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Nelms et al. Plast Aesthet Res 2019;6:21 I http://dx.doi.org/10.20517/2347-9264.2019.40 Page 5 of 12
[65]
host-host bridging, and engraftment is similar . In preclinical animal studies, autogenous bone precursor
cells seeded onto calcium phosphate ceramic scaffolds, pyrolyzed bovine bone, or calcium carbonate has
been comparable to autograft bone in mandibular reconstruction in terms of biomechanical testing, bone
bridging, and bone ingrowth [64-66] .

The second major category is the synthetic polymer (PCL, PLLA, PLA-PEG, PGA, PLGA, PLGA-PEG, etc.).
This material is promising because it allows 3D printing of complex structures that are biodegradable,
[67]
bioactive, and undergo controlled degradation . However, PCL is not ideal for mandible tissue
[68]
engineering due to inferior mechanical properties such as a low compressive strength .

[69]
The third category of material is the natural polymer (collagen, chitosan, silk fibroin, alginate, gelatin, etc. .
Although biocompatibility with natural scaffolds is obviously excellent, there remain issues with potential
immunogenicity in some cases. Because they do not induce antigen-antibody reactions, decellularized
tissue matrices obtained from processing discarded donor tissue is an attractive solution. When bone
matrix is demineralized via removal of HA, the remaining bony matrix is comprised mainly of collagen -
this biocompatible, bioactive biomaterial has the ability to induce bone morphogenesis via BMP signaling,
particularly in stem cells, and can be used as a film, gel, or sponge [70,71] . Although they have similar
osteoinductive and osteoconductive properties as autologous grafts, they lack the corresponding osteogenic
[71]
properties . Additional major downsides are sourcing, processing, immunogenicity, and disease
transmission, as well as lack of mechanical strength to withstand the forces exerted by the muscles of
mastication [72,32] .

[73]
In order to address this, Kakabadze et al. reports development of a novel biologically active bone graft
using decellularized cancellous bovine femur seeded with human bone marrow mesenchymal stem cells
(BMSCs) and growth factors, which was applied clinically to repair a large mandibular defect following
primary tumor resection that successfully repaired the defect and showed maintained mandibular bone
volume at 5 months post-op. Importantly, like the use of autologous bone, this graft construction requires
use of a barrier membrane to prevent fibrous tissue invasion, and decellularized human amnion/chorion
[73]
membrane was chosen by the authors due to its osseointegrative properties .
However, the shortcomings of using a single material in scaffold construction include: poor strength
for biologically-derived materials, brittleness for inorganic materials, and poor cell compatibility and
[56]
insufficient mechanical strength for synthetic polymers . Because of this, combining two or more materials
to create a composite scaffold has shown improvement in material properties and biocompatibility. Most
often, the polymer of choice is type I collagen, which is most often coated on scaffolds made from PCL,
[38]
HA, and TCP in order to aim to mimic the structure of native bone . Additionally, biomimetic Mg-
[74]
MgHA/collagen-based scaffolds have been shown to greatly improve osteoblast differentiation . When
choosing between ceramics to add compressive strength, it should be noted that compared to β-TCP, HA
[75]
has low absorption kinetics in vivo (1%-2% per year at 5 years postimplantation) . An HA-collagen or
β-TCP-collagen scaffold can be 3D printed, and the combination of biocompatibility, compressive strength,
and resorption rate in vivo and in vitro allows for bone replacement over time, and the degradation rate of
the material can be altered by increasing the macroscopic surface area by decreasing the strut diameter or
[61]
altering micro/nano porosity .

The scaffold surface may also be modified by the addition of nanoparticles. Most commonly, nano-HA
is combined with PCL and chitosan scaffolding . Nano-HA is of interest because it has been shown to
[38]
increase the mechanical properties and improve the protein adsorption capacity of the polymer, while
[76]
also acting as a substrate for cell attachment and migration during bone regeneration . Polyamide66 is
[77]
a synthetic polymer chosen by Cai et al. to combine with HA due to its biocompatibility, high tensile