitendinosus tendon autografts	Rabbit BMSCs/2 × 106 with 100 μg VEGF	BMSCs were injected into the bone tunnel	ACL reconstruction without BMSCs	Biomechanics, immunohistochemistry, MRI/3 and 6 wk
Thangarajah et al[65], 2018	Rat/Unilateral detachment and transosseous repair of the supraspinatus tendon	BMSCs/106	BMSCs + DBM placed on the decorticated humeral head with fibrin glue	Rotator cuff repair without DBM	Histology, cell tracking, pqCT/6 wk
Lu et al[59], 2019	Rat/The isolated flexor digitorum longus tendon were translated into tibia bone tunnels	BMSCs/106	BMSCs were injected into the tendon-bone interface	Translation without BMSCs	Histology, immunohistochemistry, biomechanics/2 and 6 wk
Liu et al[67], 2019	Dog/Unilateral full-thickness infraspinatus tendon injury was created	BMSCs/106	Detached tendon was sandwiched between the two tendon layers of TFBC and one BMSCs sheet seeded on the tendon interfaces	Rotator cuff repair without BMSCs	Histology, biomechanics/6 wk
Hur et al[55], 2019	Rabbit/Unilateral ACL reconstructions using extensor digitorum longi tendon autografts	BMSCs/1.0 -1.5 × 107	BMSCs embedded in fibrin glue was injected to the end of graft	ACL reconstruction without BMSCs	Histology, micro-CT/12 wk
Han et al[63], 2019	Rat/Unilateral detachment and repair of the supraspinatus tendon	BMSCs/-	-	Rotator cuff repair without BMSCs	Histology, biomechanics, RT-PCR/4 and 8 wk
Huang et al[71], 2020	Rat/Unilateral detachment and reconstruction of the supraspinatus tendon	BMSC-Exos/200 μg	BMSC-Exos were injected into the tail vein	Rotator cuff repair with PBS	Histology, immunohistochemistry, biomechanics, RT-PCR, micro-CT/4 and 8 wk
Shi et al[70], 2020	Mice/Destructing the enthesis of the Achilles' tendon and attaching the tendon back to the calcaneum	BMSC-Exos/-	Exos mixed with hydrogel and implantation in the mice	Defect without Exos	Histology, immunohistochemistry, biomechanics, RT-PCR/7, 14, and 30 d

BMSC: Bone marrow mesenchymal stem cell; ACL: Anterior cruciate ligament; MRI: Magnetic resonance imaging; pqCT: Peripheral quantitative computed tomography; DBM: Demineralized bone matrix; RT-PCR: Reverse transcription polymerase chain reaction; RT-qPCR: Reverse transcription quantitative polymerase chain reaction; TFBC: Tendon-fibrocartilage-bone composite; Exos: Exosomes; PBS: Phosphate-buffered saline.