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Bertolini et al. Plast Aesthet Res 2023;10:34 https://dx.doi.org/10.20517/2347-9264.2022.121 Page 19 of 25

DISCUSSION
The new and more in-depth knowledge of biology and molecular biology linked to the development and
healing of tendon tissue, coupled with the increasing scientific knowledge of the regenerative potential of
mature cells and tissues, are bringing us ever closer to the goal of achieving tendon healing by regeneration
after simple tendon trauma or loss of substance. However, unfortunately, to date the comparison between
regeneration and scarring after a tendon injury is very unbalanced in favor of the latter, with its consequent
negative consequences in terms of functional recovery, pain and return to a normal working and social life
for the patient who has suffered the injury.

As analyzed above, there are already several studies in the literature documenting the regenerative success of
cellular and molecular therapies with growth and differentiation factors in an animal model. To these
experiences, we must then add the numerically inferior studies demonstrating the effectiveness of using
bioengineered tendons in the treatment of loss of substance. These studies, which give us great hope for the
near future, unfortunately, must be rightly confronted, in the transition to clinical trials, with the strict
regulations present in highly industrially and economically developed nations and with the ethical rules
[144]
imposed by scientific societies throughout the world .
Trying to condense the different legislative codes on regeneration, cell therapies and bioinduction present in
the various nations, it can be asserted that they all more or less descend from the FDA's guidelines and
regulatory framework.

In the majority of developed countries, the only therapies that are allowed in the clinical practice are cells or
non- structural tissues-based therapies that do not cause relevant alteration of the biological characteristics
of cells or tissues and preserve their original properties and functions, such as decantation, filtration,
centrifugation, and mechanical disruption without relevant alteration. These methods are included in the
definition of minimal-grade manipulation (MGM), by which tissues are harvested, treated, and reimplanted
during the same surgical session and inside the same operating room. In this sense, for clinical application,
the basket of regenerative options should be evaluated according to the principle of low or high cellular
manipulation. Bearing this in mind, and mainly led by the need to fall within the legal parameters of the low
manipulation rules, which in Europe stipulate that cells must be extracted at the patient's bedside in the
operating theater without the use of enzymatic products, numerous medical devices have appeared on the
market. Their intrinsic feature is the promise to obtain MSCs in compliance with these regulations in order
to be able to perform primitive regenerative cell therapy.

At the same time, numerous clinical and pre-clinical scientific studies have appeared in the literature to
independently validate the ability of these medical devices to provide adequate quantities of viable MSCs at
the patient's bedside to be useful for clinical purposes. To date, these clinical purposes only aim to tip the
scales of the healing process a little more in favor of regeneration and a little less in favor of healing, yet
without providing the possibility of regenerating the injured tendon or using a histocompatible neo-tendon
that is bioengineered with the recipient patient and has several mechanical characteristics similar to the
native tendon [145-150] . Currently, one of the few viable therapeutic options, which is able to unbalance in favor
of regeneration the scarring outcome present in tendon injuries with digital canal defect is the exogenous
implementation of hyaluronic acid [151,152] .

CONCLUSION
In the past decades, various surgical techniques have been described and employed to reconstruct tendon
loss of substances. Despite significant progress in surgical and rehabilitation techniques, tendon