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Page 8 of 12 Nelms et al. Plast Aesthet Res 2019;6:21 I http://dx.doi.org/10.20517/2347-9264.2019.40

GENE THERAPY
Gene therapy makes use of native nuclear machinery in order to synthesize a protein of interest via the
[111]
process of transduction, in which a viral vector is typically used . In this way, growth factor can be
[112]
produced in the region of the defect, and has been reported to support mineralized tissue formation .
Therefore, expression in the host cell lasts longer (weeks to years) compared to pharmaceutical compounds
or recombinant protein, which ranges from several hours to days. This allows continuous production
of biologically active molecules, thereby mimicking the endogenous physiological healing response in
the microenvironment of the defect [113,114] . Viral vectors remain preferred to non-viral vectors because
they have been rendered replication-incompetent, and non-viral vectors have insufficient transfection
efficiencies [115,116] .

In order to induce de novo bone formation in the maxillofacial region in vivo, the genes of interest range
from soluble growth factors (PDGF, FGFs), morphogens (BMPs), angiogenetic factors (VEGF), intracellular
regulators (LIM mineralization protein-1), transcription factors (Runx2) associated with bone and
cartilage-related gene expression [117,118] . Due to their ability to initiate and sustain the entirety of the bone
[119]
formation process, BMPs are the preferred candidates for local gene therapy for bone regeneration .

Although gene therapy can be administered via systemic or local injection, gene therapy may be delivered
with a biomaterial. This combination of a vector and biomaterial is referred to as a gene activated matrix
[120]
that acts as a scaffold for delivery of the vector to the area of interest . This method may be especially
attractive in the repair of mandibular defects, in which cells may be removed from the donor site, be
[121]
genetically modified and implanted onto the scaffold of choice, and re-implanted into the defect .
Interestingly, BMSCs have been successfully transfected by various vector systems in order to improve
[117]
their proliferation and differentiation capacities . A meta-analysis by Fliefel et al. [115] which considered
majority animal-model studies found evidence that gene therapy improves bone formation in maxillofacial
defects. These results have not yet been confirmed in human subjects; thus, it remains an exciting approach
[115]
to mandibular defect repair that warrants future research and randomized clinical trials .

CONCLUSION
Tissue engineering for mandibular reconstruction is most successful when it can mimic and interact with
the surrounding native macro- and micro-environment in order to induce and support osteogenesis. Based
on the current literature, an optimal mandibular scaffold is comprised of three elements: (1) a biomimetic,
bioactive osteointegrative scaffold, most likely a resorbable composite of collagen or a synthetic polymer
with collagen-like properties with β-TCP that is 3D printed according to defect morphology; (2) growth
factor, most frequently BMP; and (3) stem cells, most commonly BMSCs. Overall, the use of a tissue
engineered scaffold may prevent common complications of mandibular defect repair with fibular free flap,
such as donor site morbidity, and may provide an approach for patients with depleted donor sites due to
previous surgeries.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design, analysis, interpretation, and preparation of the
review and manuscript: Nelms L
Assisted with manuscript preparation, as well as provided administrative, technical, and material support:
Palmer WJ

Availability of data and materials
Not applicable.