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Page 12 of 20 Citterio et al. Plast Aesthet Res 2020;7:41 I http://dx.doi.org/10.20517/2347-9264.2020.29

scaling the surface of the extracted third molars with sterile curettes and grafted directly into the furcation
defect. After six months, a reentry was performed on both sides to assess the defect fill. In one randomly
selected patient, gingival biopsies were taken on test and control sites. The results after six months showed
improvement in terms of horizontal and vertical defect fill, PD, and CAL in both groups, with significantly
better results in PD reduction for the grafted sites. No adverse effects or foreign body reactions were
observed in PDL grafts.

In general, the RCTs published thus far suggest safety in the use of stem cells and promising clinical results
[Table 3]. The need of a tooth that has to be extracted in order to harvest PDLSCs or DPSCs is a drawback
of these cell therapies. This may be considered the main issue in the use of stem cells. Harvest, isolation,
and possible differentiation of stem cells are time-consuming, complex, and expensive processes. Protocols
with direct use of the harvested cells were proposed and evaluated by Shailini and Ferrarotti [121,122] ; the
former suggested grafting directly the PDL tissues in the defect, while the latter suggested using biological
tissue disaggregation to obtain a micrograft. The advantage of these protocols is the reduction of time
and costs of treatment; however, the presence and viability of the cells implanted in the defects cannot be
proven since no isolation and characterization are performed.

The results of the RCTs available in the literature show promising indirect measurements of the
effectiveness of the regeneration process, assessed by means of clinical and radiographic parameters.
However, true regeneration can only be proven by histological analysis, impossible to carry out in any of
the studies because of ethical limitations.

FUTURE PERSPECTIVES FOR STEM CELLS IN PERIODONTAL REGENERATION
To overcome some limitation of the present cell therapy and based on the promising results of this animal
and human research of stem cells, a further step forward has been proposed by researchers: exogenous
human MSCs.

Thus far, autologous use of stem cells has been applied only, using an extracted tooth as the source for
either PDLSCs or DPSCs. To overcome this limitation, as well as the limitation of the use of stem cells in
elderly people, whose regenerative capacity is limited, the use of exogenous or allogenic stem cells has been
[124]
proposed .

Exogenous human MSCs have already been tested in cases of biologic refractory luminal Crohn’s disease
with fistulae formation, cranial defects, myocardial regeneration, and patients with aging frailty. Exogenous
MSC infusion seemed to be very well tolerated, with only light and short-term effects and frequently
no adverse reaction at all. Thus, exogenous MSCs appear to be a feasible technique for periodontal and
regenerative treatments in general.

Pluripotent stem cells generated from somatic cells (iPSCs) are a possible stem cell lineage to study for
periodontal regeneration [125] . They have the potential to differentiate in a spectrum of different cells and
tissues. In dental research, iPSCs-derived mesenchymal cells and osseoprogenitor cells were investigated
by scientists with great interest. To be used, these cells need to go through a process of transdifferentiation.
In this process, mature somatic cells undergo a transformation to a different somatic cell without going
through a pluripotent state or a progenitor phase. This process is also called lineage switching or linage
conversion. By means of this process, epigenetic modifications, by directly reprogramming non-osteoblasts
cells into functional osteoblasts, have started to be considered as a new therapeutic approach for alveolar
bone regeneration. At present, more knowledge for applying these cells to cell-based therapy is needed and
preclinical and clinical research will enhance our understanding of these processes. iPSCs reprogrammed
from non-dental cells have shown promising results in periodontal regeneration in mice, in combination