Table 3 MSC-exos mediated mechanisms that enhance tendon-bone healing

Mice model of the anterior cruciate ligament tendon-bone healing

Genetically modified Scleraxis-overexpressing PDGFRα( +) BMSC-derived exosomes/\({10}^{10}\) particles/once

1 week, 2, and 3 weeks after surgery

Local injection of \({BMMSC}^{\mathrm{Scx}}\)-exos or miR-6924–5p dramatically reduced osteoclast formation and improved tendon-bone healing strength; inhibition of miR-6924–5p expression reversed the prevention of osteoclastogenic differentiation by \({\mathrm{BMMSC}}^{\mathrm{Scx}}\)-exos; delivery of miR-6924–5p efficiently inhibited the osteoclastogenesis of human monocytes

Exosomes rich in miR-6924–5p could directly inhibit osteoclast formation by binding to the 3′-untranslated regions (3′ UTRs) of OCSTAMP and CXCL12

[89]

Rat model of rotator cuff reconstruction

Rat BMSC-derived exosomes/200 μg/once

4, and 8 weeks after surgery

BMSC-Exos increased the breaking load and stiffness of the rotator cuff after reconstruction in rats, induced angiogenesis around the rotator cuff endpoint, and promoted the growth of the tendon-bone interface

Promotion of angiogenesis through the VEGF and Hippo signaling pathways; inhibition of inflammation by inhibiting M1 macrophage polarization and M1 macrophage secretion of pro-inflammatory factors

[102]

Rat model of rotator cuff injury

Human ADSC-derived exosomes/25 μl of ADSC-Exos (0.3 mg/ml) mixed with 75 μl hydrogel/once

4, and 8 weeks after surgery

The hydrogel with ADSC-exos significantly improved the osteogenic and adipogenesis differentiation and improved the biomechanical RCT healing

Upregulation of osteogenic markers (RUNX2), cartilage markers (Sox-9), and tenogenesis genes (TNC, TNMD, and Scx)

[103]

Rat model of the anterior cruciate ligament construction

Infrapatellar fat pad (IPFP) MSC–derived exosomes/0.1 ml of IPFP MSC–derived exosomes (\({10}^{10}\) particles/mL) mixed with sodium alginate hydrogel (SAH)/once

2, 4, and 8 weeks after surgery

IPFP MSC–derived exosomes group showed significantly higher biomechanical properties, a thinner graft-to-bone healing interface with more fibrocartilage, greater new bone ingrowth, and significantly fewer proinflammatory M1 macrophages and larger numbers of reparative M2 macrophages than in the other groups

Decreased M1 expression and increased M2 expression by the immunomodulation of macrophage polarization

[104]

Mice model of Achilles tendon-bone reconstruction

Mice BMSC-derived exosomes/dosage not reported/once

7 days, 14 days, and 1 month after surgery

At 1 month after surgery, there was more fibrocartilage in the hydrogel + BMSC-Exos group than in the other groups. The biomechanical properties of the tendon-bone junction were significantly promoted in the hydrogel + BMSC-Exos group

Decreased the M1 macrophages, the proinflammatory factors (IL-1b and IL-6) in local tissues and cell apoptosis, increased cell proliferation, reduced ECM deposition, and suppressed excessive scar formation by regulation of the transition of macrophages from M1 to M2

[105]

Rabbit model of chronic rotator cuff tears

Human ASC-derived exosomes/dosage not reported/once

6 and 18 weeks after injury

At the end of week 18, ASC-Exos group showed significantly lower fatty infiltration, a higher histological score with more newly regenerated fibrocartilage, and greater biomechanical properties than the saline group

May reduce the infiltration of inflammatory cells (such as macrophages) into the tendon-bone interface, which can decrease the formation of fibrous scar tissue and enhance the regeneration of the normal tendon-bone insertion site

[119]