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Page 18 of 25 Bertolini et al. Plast Aesthet Res 2023;10:34 https://dx.doi.org/10.20517/2347-9264.2022.121

cellular proliferation, collagen production, and tenogenic gene expression, as well as Scx upregulation, is
[136]
found in both fibroblasts and mesenchymal stem cells when exposed to static or cyclic uniaxial tension .
Scaffolds
Scaffolds are another critical factor for tendon tissue regeneration. They provide biomechanical support and
improve tendon healing by facilitating cell proliferation and differentiation, promoting matrix production
through cellular hybridization, surface modification, growth factor attachment, and mechanical
stimulation . Because of that, the topographical cues provided by scaffolds must be carefully considered:
[137]
for example, the micro-/nano-structure of material surfaces has been widely reported to modulate cellular
behavior. Furthermore, tendon tissue is composed of parallel collagen fibers and the alignment is an
important topographical characteristic to mimic in tendon tissue engineering. This was widely
demonstrated by the experiments showing that tendon-specific markers, such as scleraxis and tenomodulin,
were significantly increased on electrochemically aligned collagen (ELAC) threads compared to randomly
[138]
oriented collagen fibers .
Three major categories of scaffolds are used:

(A) native tendon matrices; (B) synthetic polymers; (C) derivatives of naturally occurring proteins.

(A) Scaffolds derived from tendon matrices could retain both the normal biomechanical and biochemical
properties, turning out to be the ideal biomaterial to support tendon healing. However, before it can be
utilized, the native cells must be removed to prevent disease transmission and immune response .
[137]
(B) A great number of biodegradable and biocompatible polymers have been used for tendon tissue
engineering as well. In particular, for their biodegradability and material characteristics, the α-hydroxy-
polyesters including polyglycolic acid (PGA), poly-L-lactic acid (PLLA) and their copolymer polylactic-co-
glycolic acid (PLGA) have been studied. Numerous experimental studies on animal models demonstrated
the formation of mature collagen fibrils and cellular tenogenic differentiation using PGA or PLLA scaffolds
[140]
seeded with MSCs derived cells . Despite these advantages, polyester’s scaffolds suffer from several
limitations, such as the absence of biochemical motifs for cellular attachment, or the inability to fully
[141]
regulate cell activity .

(C) Scaffolds made from natural proteins.

Tendon ECMs are mainly composed of collagen type I and therefore scaffolds based on collagen derivatives
are highly biocompatible. Collagen derivatives scaffolds, in contrast with polyester ones, demonstrate better
bio-functionality by supporting cell adhesion and cell proliferation. The major disadvantage of collagen
scaffolds relates to their poor mechanical properties and their relatively short in vivo life, due to progressive
and natural enzymatic degradation, which further compromises their mechanical properties. Partial
solutions to these problems have been achieved through their modification by cross-linking or co-
fabricating with other materials to enhance mechanical strength and resistance . Beyond collagen,
[142]
scaffolds made from silk have been used in tendon tissue engineering. Tenogenesis of MSCs is enhanced
when seeded on aligned silk fibroin electrospun fibers, as evidenced by the upregulation of expression of
[143]
tendon/ligament-related proteins .