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fracture and the development of delayed foreign-body reactions, and this potential harm to the patient’s
well-being might discourage their use; consequently, the focus on “resorbable” material has consequently
shifted to “bioabsorbable” scaffolding, which combines biodegradation with osteoconduction [43,44] . Lastly,
the mechanical properties of the material must sufficiently mimic the native tissue at the implantation site
[45]
in order to support functionality . These factors will vary with scaffolding material, and will be described
below.

A key requirement of effective tissue engineering is constructing a cellular environment that mimics
critical aspects of the in vivo setting through proper control of the materials and mechanical setting as well
as the chemical environment. The macroscopic structure of bone consists of a cortical outer layer encasing
[29]
porous trabecular bone . However, it is the nanoscopic structure of bone that yields its mechanical,
biological and chemical properties, and this heterogenous structure is importantly irregular and
anisotropic [46,47] . The ECM of bone is comprised of 60% mineral [hydroxyapatite (HA)] and 30% organic
[48]
matrix . The organic components give bone tissue its flexibility, and mainly consist of collagen (type I
collagen, type III and type IV collagen), and together with fibrin and over 200 types of noncollagenous
matrix proteins (glycoproteins, proteoglycans, sialoproteins, etc.), collagen forms the native scaffold for
mineral deposition [15,48] . These HA Ca (PO ) .(OH) nanocrystals, inlayed between individual collagen
4 2
3
2
[49]
fibers, give bone its mechanical strength and rigidity . Due to this structure, bone tissue can be treated as
[48]
a ceramic-organic bio-nanocomposite complex .

In an effort to design biomimetic material, natural (some authors also called these biological) scaffolds use
existing ECM materials, and may be protein-based (e.g., collagen, fibrin) and polysaccharide-based (e.g.,
chitosan, alginate, glycosaminoglycans, hyaluronic acid) [50-52] . Such material also contains cross-linking
agents (e.g., glutaraldehyde, water-soluble carbodiimide), which can be adjusted to modify degradation
[37]
rates . One method to achieve both porosity and biocompatability is to mimic the collagen network of the
[53]
ECM of bone using nanofibrous scaffolds . This can be constructed using electrospun (PLLA) scaffolds,
which when coated with HA has been shown to induce calcium deposition and mineralization and the
formation of higher order bone structures such as trabeculi and bone marrow, when combined with stem
[54]
cells . It has also been shown that electrospun PLLA can be combined with a porous collagen membrane
to guide bone regeneration .
[55]

Single material scaffolds have shown promise in reconstructing mandibular defects. These materials
include: biological polymers (collagen, chitosan), ceramics [beta-tri calcium phosphate (β-TCP), calcium
HA, biphosphate calcium phosphate (BCP)], and synthetic polymers [polycaprolactone (PCL), PLA, PGA,
[56]
[57]
PLGA] . The advantages to ceramics are that they are osteoconductive and biocompatible. Herford et al.
generated a ceramic compression resistant osteoconductive matrix that was 15% HA and 85% β-TCP that
showed a significantly higher bone density and space maintenance than BMP2 combined with resorbable
collagen sponge. However, one of the main concerns in the application of HA bone grafts is poor
resorption, and several studies have reported fibrous encapsulation around HA ceramic particles inside
alveolar bone [58-60] . In a 12 mm full thickness mandibular defect in a rabbit model using β-TCP ceramic,
[61]
Lopez et al. found that new bone accounted for half of the defect site repair at 8 weeks post-scaffold
implantation, although no stem cell seeding or BMP signaling was used to direct osteoblast differentiation,
instead using the properties of the biomaterial itself to direct endogenous healing mechanisms. Such
calcium phosphate ceramics (β-TCP and BCP) are promising because of their biocompatibility and drug
delivery potential, and they have been shown to be osteoconductive with sufficient mechanical strength,
and they can be reliably used in 3D printing methodology [62,63] . However, calcium phosphate is insufficiently
[64]
osteoinductive and requires supplementation with growth factors to induce new bone formation . These
scaffolds do have lower mechanical strength compared to allografts because they are designed to be
degradable such that it can be replaced by new bone; however, the extent of new bone formation, lack of