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Page 10 of 20 Citterio et al. Plast Aesthet Res 2020;7:41 I http://dx.doi.org/10.20517/2347-9264.2020.29

Stem cells from human exfoliated deciduous teeth
When injected supra-periostally close to periodontal defects, SHEDs reduced gum bleeding, increased new
attachment of PL, and decreased osteoclast differentiation. Micro-CT analysis demonstrated increased bone
volume and decreased distance of cementum-enamel junction to alveolar bone crest, compared to control
[46]
with no treatment . Histopathological photomicrographs showed newly regenerated bone and decreased
number of inflammatory factors and osteoclasts. In a recent report, SHEDs were compared to PDLSCs for
the treatment of intrabony defects. Both treatments were provided in combination with hydroxyapatite and
beta tri-calcium phosphate scaffold. The results showed no significant difference between the two groups.
SHEDs significantly improved periodontal regeneration compared to the scaffold alone, in a very similar
[89]
way to PDLSCs .
Stem cells from apical papilla
Local Injection of SCAPs increased CAL and bone volume in periodontal defects compared to injection
of 0.9% NaCl. Histopathology results demonstrated remarkable regeneration in the SCAPs group, whereas
regeneration of periodontal tissue was hardly found in the 0.9% NaCl group [101] .

Other cells
Other stem cell types are less studied, yet have positive effects, especially APCs [102] , ASCs [103] , and
GMSCs [104] . The two latter lineages have another positive characteristic: they can easily be retrieved in
large quantity. As it is necessary to implant the highest possible number of cells to have better results, their
disposability is definitely an advantage in comparison with other SC types. This advantage is also shared
with iPSCs, which can be produced form a series of already differentiated cell types.

HUMAN STUDIES
Case reports, case series, and retrospective studies
Periodontal regeneration was investigated in human clinical studies using PDLSCs, DPSCs, and BMMSCs.
DPSCs were observed in two case reports [105,106] and three case series [107-109] . One of the case reports provided
positive results for allogenic transplantation of DPSCs [106] . In parallel, some initial reports in humans
demonstrated the clinical and radiographic efficacy of dental pulp micrografts in post-extraction alveolar
defects [110,111] . In general, it was found that, in periodontal regeneration, DPSC micrografts associated with
surgical procedure were able to reduce PPD and increase CAL.

PDLSCs have been tested for regenerative procedures in intrabony defects and Grade II furcation
defects [112] . A retrospective study, which included 16 defects in three patients, observed PPD reduction and
CAL gain, thus supporting a potential benefit for the use of PDLSCs in periodontal regeneration [113] . Later
on, in a case report [114] , it was observed that periodontal regenerative surgery using PDLSCs, incorporated
in a gelatin sponge, produced PPD reduction, CAL gain, and radiographic bone fill. In Grade II furcation
defects, PDLSCs provided good clinical results, reducing PPD and improving CAL in six months

BMMSCs have been tested in four case reports and one case series that reported good clinical outcomes for
the periodontal regeneration of intrabony defects [115-118] and Grade III furcation defects [119] .

Randomized controlled trials
Once the positive results in the use of stem cells in periodontal regeneration have been proven in animal
and humans studies, RCTs are needed to assess the safety and the efficacy of the use of stem cells in
periodontal regeneration compared to standard treatments.

Thus far, four RCTs [120-123] have been published on assessing the efficacy of stem cells in periodontal
regeneration, compared to open flap debridement [121,123] or compared to the use of a scaffold alone without