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Bertolini et al. Plast Aesthet Res 2023;10:34 https://dx.doi.org/10.20517/2347-9264.2022.121 Page 17 of 25

species (ROS), hypoxia, and low nutrient supply. Conversely, pro-survival factors are mediated by
extracellular membranous vesicles, better known as exosomes, containing mRNAs and signal molecules,
[120]
able to mediate intercellular communication, generically called bioactive molecules .

Bioactive molecules and markers
Numerous growth factors have been shown to be active in both tendon development and healing. Little is
known about the synergistic and antagonistic interactions of these growth factors, and likewise, there is a
poor understanding of the optimal spatial and temporal distribution of growth factors that would produce
the best effects. Because of that, the application of growth factors to clinical tendon repair remains
challenging.

[121]
IGF-1 in a rat Achilles tendon model was able to mitigate inflammation-induced functional deficits .
TGF-β is involved in matrix synthesis in tendon healing, as demonstrated by a significant increase in
[122]
collagen types I and III production in rabbit tendon cells with the addition of these TGF-β isoforms .
bFGF increases, in a dose-dependent way, proliferation and the expression of collagen type in a rat patellar
[123]
tendon treated with bFGF .

Scleraxis (Scx) is expressed in both tendon progenitor cells and mature tenocytes. Scx binds tendon-specific
element 2 (TSE2) to form the Scx/E47 heterodimer, which in turn activates the collagen type I
promoter [124,125] .

Growth differentiation factor 5 (GDF-5) has been reported to efficiently promote tenogenic differentiation
in vitro. Haimi et al. achieved a rapid tenogenic extracellular matrix production of ASCs in vitro by the use
of GDF-5. However, GDF-5-induced tenogenic differentiation has not yet been evaluated in animal
models [126-129] .

Connective tissue growth factor (CTGF) has been demonstrated to induce the differentiation of human
MSCs cells into fibroblasts. This is demonstrated by the marked increase in type I collage and tenascin-C
synthesis. Hence, CTGF may contribute to the preservation of the structural integrity of tendon tissue, and
because of that, it could play a crucial role as a therapeutic agent in tendon regeneration [130,131] .

Transforming growth factor beta (TGF-b) in a developing mouse limb model proved to be the most
significant signaling pathway in differentiating tendon stem/progenitor cells (TSPCs) into tendon cells. In
addition, Scx-GFP signaling, which gradually disappeared when TSPCs were cultured in vitro, was reported
to reappear upon TGF-b treatment. These results demonstrated the central role of TGF-b in tendon
induction [132,133] .

Mechanical Stimulation
Among the bioactive molecules, Mechanical Stimulation (MS) holds a prominent position due to its well-
known role in stimulating collagen production and cell differentiation in the tenocyte sense. After tendon
injury and repair, it is well recognized that early and controlled mobilization during the recovery process is
crucial to improving outcomes and mechanical properties of the healed tendon, although the optimal
timing and loading are largely debated . In animal models, the complete removal of load during the
[52]
tendon’s healing results in inferior mechanical properties of the repaired tendon [134,135] . Conversely, increased
loading and movement are also detrimental to tendon properties if implemented too quickly . Increased
[135]