Craniofacial and dental regenerative medicine

Craniofacial and dental structures are complex tissues that perform vital functions, such as
seeing,hearing, breathing, chewing, tasting, speaking, and protecting the brain and eyes
(Costello et al., 2010).Standard-of-care craniofacial and dental regenerative medicine consists
largely of musculoskeletal reconstructive techniques analogous to orthopedic and general
surgical reconstructive techniques, withspecial attention to the complex 3D structure (Figure
9.1) (Sanchez-Lara and Warburton, 2012). Mostof these procedures are aimed at restoring
function (e.g., mastication) and structure in an aestheticallyappropriate reconstruction. What
has changed over the past decade is the expected role that tissue engineering has and will
have in regenerative medicine. This is illustrated by the conceptual move awayfrom research
in whole organ regeneration to structure- and defect-specific “regenerative medicine,”
which includes elements of grafting, bone and dental substitute materials, and off-the-shelf or
customdevices. Initial research success in all three of these areas is being translated to the
repair of particulartissue deficits with a focus on the restoration of function through the
augmentation of standard-of-careprocedures. Many if not most reconstructive procedures
continue to involve transplantation and alloplastic hardware or tissue substitutes.Tissue
engineering remains a scientific activity that has the potential to improve therapies for
specific indications. However, tissue engineering has yet to contribute to the craniofacial
therapies involving bone, glands, sense organs, joints, muscles, or dental tissues. Careful
study of growth factors andprogenitor cells in restoring failed craniofacial tissues is now done
mostly in parallel to research intosurgical therapies, material research, and mass market or
patient-specific device research. All of thisresearch is aimed at improving the treatment of
craniofacial patients who suffer from traumatic injuries,cancer, or congenital
deformity.Custom devices do not yet involve biological components; thus, there is no true
“bioprinting” However,there is initial use of growth factors, such as BMP-2, in some
craniofacial therapies. There is much use ofnanotechnology in the development of
biomaterials for these implants and other surgical devices. A newwave of developments is
occurring in developing biomaterials with a wide range of properties that can berendered in
3D printers. It is likely that those materials will eventually be used as resorbable models, or
scaffolds, for tissue engineering applications that utilize craniofacially relevant stem cells and
growth factors.
 Figure. Current craniofacial regenerative procedures
(Source: Sanchez-Lara, Pedro A., Zhao S Hu, Bajpai S Ruchi, Abdelhamid, Alaa I., Warburton, David, 2011. Impact of
stemcells in craniofacial regenerative medicine. Frontiers in Physiology 3, 188–188.)

CLINICAL IMPORTANCE OF DENTAL AND CRANIOFACIAL REGENERATIVE

MEDICINE

the craniofacial region is the central interface between the individual and their environment;
it is alsoresponsible for sending communicative signals by embodying voice into speech,
expressing emotions,disclosing identity, displaying aesthetics, and cueing gender, race, and
age. With the craniofacial regionplaying so many key functions, defects and deformities of
this area can severely affect an individual’squality of life, leading to both significant physical
impairments as well as psychological sequelae.Indeed, it has been shown that patients who
have undergone resection of tumors of the head and neckactually more readily adjust to their
dysfunction than to their disfigurement (Dropkin, 1999; Gambaet al., 1992). For all these
reasons, reconstruction and restoration of craniofacial defects demandsstate-of-the-art
techniques and advanced materials.

Aetiology of major deformities of craniofacial region

Defects and deformities of the craniofacial region arise from dental disease, trauma, aging,
cancer, andcongenital malformations. Each of these will presently be discussed.

Dental Disease

Statistics show that 100% of adults have dental caries, and it is estimated that 15–20% of
adults
between the ages of 35–44 suffer from severe periodontal disease that will result in tooth loss.
Dentaldisease is cumulative with age, resulting in 30% of people aged 65–74 becoming fully
edentulous. Themandible and maxilla of the edentulous naturally atrophy with time,
becoming much thinner and moresusceptible to fracture.

Trauma
The primary cause of death in people under 40 years of age is trauma. Approximately 25,000
people peryear require surgery to fix maxillofacial trauma in the United States. Maxillofacial
trauma results from assault, motor vehicle collisions, falls, and sporting accidents. The
relative incidence of these causeshas been shifting. With increasing widespread use of airbags
and seatbelts, the number and severity ofmaxillofacial fractures from motor vehicle collisions
has been decreasing. On the other hand, as thepopulation is aging and the elderly are seeking
active lifestyles, the number of fractures from falls istrending up (Martinez et al., 2014).
Aging

As people age, the collagen framework loosens, the dermis thins, there is a cumulative solar
elastosis,and muscles and bones of the face thin and atrophy. These result in an inferomedial
descent of the soft tissue and the stigmata of aging including wrinkles, furrows, jowls,
decreased dental show, the downward tilt of the corners of the mouth, and sunken cheeks.
Cancer

In the United States more than 40,000 people are diagnosed with oral and pharyngeal cancers
each year (The Oral Cancer Foundation; http://oralcancerfoundation.org/facts/). An additional
3.5 million peopleare diagnosed with a new skin cancer (basal cell, squamous cell, or
melanoma). A majority of theseoccur in the highly sun-exposed craniofacial region. The
ablation of craniofacial malignancies oftenrequires resection of multiple surrounding tissue
types (skin, subcutaneous fat, bone, and mucosa), ensuring adequate margins but leaving the
patient with exposed bone, vessels, and nerves and defects thatcannot be closed primarily.
Radiation treatments further complicate wound healing by compromisingthe local
vasculature.
Congenital

In the U.S. approximately 38,000 infants undergo surgery each year for the treatment of
congenital defects. One in 1000–2000 infants are born with sporadic or inherited
craniosynostosis (fusion of cranial plates), which can lead to a malformed cranium,
intracranial hypertension, and restricted brain growth.An additional 1:1000 children are born
with cleft lip and palate. Certain syndromes can result in hypoplasia of the maxilla (i.e.,
Apert’s or Crouzon’s) or mandible (i.e., Treacher Collins or Pierre RobinSequence) and
airway compromise. Furthermore, many are born with microtia or contour irregularities
which they find aesthetically displeasing (CDC, 2008).
CRANIOFACIAL AND DENTAL REGENERATIVE MEDICINE RESEARCH
Despite the great need, there is very little penetration of tissue engineering, especially
additive manufacturing or cell printing for tissue engineering, in standard-of-care craniofacial
surgical and/or dental therapeutic procedures that repair critical size defects (Schmitz and
Hollinger, 1986). However,the significant use in these specialties of bone and tooth substitute
materials, especially in regard to the additive manufacture of patient-specific medical
implants, may eventually forge a link between tissueengineering and craniofacial and dental
care.
Novel materials

Implants and surgical reconstruction hardware for the craniofacial and dental regions have
typically used the same materials as elsewhere in the body. However, there are many
advanced materials that areused fairly exclusively in the craniofacial region.
ResorbableLactosorb® (Lorenz [Biomet], Jacksonville, FL), which is 82% poly(-l lactic acid)
and 18% poly(glycolic acid) is one such example (Biomet microfixation, 2010). These plates
and screws resorb by hydrolysis within a year, allowing uninhibited growthof the bones and
obviating the need for a secondary procedure to remove the hardware. These plates
haveparticular application in softer bones, such as in the orbit and in infants. Solid-state
hyaluronic acid in the
form of a thread is another advanced material used in the craniofacial region. This promising
new productallows for more controlled wrinkle effacement and soft tissue augmentation
(Franklin, 2014). Nitinolshape memory metals are used in orthodontic wire; these wires are
superelastic at body temperature.As mentioned previously, titanium dental implant bone
screws and abutments are very successful.However, there is a great deal of innovation with
other alloys, zirconia, and coatings designed to improveosseointegration. Single crown or
fixed prosthesis implant dental systems are currently more expensivethan nonfixed systems
(e.g., traditional dentures), but they also provide for better mechanical function,stimulation,
and maintenance of oral cavity muscles and skeletal structures. However, the most exciting
and cutting-edge application of such advanced biomaterials is in their use in the additive
manufacture(3D printing) of patient-specific implants in teeth, craniofacial bone, and the
temporomandibular joint.

Teeth
The Sirona CEREC1 (Chairside Economical Restorations of Esthetic Ceramics), the first
system tocombine digital scanning of the teeth, and computer-aided design (CAD) of
prosthetic crowns, appeared in 1985. Most of these crown restorations are currently prepared
in the prosthodontist’s office or by anearby service with computerized milling devices. These
systems are sufficiently accurate (Figure 9.4),therefore there seems to be no benefit in terms
of quality or price at this time in moving to moreadvanced fabrication strategies (Schaefer et
al., 2013).Ng et al., (2014) noted that it is only recently that restorations prepared in this way
have become more economical and perform better than traditional manual methods. Given
the success ofthese post-and-crown systems, the challenge for oral health has reverted back to
the issue of sufficientbone bulk to support dental posts. This is especially challenging in
edentulous individuals (Cho andRaigrodski, 2014). Dental implants and single crown or fixed
prostheses may require autologous and/or alloplastic bone graft materials. This depends on
the size of the alveolar cavity left following dentalextraction. It is unclear at this time whether
these expensive fixed prostheses will become standard ofcare under the United States’
Affordable Care Act in nontraumatic situations (O’Brien, 2014).
Figure. A comparison of image-based crown design (pre) and rendered crown (post) showing
high accuracy of the milled crowns.(Source:Schaefer, O., Kuepper, H., Thompson, G.A., Cachovan, G., Hefti,
A.F., Guentsch, A., 2013. Effect of CNC-milling on the marginal and internal fit of dental ceramics: a pilot study. Dent
Mater 29, 851–858. )

Bone
In cases of craniofacial bone shortage, there are no tissue engineered therapies. Alloplastic
materialshave been explored. Polymethylmethacrylate (PMMA) is the most common material
used followedby grade 5 surgical titanium (Ti-6Al-4V). These materials have been used to
make custom cranioplasties (skull plates) for more than a decade (Dean et al., 2003a). Cranial
plates are now commonly3D printed directly from CAD files in PEEK (Lethaus et al., 2012)
with a newer material, PEKK(Baum, 2013), having more appropriate material properties for a
bone substitute implant. If alloplasticmaterials are used, a key consideration is how well they
transfer strain to and from the surrounding skull (Figure 9.5). Creating adaptive, rather than
stress-shielding or stress-concentrating, reconstructionsis a major consideration in the
treatment of mandibular segmental defects if permanent surgicalgrade 5 titanium fixation is
used (Zoumalan et al., 2009). The topological optimization of very stiffimplant components
in craniofacial implants
has been studied by
Sutradhar et al., (2010).
Figure. Custom cranial implant material properties: A. Mechanical testing device. B. Results
of mechanical testing. (Source:Lethaus, B., Safi, Y., terLaak-Poort, M., Kloss-Brandstatter,
A., Banki, F., Robbenmenke, C., Steinseifer, U.,Kessler, P., 2012. Cranioplasty with
customized titanium and PEEK implants in a mechanical stress model. JNeurotrauma 29,
1077–1083 ).
Mandibular segmental defects are now commonly being repaired with fibular bone grafts
where fibularand mandibular cutting guides are provided and Ti-6Al-4V immobilization
plates are prebent. This savesoperating room time, and enhances reproducibility and
precision, which in turn aids boney union and prevents fibrous ingrowth of the defect space
(Wang et al., 2013; Saad et al., 2013). Others have presented theirexperience with the
replacement of most (Zhou et al., 2010) to all (van Kroonenburgh et al., 2012) of themandible
with 3D printed titanium prosthetics. The long-term outcomes of such cases remain to be
seen;it is known that the use of titanium or acrylic instead of bone graft or Guided Tissue
Regeneration (Parkand Wang, 2007) devices directly under the gingivae may risk dehiscence
(Chiapasco and Zaniboni, 2009).

Temporomandibular joint

Involvement of the temporomandibular joint (TMJ) in the repair of segmental mandibular

defectselevates the complexity. The TMJ includes the head of the mandible, articular disc, or
the articular tubercle(of the zygomatic arch). This joint has been cited as one of the most
active joints in the body (Guarda-Nardiniet al., 2008). Early attempts at total joint
replacement involving Teflon joint surfaces were associated withforeign-body giant cell
reactions resulting in damage to the surrounding host structures and an unstablejoint
(Abramowicz et al., 2008). Recent experience has found a wide variety of stable implant
configurations, with good performance by patient- specific devices (Mercuri, 2012) and using
metal-on-polyethylene
TMJ replacements (Figure 9.6) with
stable, long-term outcomes (Leiggener
et al., 2012).
Figure. Topology optimization of stress-strain trajectories suggesting the need for appropriate
strength in thedisplayed struts. (Source:Sutradhar, A., Paulino, G.H., Miller, M.J., Nguyen, T.H., 2010.
Topological optimization for designing patientspecific large craniofacial segmental bone replacements. Proc Natl AcadSci U
S A 107, 13222–13227. )

BONE TISSUE ENGINEERING STRATEGIES

Tissue engineering strategies have the potential to augment traditional restorative approaches
that utilize transplanted tissues and bone substitute materials. Some key considerations in the
development oftissue-engineered strategies for craniofacial/dental tissue are as follows: (1)
are there any stem cells that can be used; (2) can aesthetic demands be met; (3) can tissue-
engineered constructs be used as partof a composite strategy; (4) can adequate vascularization
demands be met; and (5) can the high risk ofinfection in the oral and nasal cavities be
managed (Moioli et al., 2007). These aspects have also beendiscussed in detail by Mikos et
al., (2006) (Table 9.3). Craniofacial tissue-engineered strategies arelikely to be required to
regenerate more than one tissue phenotype at the same time (Moioli et al., 2007;Rahaman and
Mao, 2005).
Bone tissue engineering-based strategies for craniofacial/dental tissue regeneration can be
dividedbroadly into three main categories based on the scaffold, cellular, or growth factor
component that playsthe major role in the expected regeneration phenomenon. Bioreactor
preculture or surface functionalizationof these implants may also be used to limit the
attachment of cells to a specific type and to help those cellscommit to play a role after
implantation by having a functioning tissue type (e.g., by producing extracellular matrix) or
by prevascularizing the tissue via coculture with endothelial cells (Temple et al., 2013).

Scaffolds

Artificial scaffold materials for craniofacial/dental tissue regeneration may act like the
extracellularmatrix of the desired tissue by supporting cell attachment, proliferation, and
differentiation of hostor seeded cells in the presence of biological cues. The scaffolds are
commonly resorbable and are expected to resorb at a rate similar to that of new bone
formation (Hutmacher, 2000). These scaffolds canbe used in different forms such as porous
3D solids (Dean et al., 2012; Kim et al., 2011), nanofibers(Gupte and Ma, 2012; Li et al.,
2014), cement/putty (Kim et al., 2012a), among others. Various typesof scaffolds used for
craniofacial/dental tissue regeneration can be divided into three main
classes:ceramic/bioactive glasses, natural/synthetic polymers, and composites (Salgado et al.,
2004).
Ceramic/bioactive Glasses

The ceramic/bioactive glasses are a class of biomaterials made up of inorganic materials

having high compressive strength, but low tensile strength (brittle) characteristics. Calcium
phosphate-based materials have been extensively used for craniofacial/dental tissue
engineering in the form of injectablecalcium phosphate cement (CPC) (Chen et al., 2014;
Thein-Han et al., 2012) or implanted scaffolds(Chan et al., 2009). Hydroxyapatite in the form
of BoneSource® cement (Stryker, Kalamazoo, MI)has also been used for applications in
craniofacial tissue engineering and reconstruction (Costantinoet al., 1992; Friedman et al.,
1998). Hydroxyapatite scaffolds prepared by additive manufacturing(a.k.a. 3D printing) have
been studied for their repair capability in minipig mandibular defects for 6and 18 weeks
(Hollister et al., 2005). Bioactive glasses have also been studied as biomaterials
forcraniofacial reconstruction (Cho and Gosain, 2004; Gosain, 2004). One exciting new
product whichpromises to be quite adaptive is being developed by Filardo et al. Using a novel
bioceramization process, they have been able to turn wood into a strong, highly porous
product with an elastic modulus that
approaches that of bone (Filardo et al., 2014).

Natural/synthetic Polymers

Biopolymers can be prepared synthetically or from naturally occurring sources. Polymers

tend to be moreflexible or ductile in nature than ceramics, although they usually have less
compressive strength thanceramics. Biopolymers derived from natural sources used for
craniofacial regeneration include collagen(Narotam et al., 2007), fibrin, hyaluronic acid
(Kretlow et al., 2009), alginate, silk (Ye et al., 2011), andchitosan (Canter et al., 2010).
Biopolymers of synthetic origin studied in bone tissue engineering applications include
poly(propylene fumarate) (PPF) (Dean et al., 2012, 2003b), polylactic acid (PLA) (Di
Bella et al., 2008), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA) (Kaigler et
al., 2006),polycaprolactone (PCL) (Schantz et al., 2003), and polyethylene glycol (Terella et
al., 2010). Most ofthese biopolymers have also been used for dental tissue engineering (Horst
et al., 2012).

Composites

Blending ceramic, polymeric, and possibly metal or graft tissue components may result in an
implantwith the desired material properties that is at least partially resorbable. Polymers and
ceramics aremost likely to mimic bone extracellular matrix which in itself is a blend of
inorganic (hydroxyapatite)and organic (collagen type I) components. Some of the composites
that have been used in variouscombinations for craniofacial/dental tissue engineering are:
beta-tricalcium phosphate, collagen, andautologous bone fragments (Kishimoto et al., 2006);
polycaprolactone (PCL)-tricalcium phosphate (TCP) (Probst et al., 2010);
biocompositecryogels (Mishra et al., 2014; Mishra and Kumar, 2014); andchitosan and
inorganic phosphates (Stephan et al., 2010).

GROWTH FACTORS

Bone morphogenetic proteins (BMPs) are the most studied signaling molecules related to
bone maturation. Twenty types of BMPs encoded by the human genome have been identified
(Nakashima andReddi, 2003). Out of these, the BMPs that have been most widely studied for
craniofacial/dental regeneration 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; Wikesjo et al., 2005). GMP (Good Manufacturing
Practice) level recombinant human bone morphogeneticprotein-2 (rhBMP-2) provided by
R&D Systems (Minneapolis, MN) and Akron Biotechnology (BocaRaton, FL) has been
approved for bone applications such as interbody spinal fusion, open tibial fractures, 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
absorbablecollagen sponge (ACS) functioning as a carrier. For certain craniofacial/dental
applications such as fordefects related with extraction sockets, INFUSE® Bone Graft
received FDA approval for sinus augmentations and localized alveolar ridge augmentations
in 2007 (McKay et al., 2007). Problematic sequellaehave 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; Smuckeret 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 andvasculogenesis is expected to facilitate bone regeneration (Kaigler et al.,
2006). Section 9.4.5 discussesbioreactor administration of growth factors. The use of
bioreactors avoids in vivo use and therefore anyunintended pleiotropic effects such as those
observed with BMP-2. Where growth factor pharmacokinetics and sensitivity are well
understood, there are a variety of delivery mechanisms (Vo et al., 2012).
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 theyare clonogenic and capable of self-renewal, therefore small
populations of stem cells can proliferateto provide the desired cell number within a shorter
time span. They have the potential to differentiateinto 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
marrowor 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) (Bhattand Le Anh, 2009; Costello et al., 2010; Machado et al., 2012;
Risbud and Shapiro, 2005). Dentaltissue derived mesenchymal stem cells is a relatively new
area of research that may find a wider rolein craniofacial/dental repair (Yang et al., 2014).
However, it is still not determined whether MSCsfrom bone marrow, adipocytes, or dental
sources will be more favorable for stem cell-based repair ofcraniofacial/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 dentaltissue
engineering (Syed-Picard et al., 2014).
Figure. Mandibular positions during chewing following unilateral total TMJ replacement: A.
mouth closed (lateral view).B. Maximum gape (lateral view). C. Maximum gape (frontal
view). (Source:Leiggener, C.S., Erni, S., Gallo, L.M., 2012. Novel approach to the study of jaw kinematics in an
alloplastic TMJreconstruction. Int J Oral MaxillofacSurg 41, 1041–1045. )

NEW CRANIOFACIAL TISSUES

Two of the more difficult craniofacial tissues are now being explored to see if stem cells can
be used inregenerative therapies. The first tissue is retina, where retinal stem cells have
received attention giventheir role in producing sight (Hambright et al., 2012). This work is
currently focused on elucidating themechanisms of retinal tissue repair and treatments for
degenerative diseases. The regeneration of sightmay be somewhat further off (Yip, 2014).
The second tissue is oral mucosa, a highly specialized tissuethat is at a high risk of failure and
infection following masticatory and dental reconstructive surgery.Good integration between
oral mucosa, underlying reconstructed structures, and around percutaneousimplants is the
goal of this work (Jones and Klein, 2013).

BIOREACTORS

Preculturing of cells inside a bioreactor, with and without shear stress (i.e. from flow or
external compression or tension), nutrients, and signaling molecules has been studied as a
way of preculturingcells. One of the advantages of preculturing is the production of sufficient
cells (starting from low cell densities) to coat the scaffold and to bring about their maturation
to facilitate the host’s recognition andintegration of the implant as osseous tissue (Mikos et
al., 2006). Such a biomaterial represents a tissueengineered graft (Wallace et al., 2014). This
is especially important in clinical settings where it may be difficult to carry out rigorous
capture and handling of autologous cells in a distributed, as opposed toa centralized, fashion.
It may be especially difficult to characterize the potency (i.e., ability to producethe desired
tissue) of all sources of autologous cells.Bioreactor culturing of well-characterized cells may
also offer the advantages of acclimatizingcells to the scaffolds prior to implantation, uniform
distribution of oxygen and nutrients throughout the clinical-size bone substitutes, and
controlling the amount, nature, and duration of mechanicalstimulation applied to seeded cells
(de Peppo, 2014). Bioreactor culture of
cells has been found to befavorable for
craniofacial applications such as
the generation of the mandibular condyle
(Alhadlaqand Mao, 2003), auricular
cartilage (Alhadlaq et al., 2004), the entire
TMJ condylar bone (Graysonet al., 2010),
and dental applications such as
periodontal tissue regeneration (Jin et
al., 2003). Theprotocol for the
bioreactor cultivation of cells in tissue
engineering of a TMJ by Grayson et al.,
(2010 is demonstrated in
Figures 9.8 and 9.9.
Figure. Specialized tissues where regenerative scaffolds may benefit from preculturing and
stem cell differentiation, perhaps in a bioreactor. (Source: Sanchez-Lara, Pedro A., Zhao S Hu, Bajpai S
Ruchi, Abdelhamid, Alaa I., Warburton, David, 2011. Impact of stemcells in craniofacial regenerative medicine. Frontiers in
Physiology 3, 188–188.)

Figure. Bioreactor cultivation for the development of human temporomandibular joint (TMJ)
condyles: (a–d) scaffolddevelopment; (d) image showing scaffold complexity; (e) The
seeding of hMSCs in a bioreactor; (f) photographof perfusion bioreactor; (g–h) images
representing bioreactor assembly. (Source: Grayson, W.L., Frohlich, M., Yeager, K., Bhumiratana, S., Chan,
M.E., Cannizzaro, C., Wan, L.Q., Liu, X.S., Guo,X.E., Vunjak-Novakovic, G., 2010. Engineering anatomically shaped
human bone grafts. Proc Natl AcadSci
U S A 107, 3299–3304. )

In conclusion, bioprinting and nanotechnology research into craniofacial and dental

regenerative medicine therapies has utilized growth factors; however, the use of resorbable
scaffolds and autologous or banked cells—the remaining elements of tissue engineering—
have not yet made their way to the clinic. Craniofacialand dental bioprinting and
nanotechnology are concentrated on patient-specific inert devices. This is alarge industry that
has recently shown dramatic improvements in therapeutic efficacy and safety. Thereis a
revolution occurring in developing

materials that cover the range of material properties needed for patient-specific implants to
perform mechanically like, indeed in tandem with, the tissues to which they are attached. As
advances are made in bone, retina, and other areas of craniofacial and dental tissue
engineering, they are likely to be incorporated into standard-of-care therapies, unlessthey are
novel enough to shift the current paradigm. Bioprinting and regenerative medicine
promisetrue quality care by facilitating the physician in “doing the right thing, at the right
time, in the right way,for the right person—and having the best possible results.” However,
the current paradigm is relativelynew; therefore, it remains to be seen whether the benefits of
patient-specific medicine will be madeavailable throughout society through mechanisms like
the Affordable Care Act in the United States.