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Page 8 of 14 Velasquillo et al. Plast Aesthet Res 2020;7:31 I http://dx.doi.org/10.20517/2347-9264.2020.30

bone sequestration, infection or bone resorption), donor area complications (hematoma, infection,
abnormal scar, pain and temporary inability to walk) [103] , and insufficient bone graft [104,105] . In these cases,
the possibility of synthetic bone substitutes (silicone, polytetrafluoroethylene, polyethylene, polyester,
polyamides, acrylic, metals, cyanoacrylate, resins) [106-111] , or natural bone substitutes (calcium phosphate,
granules) has been suggested [112-119] .

The use of cell-based therapy represents one of the most advanced methods to approach craniofacial
abnormalities. Several animal models have been used to test alveolar cleft-grafting materials including
mice, rabbits, cats, dogs, goats, sheep, and monkeys. Studies have shown heterogeneous results in terms of
biocompatibility, bone regeneration capacity, integration, resorption, and mechanical resistance due to the
physicochemical characteristics of each material [120,121] . Existing systematic reviews support the ability of
bone regeneration on these materials for the treatment of small periodontal bone defects, but recommend
further studies on major bone defects such as palatal fissures [122-124] .

Scaffolds, as in all biotechnology-related applications, have been a major research topic regarding CLP. The
ideal scaffold should have macro-geometry, micro-architecture, bioactivity, and appropriate mechanical
properties [125] . The first two characteristics have been addressed with the introduction of 3D printed
scaffolds. A head CT scan is performed in patients with CLP, and a scaffold with the patient’s exact
macroscopic geometry is created. Bioactivity and mechanical properties are determined by the scaffold
material. Several different materials like polycaprolactone (PCL) with hydroxyapatite and platelet-derived
growth factor-BB [125] , cryogels [126] , demineralized bone matrices, PLA, among others, have been tested to
evaluate bone regeneration and cellular migration [127-131] . Today, the use of bioceramics, such as calcium
phosphate, in combination with biomimetic polymer scaffolds, folic acid derivatives, morphogens, and
stem cells are currently considered the most promising alternatives for CLP regeneration [127] .

The use of mesenchymal stem cells is emerging as an alternative treatment or in combination with
previously-described therapies for patients with CLP. As mentioned earlier, MSC can be obtained from
different parts of the body such as adipose tissue, bone marrow, and umbilical cord. The generation
of an artificial alveolar cleft and the implantation of teeth in the regenerated bone region have been
accomplished in dog models using BM-MSC [132-134] . Ahn et al. [135] reported the first case of regeneration of
an alveolar cleft defect. Patient-specific 3D-printed bioresorbable polycaprolactone (PCL) scaffolds were
seeded with iliac BM-MSC and showed 45% defect regeneration 6 months after transplantation, with a
75% bone mineral density compared to the surrounding bone. AD-MSC, due to their availability and easy
handling, are excellent candidates for tissue engineering in CLP patients. Preclinical studies comparing
bone regeneration between AD-MSC and autogenous bone graft in canine maxillary alveolar cleft models
showed no significant differences, meaning AD-MSC can be an acceptable alternative [136] . However, clinical
studies are needed to confirm their efficacy and reproducibility in humans.

Unlike other alternatives, MSC derived from dental tissues have been studied for CLP patients due to their
higher accessibility and less invasive retrieval. Lee et al. [137] reported that stem cells from human exfoliated
deciduous teeth (SHEDs) have mineralization potential after expressing bone-specific osteogenic markers
following insertion into ex vivo‐cultured embryonic palatal shelves and in novo culture. Furthermore,
Nakajima et al. [138] compared the bone regeneration ability of SHEDs, BM-MSC, and dental pulp stem
cells in mice. They concluded that after 12 weeks of transplantation, the ratio of new bone formation was
not significantly different among these groups. However, SHED produced the largest osteoid and widely
distributed collagen fibers. Up until now, no clinical studies have been conducted using SHEDs. Although
a huge effort has been devoted to the use of tissue engineering as a solution for treating bone defects, more
evidence is still needed.