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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 7 of 12

induces the formation of bone and cartilage. In order to mimic this endogenous microenvironment, BMPs
are often combined with MSCs in order to amplify their bone-forming potential. This use of MSCs with BMPs
[93]
to repair mandibular bony defects has shown its effectiveness in animal models [72,92] . Jiang et al. showed that
transfection of BMSCs with hBMP-4 enhances their inherent osteogenic capacity in mandibular defect
[94]
repair. Zhou et al. showed rhBMP-2 combined with prefabricated tissue engineered vascularized bone
[95]
flaps produced in vivo induced successful reconstruction of the mandibular defect. Chen et al. found
that loading a demineralized bone matrix with a formulated collagen-targeting BMP-2 induced better
bone formation compared to rhBMP-2, and the authors note remarkable osteoinductive properties with
homogenous bone formation. Additionally, BMPs may be combined with non-vascularized bone grafts,
[24]
such as cadaveric fibula or other non-vascularized bone grafts, to stimulate osteogenesis . Such a design
[25]
has shown capability to reconstruct mandibular defects up to 12 cm . It should be noted that BMP is
contraindicated in cancer, because it is thought to stimulate cancer growth (shown in vivo) .
[96]
The importance of scaffold selection when using BMP-2 and BMP-7 has been well documented. The
material must allow sustained diffusion of BMPs throughout the environment and provide matrix for
in-growth of osteoprogenitor cells and blood vessels, and the properties of scaffolds constructed with
[69]
BMP and ceramics, synthetic polymers, or biological polymers differ . Currently, collagen is the gold
standard delivery system for BMPs. Composite scaffolds are also promising for BMP use, such as PLA/
PEG/HAP which is oseoconductive, or a PLGA-collagen hybrid, which has osteoinductive activity and
long stimulation effect [97,98] . In terms of novel carriers, nanoparticles and microparticles are becoming
increasingly popular due to localized and sustained delivery of BMPs, which can be designed with
natural polymers, synthetic polymers, or ceramics. Quinlan et al. loaded alginate and PLGA MPs with
[99]
rhBMP-2 in order to incorporate the polymer into porous HAp-collagen scaffold for bone regeneration,
which showed new bone formation in a rat model in vivo. Dual-interacting polymeric nanoparticles were
prepared by Seo et al. [100] to form nanocomplexes with BMP-2, which resulted in sustained BMP-2 release
and significant bone generation.

BMPs combined with biomaterial appears equivalent to autogenous osteogenic tissue. In humans, native
human BMPs, xenogeneic BMPs, rhBMP-2, or rhBMP-7 were reported to yield complete mandibular bony
defect bridging without simultaneous use of autogenous osteogenic issue in 29 out of 34 patients . It has
[85]
[57]
long been thought that bone growth cytokines could be reliably used in lieu of traditional bone grafting .
While tissue-engineered autogenous osteogenic tissues without application of osteoinductive BMPs has
been reported to restore mandibular continuity (n = 16 patients), osteoinductive rhBMP-2 loaded onto
various scaffolding materials without concomitant transplantation of autogenous osteogenic tissue has also
been shown to restore mandibular continuity [4,101-103] .

Other growth factors that have been explored for promoting osteogenesis include recombinant human
platelet-derived growth factor, TGF-b, fibroblast growth factor, recombinant human growth/differentiation
[85]
factor-5, VEGF, and insulin-like growth factor . However, BMPs remain the most frequently used
[38]
compared to other growth factors . Beside their ability to induce osteogenic differentiation in stem cells,
[104]
BMPs can accelerate the healing process . However, it should be noted that in a calvaria defect model,
BMP-2 and VEGFA had similar bone healing capacities, with FGF-2 displaying a significantly higher bone
[105]
regeneration capacity; however, the healing rate was lower than with BMP-2 and VEGFA . BMP-2 and
VEGFA also showed increased angiogenic response upon healing . It should also be noted that undesirable
[105]
clinical outcomes with BMPs have been shown, namely extreme bone proliferation (albeit in a calvarial
model), ectopic bone formation, radiculitis, and potential stimulation of neoplasms [106-108] . Because of
this, investigation into β-TCP ceramic scaffold coated with an adenosine A2 receptor indirect agonist
augmented bone growth as effectively as rhBMP-2 in a 3 mm defect . Adenosine A2A receptor signaling
[109]
appears to be important for osteoclast differentiation both in vitro and in vivo, and has been shown to
[110]
promote bone regeneration .