CRANIOFACIAL AND DENTAL TISSUE - 3D Bioprinting and Nanotechnology in Tissue Engineering and Regenerative Medicine - page 198

(TCP) ( Probst et al., 2010 ); biocomposite cryogels ( Mishra et al., 2014 ; Mishra and Kumar, 2014 ); and
chitosan and inorganic phosphates ( Stephan et al., 2010 ).
9.4.2 GROWTH FACTORS
Bone morphogenetic proteins (BMPs) are the most studied signaling molecules related to bone matu-
ration. Twenty types of BMPs encoded by the human genome have been identified ( Nakashima and
Reddi, 2003 ). Out of these, the BMPs that have been most widely studied for craniofacial/dental regen-
eration are BMP-2 and BMP-7. These BMPs have been studied for cranial regeneration (Guda et al.,
2014) and alveolar tissue as well as oral or dental implant osseointegration ( Dunn et al., 2005 ; Wikes-
jo et al., 2005 ). GMP (Good Manufacturing Practice) level recombinant human bone morphogenetic
protein-2 (rhBMP-2) provided by R&D Systems (Minneapolis, MN) and Akron Biotechnology (Boca
Raton, FL) has been approved for bone applications such as interbody spinal fusion, open tibial frac-
tures, and sinus and alveolar ridge augmentations. It is available commercially in the INFUSE ® Bone
Graft product ( McKay et al., 2007 ). Infuse is composed of rhBMP-2, which is present on an absorbable
collagen sponge (ACS) functioning as a carrier. For certain craniofacial/dental applications such as for
defects related with extraction sockets, INFUSE ® Bone Graft received FDA approval for sinus augmen-
tations and localized alveolar ridge augmentations in 2007 ( McKay et al., 2007 ). Problematic sequellae
have been reported for approved and “off-label” use of BMP-2 such as hematoma, seroma, and swelling,
among others . The safety of BMP-2 has been discussed ( Epstein, 2013 ; Neovius et al., 2013 ; Smucker
et al., 2006 ). Other growth factors involved in vasculogenesis, such as vascular endothelial growth factors
(VEGFs), are also used for craniomaxillofacial regeneration because bone is a highly vascular tissue and
vasculogenesis is expected to facilitate bone regeneration ( Kaigler et al., 2006 ). Section 9.4.5 discusses
bioreactor administration of growth factors. The use of bioreactors avoids in vivo use and therefore any
unintended pleiotropic effects such as those observed with BMP-2. Where growth factor pharmacokinet-
ics and sensitivity are well understood, there are a variety of delivery mechanisms ( Vo et al., 2012 ).
9.4.3 CELL-BASED THERAPIES
The cells used for cell-based therapies for craniofacial/dental tissue engineering are mostly stem cells
( Krebsbach and Robey, 2002 ). Stem cells are attractive candidates for tissue engineering because they
are clonogenic and capable of self-renewal, therefore small populations of stem cells can proliferate
to provide the desired cell number within a shorter time span. They have the potential to differentiate
into different cell types ( Rosa et al., 2012 ). Some of the cells that have been used for craniofacial/
dental tissue engineering ( Figure 9.7 ) are mesenchymal stem cells (MSCs) derived from bone marrow
or adipocytes ( Marra and Rubin, 2012 ), dental pulp stem cells (DPSCs), differentiated osteoblasts,
perivascular cells, stem cells from exfoliated deciduous teeth (SHEDs), stem cells from apical papilla
(SCAPs), periodontal ligament stem cells (PDLSCs), and dental follicle precursor cells (DFPCs) ( Bhatt
and Le Anh, 2009 ; Costello et al., 2010 ; Machado et al., 2012 ; Risbud and Shapiro, 2005 ). Dental
tissue derived mesenchymal stem cells is a relatively new area of research that may find a wider role
in craniofacial/dental repair ( Yang et al., 2014 ). However, it is still not determined whether MSCs
from bone marrow, adipocytes, or dental sources will be more favorable for stem cell-based repair of
craniofacial/dental tissue ( Estrela et al., 2011 ; Mao et al., 2006 ; Marra and Rubin, 2012 ). Recently,
constructs developed by cells alone (scaffoldless) have been studied as a potential cell source in dental
tissue engineering ( Syed-Picard et al., 2014 ).