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In order to accomplish this, an effective bone scaffold must satisfy the following requirements:
[27]
osteoconductivity, osteoinductivity and osseointegration . Osteoinductivity is the ability of a material to
[28]
recruit multipotent cells and encourage their differentiation into an osteoblastic lineage . This is typically
accomplished adding both growth factors and stem cells, such that growth factors signal to surrounding
mesenchymal stem cells to differentiate into chondroblasts and osteoblasts to form new bone [29,30] . In the
context of mandibular reconstruction, stem cells have potential to regenerate oral and dental tissues, such
[22]
as bone, dentin, cementum, periodontal ligaments, mucosa, and salivary glands . Mesenchymal stem cells
are the most common source of osteoprogenitor cell used, and may be derived from bone marrow, adipose
tissue, and dental and periodontal tissue, and their differentiation is guided by growth factors [such as
bone morphogenic protein (BMP)]. Such involvement and interaction between growth factors are essential
to the process of native bone healing, including vascular endothelial growth factor (VEGF), fibroblastic
[31]
growth factors, insulin-like growth factors, platelet-derived growth factor, and BMP, to name a few .
During osteogenesis, an osteoconductive material will allow the growth of bone not only on the scaffold
surface, but also into pores and channels, such that both cortical and cancellous bone are formed around
[32]
and within the framework . Such materials may also be designed to be resorbed in order to encourage
growth of native bone. Osseointegration is the degree to which the native bone and the implant favorably
interact, and such incorporation of a graft is influenced by many factors, such as the type of bone scaffold
used and the site of implantation . Thus, the general principle underlying third generation biomaterials is
[33]
the regeneration triad: (1) an extracellular matrix (ECM) scaffold, which can be made of varying material
to create a porous 3D structure that may be seeded with; (2) growth factors; and (3) stem cells [34,35] . Ideally,
scaffolds should be designed to provide regenerative signals to surrounding cells, while simultaneously
[37]
improving cell adhesion, proliferation, and differentiation , and mechanical rigidity or flexibility .
[36]

Thus, there is extensive flexibility in assembling a scaffold. The choice of scaffold material itself can be
varied, and sometimes may be used successfully on its own or in combination with other materials.
Furthermore, modification of the scaffold material by coating its surface with nanoparticles, an ECM
molecule (such as collagen), or a growth factor (such as BMP-2) has been shown to improve tissue
[38]
properties . In this review, we will explore the success of varying combinations of the above scaffolding
materials, and will examine their success in vivo and in vitro in inducing and guiding osteogenesis in
mandibular defects.

SCAFFOLD MATERIALS AND STRUCTURE
[21]
Beyond the biocompatibility of a scaffold, as has been argued by Chocholata et al. , the most important
aspect of scaffold design is its three dimensional structure, namely the degree of pore interconnectivity and
pore size, both of which effect the degree of cell attachment and three dimensional regeneration of tissue,
as well as cell growth, proliferation, and differentiation, diffusion of waste and the degradation products
of scaffolds. The goal of these materials is to initiate or enhance bone formation - if pore size is too small,
it can hinder cell migration, and if too large will result in suboptimal binding of cells to the scaffold [18,39] .
[40]
For maximal osteoconductivity, the ideal pore size as described by Ghayor and Weber based on in vivo
data is 0.7-1.2 mm, and the size of connections between pores should be between 0.5-1.2 mm; sizes larger
than this are detrimental to osteoconductivity. During osteointegration, these porous spaces are initially
populated by capillaries, perivascular tissues, and osteoprogenitor cells, followed by incorporation of the
[41]
porous structure within the newly formed bone . Additionally, the scaffold must be designed to degrade
at an appropriate rate so that there is enough time for bone regeneration . This is especially relevant in
[42]
pediatric patients, where the future growth of the mandible must be considered. In this case, fixation of
the mandible using titanium locking reconstruction plates does not allow for mandibular growth over
[24]
time, and might result in facial asymmetry and problems with occlusion as the patient grows . Resorbable
plates have been developed in order to address this, but their drawbacks include postoperative plate