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Citterio et al. Plast Aesthet Res 2020;7:41 I http://dx.doi.org/10.20517/2347-9264.2020.29 Page 15 of 20

With all these different possible therapeutic approaches, we must not forget the four key factors needed
to reach the goal of a “restitutio ad integrum” of the periodontal apparatus and have a true regeneration:
cells, environment, signals, and time. Stem cells (MSCs, PDLSCs, iPSCs, etc.) have to be put or recruited
in a favorable and protected environment (e.g., 3D scaffold) and guided in their transformation process by
signaling molecules (homing and differentiating factors), for long enough to mature.

A pivotal role is also played by MSCs adhesion capacities and longevity. In fact, cell adhesion is critical for
survival, proliferation, and differentiation of MSCs. Similarly, MSCs’ longevity may influence the outcomes
of the regeneration therapies. Therefore, to maximize the potential of tissue engineering therapies,
researchers have to focus their attention on well-designed scaffolds and precise signaling molecules. The
former are meant to favor adhesion and impede anoikis and the latter are to be used both before and
during transplantation to stimulate cell proliferation and longevity in order to overcome possible low cells
survival rates [137] .

These different methods might have to be combined to achieve the maximum result in tissue regeneration.
Ideally, an optimum protocol should focus on three key points: (1) the use exogenous or endogenous MSCs
pre-treated with bioactive factors; (2) a protective scaffold that favors cells adhesion and spreading; and (3)
signaling molecule doping of the scaffold to boost cells’ regenerative abilities, increase their longevity, and
recruit nearby already present stem cells.

Finally, the future research is focused on the possible application of cell therapy for regeneration. The fields
that are being investigated extend from what is possible at the present time (dentin–pulp regeneration and
periodontal regeneration) to future applications (whole-tooth regeneration) [138] . Thus far, the evidence for
whole-tooth regeneration is limited in vitro and in animal models, but research is progressing quickly.

CONCLUSION
The goal of periodontal tissue engineering is to restore the normal function of the diseased periodontium
to support the teeth. To achieve this objective, stem cells, appropriate scaffold, and infection control are
required at the diseased site. Even if some studies reported conflicting results and irregular outcomes,
the available evidence in animal models supports the applicability of stem cells in periodontal tissue
regeneration. We hypothesize that this heterogeneity of results could be due to the different methodologies
used. In fact, differences in study models (animal and defect ones), treatment modalities, isolation
protocols, and study designs are some of the factors that can influence the final results of the investigation.
This leads to the present impossibility to propose a specific protocol or MSC type which may be considered
superior to others. The efficacy and safety of cell-based interventions in humans have been proven by case
reports and case series, but sparsely by RCTs. PDLSCs and DPSCs have been tested and showed promising
results both in animal models and in humans. However, it is yet to be defined which protocol performs
better, and, although experimental data have allowed the beginning of clinical trials in periodontal cell
therapy, proper consideration of the cell source, material type, and regulatory concerns is crucial to
facilitate clinical translation. Furthermore, histological evidence of periodontal regeneration is still lacking
and the power of studies is hampered by major limitations. One of the major shortcomings is the defects
used in animal models, which may not adequately reflect the complex microbiological and immune-
inflammatory environment of the periodontal pocket. Actually, in many cases, the periodontal defects
generated in the currently used animal studies do not sufficiently represent those of human periodontitis.
Evidence for exogenous MSCs grafting, 3D printed-scaffold, and stem cell homing is promising but still
limited. Despite all these shortcomings, tissue engineering in periodontology is fascinating and hopefully
will help clinicians to overcome the limitations of present periodontal treatments. In fact, MSCs have
provided surprisingly favorable outcomes in conditions in which standard procedures for periodontal