Stem cell therapies in tendon-bone healing

Table 1 Summary of differentiation capacities between different mesenchymal stem cell types

MSC type	Clinical extraction methods	Osteogenic	Chondrogenic	Adipogenic
BMSCs	From the anterior iliac crest, posterior superior iliac crest, tibial tubercle, or sternum	++	++	+
SMSCs	From the knee joints and shoulder during surgery	++	++++	+++
ADSCs	Liposuction at subcutaneous adipose tissue	+	+	+++
PSCs	Stripped from the tibia	+++	+++	++

MSC: Mesenchymal stem cell; BMSCs: Bone marrow mesenchymal stem cells; SMSCs: Synovium-derived mesenchymal stem cells; ADSCs: Adipose-derived stem cells; PSCs: Periosteum-derived periosteal stem cell.

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.

Table 3 Summary of pre-clinical studies using gene-modified bone marrow mesenchymal stem cells

Ref.	Animal/model	Cell/cell number	Transfected gene	Method of delivery	Control	Timeline	Outcome measurement
Gulotta et al[72], 2010	Rat/Unilateral detachment and repair of the supraspinatus tendon	BMSCs/× 106	MT1-MMP	BMSCs were pelleted down and mixed with fibrin sealant for implantation	Rotator cuff repair with normal BMSCs	2 and 4 wk	Histology, biomechanics
Gulotta et al[76], 2011	Rat/Unilateral detachment and repair of the supraspinatus tendon	BMSCs/× 106	Scx	BMSCs were pelleted down and mixed with fibrin sealant for implantation	Rotator cuff repair with normal BMSCs	2 and 4 wk	Histology, biomechanics
Gulotta et al[77], 2011	Rat/Unilateral detachment and repair of the supraspinatus tendon	BMSCs/× 106	BMP-13	BMSCs were pelleted down and mixed with fibrin sealant for implantation	Rotator cuff repair with normal BMSCs	2 and 4 wk	Histology, biomechanics
Dong et al[78], 2012	Rabbit/Unilateral ACL reconstructions using gastrocnemius tendon autografts	BMSCs/× 107	BMP-2	Grafts were coated with BMSCs in a fibrin glue carrier	ACL reconstruction without BMSCs	4 and 8 wk	Histology, biomechanics
Wang et al[79], 2017	Rabbit/Unilateral ACL reconstructions using flexor digitorum longus tendon autografts	BMSCs/-	TGF-β	BMSCs were injected into the bone tunnel and graft tendon cavity	ACL reconstruction with normal BMSCs	6 and 12 wk	Histology, immunohistochemistry, biomechanics, 3D-CT
Wang et al[80], 2018	Rat/Bilateral detachment and repair of the supraspinatus tendon	BMSCs/1.6 × 107	PDGF-B	BMSCs with fibrin glue implanted into the defects	Rotator cuff repair with irrelevant plasmid-transfected BMSCs	4 and 8 wk	Histology, immunohistochemistry, biomechanics

BMSC: Bone marrow mesenchymal stem cell; MT1-MMP: Membrane type 1 matrix metalloproteinase; Scx: Scleraxis; BMP-13: Bone morphogenetic protein-13; BMP-2: Bone morphogenetic protein-2; TGF-β: Transforming growth factor-beta; PDGF-B: Platelet-derived growth factor subunit B.

Table 4 Summary of clinical studies using bone marrow mesenchymal stem cells

Ref.	Study type/patient number	Cell/cell number	Method of delivery	Control	Follow up	Outcome measurement
Jo et al[82], 2013	Cohort study/124	BMSCs/-	Drilling into the bone marrow was performed in the greater tuberosity	Arthroscopic rotator cuff repair without drilling	At a minimum of 2 yr	VAS, ROM, muscle strength, functional scores, MRI, CTA
Hernigou et al[84], 2014	Case-controlled study/90	BMSCs/12 mL (51000 ± 25000 cells)	BMSCs were injected into the tendon-bone interface	Arthroscopic rotator cuff repair without BMSCs	At a minimum of 10 yr	ROM, muscle strength, MRI, ultrasound
Silva et al[85], 2014	RCT/43	BMSCs/-	BMSCs were injected in the tunnel	ACL reconstruction without BMSCs	3 mo	MRI
Taniguchi et al[83], 2015	Retrospective cohort study/111	BMSCs/-	Drilling into the bone marrow was performed in the greater tuberosity	Arthroscopic rotator cuff repair without drilling	12-24 mo	MRI

BMSC: Bone marrow mesenchymal stem cell; VAS: Visual analog scale; ROM: Range of motion; MRI: Magnetic resonance imaging; CTA: Computed tomography arthrography; RCT: Randomized controlled trials.