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Page 6 of 12 Nelms et al. Plast Aesthet Res 2019;6:21 I http://dx.doi.org/10.20517/2347-9264.2019.40
[78]
strength, and its similarity to collagen in chemical structure and functional groups . When combined
with BMSCs in a mandibular defect, this scaffold showed greater biocompatibility and osteoconductivity
with the surrounding host bone compared with commercial porous polyethylene (MEDPOR) constructs
[77]
seeded with BMSCs .

[79]
One of the fundamental hurdles of bone-tissue engineering is vascularization of tissue. Zhu et al.
fabricated pre-vascularized tissues using a method derived from rapid 3D printing, termed microscale
continuous optical bioprinting, in which two types of biocompatible and photopolymerizable hydrogels-
glycidal methacrylate-HAp and gelatin methacrylate scaffolds - were pre-designed with vascular channels
into which endothelial cells and mesenchymal cells were printed, which resulted in the spontaneous
formation of a functional endothelial network both in vitro and in vivo.

Graphene and its derivatives, such as graphene oxide and reduced graphene oxide, is also a promising
scaffold material because it is not only biocompatible, but also has been shown to regulate cell behavior,
[21]
help in differentiation, and improve adhesion, growth and proliferation of cells . Graphene is built
[80]
by layering SP2 bonded carbon atoms with atomic graphite in a honeycomb lattice structure . When
combined with natural and synthetic biomaterials, graphene has been shown to increase osteogenic
potential and mechanical strength of the scaffold [80,81] . However, graphene has been shown to be toxic at
higher concentrations and is not reliably biodegradable, warranting further investigation before clinical
trials [80,81] .

STEM CELLS AND GROWTH FACTORS
Most tissue engineering utilizes living cells, and supplying enough cells is obviously a critically important
issue. Cells are typically derived from: (1) donor tissue, which is often in very limited supply; (2) stem or
progenitor cells. Stem cells possess two major properties that make them attractive for deriving large cell
quantities: (1) their high proliferative capacity; (2) their multipotency, or ability to differentiate into cells
[37]
of multiple lineages . Bone marrow stoma contains progenitor cells with osteogenic potential, which
[82]
are referred to as bone marrow stromal cells, or BMSCs . BMSCs are a major seed cell source for bone
tissue engineering due to their well-known capability of self-renewal (which is an outcome of asymmetric
division), and differentiation into the osteoblastic lineage in vitro and in vivo [83-85] . Scaffolding has been
shown to be capable to support ectopic bone formation when seeded with BMSCs in a mouse model, and
the repair of large segmental defects [86,87] . Moreover, many previous studies have succeeded in repairing
[88]
bone defects by using BMSCs in animal models as well as in humans .
The procedure to extract autologous BMSCs is painful and associated with potential complications, so
effort has been made to explore the use of adipose derived stem cells (ADSCs). Although ADSCs have a
higher cell yield, the literature suggests they possess an inferior osteogenic capacity compared to BMSCs,
so they are not as desirable in mandibular reconstruction . Dental pulp stem cells are also of interest due
[88]
to their ease of access, low donor site morbidity, and ability to differentiate into fibroblasts, nerve cells,
endothelial cells, and odontoblasts in order to facilitate creation of new connective tissue . Raspini et al.
[90]
[89]
showed that dental pulp stem cells combined with bioactive glass scaffold that was treated with osteogenic
medium in vitro showed good biocompatibility and osteogenic induction, making it a promising
combination for hard tissue regeneration in the cranio-maxillofacial skeleton. However, the comparative
[91]
efficacy of these cells between laboratory study and patient intervention remains to be seen .

When bone is transplanted, it is degraded and replaced through a process termed “creeping substitution”,
and this degradation process releases calcium phosphates and osteoinductive proteins that amplify bone
regeneration . BMPs are a member of the transforming growth factor-beta (TGF-β) superfamily that
[41]