Jojo Kottoor

Technology - Biomimetic endodontics: barriers and strategies

TECHNOLOGY

BIOMIMETIC ENDODONTICS : BARRIERS

AND STRATEGIES
JOJO KOTTOOR
Department of Conservative Dentistry and Endodontics,
Mar Baselios Dental College, Kothamangalam, Kerala, India
Correspondence to: drkottoor@gmail.com
Abstract
Biomaterials used in the medical field lack the ability to integrate with biological
systems through a cellular pathway. Conversely, biomimetic materials transcend
the regular biomaterial in utility and will suitably perform the functions of the
biological molecule that needs to be replaced. However, certain practical obstacles
are yet to be overcome before biomimetic approaches can be applied as evidencebased approach in clinics. The article highlights on the past achievements, current
developments and future prospects of tissue engineering and regenerative therapy
in the field of endodontics and bioengineered teeth.
Introduction
Biomimetics is defined as the study of the
formation, structure, or function of
biologically produced substances and
materials and biological mechanisms and
processes especially for the purpose of
synthesizing similar products by artificial
mechanisms which mimic natural ones. A
material fabricated by biomimetic technique

Health Sciences 2013;2(1):JS007

based on natural process found in biological

systems is called a biomimetic material.1,2
Biomimicry or biomimetics (from bios,
meaning life, and mimesis, meaning to
imitate) involves studying natures most
successful developments and then imitating
these designs to create new materials. The
main
disadvantage
with
traditional
biomaterials used in the medical field is that
they lack the ability to integrate with

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Technology - Biomimetic endodontics: barriers and strategies

biological systems through a cellular

pathway which can lead to failure of the
material. However, biomimetic materials
transcend the regular biomaterial in utility
and will suitably perform the functions of
the biological molecule that needs to be
replaced.3 A biomimetic approach to restore

tooth structure is based on regenerative

endodontic procedures by application of
tissue engineering which opens up a whole
new arena for the practioner. The key
elements of tissue engineering are stem cells,
morphogen, and a scaffold of extracellular
matrix (Figure 1).4

F ig u r e 1 . T i s s u e e n g i n e e r i n g t r i a d

Stem cells are defined as cells that have the

ability to continuously divide and produce
progeny cells that develop into various other
cells or tissues.5 There are two major types of
stem cells, Embryonic and Adult stem cells
their most important properties being their
ability of self renewal and their ability to
grow in-vitro. Comparing the different stem
cell types, adult stem cells, which have the
least amount of ethical concerns, are
presently being used in medical therapies
and are readily accessible.6 Postnatal stem
cells have been found in almost all body
tissues, including dental tissues. To date,
eight types of human dental stem cells have
been isolated and characterized: i) Dental

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pulp stem cells (DPSCs), ii) Stem cells from

human exfoliated deciduous teeth (SHED),
iii) Stem cells from apical papillae (SCAP),
iv) Periodontal ligament stem cells
(PDLSCs), v) Epithelium-originated dental
stem cells (EpSC), vi) Mesenchymal stem
cells (BMSC), vii) Stem cells from the
dental follicle (DFSC), and viii) Endothelial
progenitor cells (EPCs).
Signaling molecules or morphogens are
extracellular secreted signalling molecules
that play a key role in signaling many of the
events of repair and regeneration including
tertiary dentinogenesis, a response of pulpdentin repair. These signalling networks can

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Technology - Biomimetic endodontics: barriers and strategies

be generally classified into growth factors

and inflammatory cytokines.7 Growth
factors are soluble proteins that act as
signaling agents for cells, and influence
critical functions, such as cell division,
matrix synthesis and tissue differentiation.
Primarily, five eminent families of growth
factors appear to regualate the process of
odontogenesis: Fibroblast growth factor,
Bone morphogenic protein (BMP),
Hedgehog,
Wingless
(WNT)
and
Transforming growth factor. Inflammatory
cytokines (Interleukin and Tumor necrosis
factor) are molecules that regulate cellular
behaviour of bone under inflammation,
infection and wound healing.8
The scaffold or the extracellular matrix is a
mixture of proteins including collagen,
fibronectin, polysaccharide hyaluronic acid,
proteoglycans and laminins forming an
elastic network surrounding most cells and
tissue structures.9 Current scaffolds used in
tissue engineering can be grouped into three
main categories. Natural scaffolds like
Collagen, lyophilized bone and coral are the
most commonly used natural scaffold. The
main disadvantage of natural scaffolds is that
they often lack the desired structural
integrity for its independent use in load
bearing areas. Mineral based scaffolds
usually are made of calcium phosphates in
the form of hydroxyapatite or beta
Tricalcium phosphate and by varying the
content of calcium the rate of degradation of
these scaffolds can be controlled. They lack
the strength of natural scaffolds and are

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brittle making it susceptible to fracture 10 and

hence were introduced the synthetic
scaffolds. These include the porous
ceramics, spongiosus collagen, fibrous
titanium mesh, poly lactic acid (PLA), poly
glycolic acid (PGA), and their copolymers,
poly lactic-co-glycolic acid (PLGA) which
are all polyester material that degrade within
the human body. They have the advantage
of being able to function in load bearing;
but have the disadvantage of lacking
osteoinductiveness and an inherent difficulty
in obtaining high porosity and regular pore
size.11 This has led researchers to concentrate
efforts to engineer scaffolds at the
nanostructural level to modify cellular
interactions with the scaffold.12
B io m i m e t i c
regeneration

approaches

for

The creation and delivery of new tissues to

replace diseased, missing, or traumatized
pulp is referred to as regenerative
endodontics. Although current root canal
treatment modalities offer high levels of
success for many conditions, an ideal form
of therapy might consist of regenerative
approaches in which diseased or necrotic
pulp tissues are removed and replaced with
healthy pulp tissues to revitalize the teeth.
However, the challenge lies in designing and
fabricating biomimetic materials like
enamel, dentin, cementum, pulp, bone and
periodontal ligament and focus should be
toward regenerating the diseased and
necrotic tissues rather than replacing them

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with some conventional replacement

materials. This article reviews current
biomimetic approaches for regeneration
tooth and its associated structures.
a.

Root canal revascularization

Treatment of the young permanent tooth

with a necrotic root canal system and an
incompletely developed root is fraught with
difficulty. Not only is the root canal system
often difficult to fully debride, but the thin
dentinal walls increase the risk of a
subsequent fracture. Other than the
procedure
like
maturogenesis
or
apexogenisis, root canal revascularization is a
procedure to establish the vitality in a
nonvital tooth to allow repair and
regeneration of tissues. The typical
revascularization protocol advocates that the
immature tooth, diagnosed with apical
periodontitis, should be accessed and
irrigated with either 5% NaOCl _ 3%
H2O2 or 5.25% NaOCl and Peridex TM
(Procter & Gamble, Cincinnati, OH). An
antimicrobial agent (either an antibiotic
such as metronidazole, ciprofloxacin or
ciprofloxacin, metronidazole, minocycline
or Ca (OH)2 should be then applied into
the root canal system, and the access cavity
is sealed. After an average of 3 weeks, in the
absence of symptoms, the tooth is reentered, the tissue is irritated until bleeding
is started and a blood clot produced, and
then MTA is placed over the blood clot, and
the access is sealed. Within the next 2 years
a gradual increase in root development can

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be observed.13 However, revascularization

procedures lack standardization of treatment
protocols with a myriad of reported
techniques, intracanal medicaments and
irrigants.
b.

Stem cell therapy

The simplest method to administer cells of

appropriate regenerative potential is to inject
the postnatal stem cells into the disinfected
root canal system. Autologous dental stem
cells are the most accessible stem cells for
this therapy. Among the eight different post
natal dental stem cells Dental pulp stem cells
(DPSCs), Stem cells from human exfoliated
deciduous teeth (SHED), and Stem cells
from the apical papilla (SCAP) were more
commonly used in the field of regenerative
endodontics.14
DPSCs are the stem cells isolated from
human dental pulp. The most striking
feature of DPSCs is their ability to
regenerate a dentin-pulp-like complex that is
composed of mineralized matrix with
tubules lined with odontoblasts, and fibrous
tissue containing blood vessels in an
arrangement similar to the dentin-pulp
complex found in normal human teeth.15
Stem cells from human exfoliated deciduous
teeth (SHED) have become an attractive
alternative for dental tissue engineering. The
use of SHED might bring advantages for
tissue engineering over the use of stem cells
from adult human teeth as follows: (a)

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SHED were reported to have higher

proliferation rate compared with stem cells
from permanent teeth, which might
facilitate the expansion of these cells in vitro
before replantation. (b) SHED cells are
retrieved from a tissue that is "disposable"
and readily accessible in young patients. ie,
exfoliated deciduous teeth. It also has an
added advantage of abundant cell supply,
and painless stem cell collection with
minimal invasion.16
A recent finding is the presence of a new
population of a mesenchymal stem cells
residing in the apical papilla of incompletely
developed teeth. They are termed stem cells
from the apical papilla (SCAP). It is
hypothesised that SCAP appear to be the
source of primary odontoblast that are
responsible for the formation of root
dentine, whereas DPSCs are likely the
source of replacement odontoblast. 17 Since
these stem cells are in the apical papilla, they
are benefited by its collateral circulation,
which enables it to survive during the
process of pulp necrosis.
There are several advantages to an approach
using postnatal stem cells. First, autogenous
stem cells are relatively easy to harvest and
to deliver by syringe, and the cells have the
potential to induce new pulp regeneration.
Second, this approach is already used in
regenerative medical applications, including
bone marrow replacement, and a recent
review has described several potential
endodontic applications.18 However, there

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are several disadvantages to a delivery

method of injecting cells. First, the cells may
have low survival rates. Second, the cells
might migrate to different locations within
the body, possibly leading to aberrant
patterns of mineralization.
c. Pulp implantation
Dental pulp tissue is vulnerable to infection.
Currently, entire pulp amputation followed
by pulp-space disinfection and filling with
an artificial rubber-like material is employed
to treat the infection - commonly known as
root-canal therapy. In pulp implantation,
replacement pulp tissue is produced by
tissue engineering triad and is transplanted
into cleaned and shaped root canal systems.
Rebecca et al had generated Dental pulp like
tissue by using the tissue engineering triad,
the Dental Pulp Stem Cells (DPSCs), a
Collagen Scaffold, and Dentin Matrix
protein 1 after subcutaneous transplantation
in mice. Collagen served as the scaffold, and
dentin matrix protein 1 (DMP1) was the
growth factor. The result concluded that the
triad of DPSCs, a collagen scaffold, and
DMP1 can induce an organized matrix
formation similar to that of pulpal tissue,
which might lead to hard tissue formation. 19
Similarly pulp tissue has also been
successfully regenerated in-vitro using the
tissue engineering triad, but by using a
different
stem
cell,
scaffold
and
morphogens.20

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One of the potential problems associated

with the implantation of cultured pulp
tissue is that specialized procedures may be
required to ensure that the cells properly
adhere to root canal walls. When implanting
pulp into the root canals that have blood
supply only from the apical end, enhanced
vascularization is needed in order to support
its vitality. As a result, microscale
technologies that provide open channels or
the ability to guide vascular ingress from the
apex through the pulp may be of particular
benefit.21 Recent efforts in developing
scaffold systems for tissue engineering have
been focusing on creating a system that
promotes angiogenesis for the formation of a
vascular network.22 These scaffolds are
impregnated with growth factors such as
VEGF (vascular endothelial growth factor)
and/or platelet derived growth factor or
further, with the addition of endothelial
cells.
d. Injectable scaffold delivery
Rigid tissue engineered scaffold structures
provide excellent support for cells used in
bone and other body areas where the
engineered tissue is required to provide
physical support. However, in root canal
systems a tissue engineered pulp is not
required to provide structural support of the
tooth.23 This will allow tissue engineered
pulp tissue to be administered in a soft
three-dimensional scaffold matrix. Among
the injectable biomaterials investigated so
far, hydrogels are more and more attractive

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in the field of tissue engineering. Hydrogels

are injectable scaffolds that can be delivered
by syringe and have the potential to be noninvasive and easy to deliver into root canal
systems. In theory, the hydrogel may
promote pulp regeneration by providing a
substrate for cell proliferation and
differentiation into an organized tissue
structure. Past problems with hydrogels
included limited control over tissue
formation and development, but advances in
formulation have dramatically improved
their ability to support cell survival. 24
Despite these advances, hydrogels at are at
an early stage of research, and this type of
delivery system, although promising, has yet
to be proven to be functional in vivo. 52 To
make hydrogels more practical, research is
focusing
on
making
them
photopolymerizable to form rigid structures
once they are implanted into the tissue site.25
e. Three-dimensional cell printing
One of the most promising approaches in
tissue engineering is the application of 3D
scaffolds, which provide cell support and
guidance in the initial tissue formation
stage. The porosity of the scaffold and
internal pore organization influence cell
migration and play a major role in its
biodegradation dynamics, nutrient diffusion
and mechanical stability. In order to control
cell migration and cellular interactions
within the scaffold, novel technologies
capable of producing 3D structures in
accordance with predefined design are

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Technology - Biomimetic endodontics: barriers and strategies

required. In theory, an ink-jet-like device is

used to dispense layers of cells suspended in
a hydrogel to recreate the structure of the
tooth pulp tissue.26,27 The three-dimensional
cell printing technique can be used to
precisely position cells, and this method has
the potential to create tissue constructs that
mimic the natural tooth pulp tissue
structure. This may involve positioning of
odontoblasts around the periphery, with
fibroblasts in the core. The major challenge
involved is the precise orientation of cellular
suspensions according to the apical and
coronal asymmetry of pulp.28 Theoretically,
the disadvantage of using the threedimensional cell printing technique is that
careful orientation of the pulp tissue
construct according to its apical and coronal
asymmetry would be required during
placement into cleaned and shaped root
canal systems.
f. Gene Therapy
Gene therapy is a method of delivering
genes with the help of viral or non-viral
vectors. The gene delivery in endodontics
would be to deliver mineralizing genes into
pulp tissue to promote tissue mineralization.
Viral vectors are genetically altered to
eliminate ability of causing disease, without
losing infectious capacity to the cell. At
present
adenoviral,
retroviral,
adenoassociated virus, herpes simplex virus,
lentivirus are being developed. Nonviral
delivery systems uses plasmids, peptides,
cationic liposomes, DNA-ligand complex,

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gene
guns,
electroporation,
and
sonoporation to address safety concerns such
as immunogenicity and mutagenesis.29
Most of the risks of gene therapy may arise
from the vector system rather than the gene
expressed. Widespread clinical application
still awaits the development of vectors that
are safe, affordable, efficient, simple for
application, and that have ability to express
the required level of transgene for the
sufficient long term.30
Both in vivo and ex vivo approaches can be
used for gene therapy. In the in vivo
approach, the gene is delivered systemically
into the blood stream or locally to target
tissues by injection or inhalation. In the field
of conservative dentistry, BMPs or BMP
genes are directly applied to the exposed
pulp. The ex vivo approach involves genetic
manipulation of cells in vitro, which are
subsequently
transplanted
to
the
regeneration site. In conservative dentistry,
DPSCs were isolated, differentiated into
odontoblasts with recombinant BMPs or
BMP genes, and finally autogenously
transplanted to regenerate dentin.32
The main challenges for gene therapy in the
next decade will be the requirements to
demonstrate that gene therapy can provide
cost-effective and safe long-term treatments
for conditions that would otherwise lead to
significant pulp necrosis. This indicates the
potential of adding growth factors before
pulp capping, or incorporating them into

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Technology - Biomimetic endodontics: barriers and strategies

restorative and endodontic materials to

stimulate dentin and pulp regeneration.
g. Bioengineered tooth
The ultimate goal of regenerative therapy is
to develop fully functioning bioengineered
organs that can replace lost or damaged
organs following disease, injury, or aging.
Research on whole tooth regeneration is also
advancing using a strategy of transplanting
artificial tooth germ and allowing it to
develop in the adult aral environment.
Tissue engineering builds a tissue such as
skin, bone and cartilage, by seeding cells
into a scaffold.33 Research on the fabrication
of teeth from dissociated cells was first
performed using tooth germ cells.34 When
explanted, seeded with porcine third
impacted tooth bud cells, were implanted
for 20-30 weeks
into omentum,
bioengineered teeth were visible within the
explants.35 However, the regenerated teeth
were not identical to their naturally formed
counterparts.
Ikeda et al reported a fully functioning tooth
replacement achieved by transplantation of a
bioengineered tooth germ into the alveolar
bone of a lost tooth region in an adult
mouse.36 Bioengineered tooth, which was
erupted and occluded, had the correct tooth
structure, hardness of mineralized tissues for
mastication. However, the bioengineered
tooth was smaller than the other normal
teeth. In addition, the authors couldnt
regulate the crown width, cusp position, and

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tooth
patterning
including
anterior/posterior
and
buccal/lingual
structures. However, in a more recent study
Oshima et al showed that the crown widths
and the cusp numbers of bioengineered
molar could be regulated by cell
manipulation method.37 Tooth regeneration
is an important stepping stone in the
establishment
of
engineered
organ
transplantation, which is one of the ultimate
goals of regenerative therapies.
C o n c l u s io n s
The practice of endodontics has grown by
leap and bounds in the past few decades.
Replacement of diseased or lost tooth
structure with biocompatible restorative
materials is currently the order of today but
each of these procedures does have their own
limitations and drawbacks. Regeneration of
the lost tooth structure rather than
replacement during treatment will ensure
better prognosis and higher rate of success.
Hence the future of endodontics would
involve the use of such biomimetic materials
which could successfully replace lost enamel,
dentine, cementum and even the pulp
tissue.
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