missing tooth tissue replacement—the milestones- a ... - Aosr.co.in

MISSING TOOTH TISSUE REPLACEMENT—THE
MILESTONES- A REVIEW
Sahana N S * , Srinath S K † , S Hemavathy * , Vishwanath S K ‡
ABSTRACT:
Objective: This review focuses on past, recent and promising developments in the fields of tooth replacements that are of
particular relevance for dental tissue and whole-tooth regeneration. Here the literature pertaining to different methods used to
replace the missing tooth tissue were compiled and reviewed.
Material and Methods: Relevant literature concerned with tooth tissue replacement in the past as well as the recent ongoing
research work on tooth tissue regeneration were searched in the Google/Medline and 53 articles were reviewed, analyzed and
compiled in this article.
Conclusion: In the last decade, significant advances have been made in approaches used to replace missing teeth. As adult
tissue derived cell sources are anticipated to be useful in clinical applications for tooth regeneration, several stem cells/
progenitor cells have been found, which were isolated from adult dental/non-dental tissues. The future for regenerative and
tissue-engineering applications to dentistry is one with immense potential, capable of bringing quantum advances in treatment
for our patients. With today’s 21st century technological advancements, it is expected that individuals will either retain their
natural teeth or obtain functional tooth replacements throughout their entire life. Even though the tooth regeneration looks
exiting many hurdles must be overcome to develop tooth regenerative therapy in humans and reviews regarding the tooth
regeneration processes must be welcome.
AOSR 2012;2(1):47-52.
Key Words: Dentures, Implants, Transplantations, tooth regeneration, Scaffolds, Cell aggregate methods.
* Department of Oral Pathology, Government Dental College and Research Institue, Bangalore, India.
† Department of Pedodontics, Government Dental College and Research Institue, Bangalore, India.
‡ Department of Prosthodontics, Government Dental College and Research Institue, Bangalore, India.
Archives of Oral Sciences & Research
INTRODUCTION:
The Teeth are highly mineralized appendages found in the
entrance of the alimentary canal of both invertebrates and
vertebrates, first appeared at Ordovicium, approximately
460 million years ago. Some jawless fish developed
superficial, dermal structures known as odontodes 1-3
which were located outside the mouth. The encroachment
of odontodes into the oropharyngeal cavity created the
buccal teeth, which covered the entire surface and later
were localized to the jaw margins. 4
The WHO World Oral Health Report 2003 identified caries
as a continuing global problem, with an estimated five
billion people worldwide having experienced the disease. 5
Tooth loss is an early indicator of accelerated aging.
Edentulism not only results in reduced oral and social
functions but also remains a major public health issue. 6
In the last decade, significant advances have been made in
approaches used to replace missing teeth. 7
Milestone:
The earliest dental material science began in the laboratory
of G.V. Black at Northwestern University in 1900. 8 A major
concentration has been in the area of dental materials used
to restore tooth structure, fabrication of crowns, dentures,
partials, and other restorative approaches and also in
improvements in the design of materials used to restore
teeth/periodontium/bone lost as a consequence of disease
or disorders. 9 While these synthetic materials post various
degrees of success, they bear little resemblance to the
enamel tissue in their chemical and structural makeup. 7
History of Dentures starts way back. Around 700BC,
Etruscans in northern Italy made dentures out of human
or other animal teeth. 10 Dentures can be either partial or
complete.
Partial dentures are for patients who are missing some of
their teeth on a particular arch and are made from crowns
that resemble the missing teeth which are fitted on the
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Sahana N S et al.
remaining teeth to act as abutments and pontics . Fixed
bridges are more expensive than removable appliances but
are more stable. 3
Complete dentures are worn by patients who are missing
all of the teeth in a single arch. The oldest complete denture
appeared in Japan, and it was a wooden denture. Laterthe
porcelain dentures were made around 1770 Thenin 1820
dentures were mounted on 18 carat gold plates, later from
vulcanite, in 20th century- acrylic resin and other plastics.
Complete denture therapy, is associated with complications
such as denture-induced stomatitis, soft tissue hyperplasia,
traumatic ulcers, altered taste perception and burning
mouth syndrome. 11 Therefore, the need for alternative
tooth replacement therapies is quite evident. 12
Implants carry a success rate of around 95% over 15 years,
which makes dental implants the most popular method for
replacing a missing tooth at the present time. 12 However,
osseointegration represents a direct connection between
the implant and bone tissue and lacks the periodontium
and cementum tissues present in naturally formed teeth,
which function to cushion and modulate the mechanical
stress of mastication. Therefore, strategies to generate
dental implants with associated periodontal tissues have
become a new approach in tooth replacement therapies. 12-15
The first transplantation attempts were made without
any knowledge of the species barrier. The pioneers of
xenotransplantation realized xenotransfusions as early as
the 16th century. 16 Transplantation can be of two types;
Allotransplantation and Autotransplantation. 17
Allotransplantation of teeth is moving teeth from one
person to other .The earliest reports of tooth transplantation
involve slaves in ancient Egypt who were forced to give
up their teeth to the pharaohs. 18 There are reports of
men scavenging the aftermaths of battlefields during the
Napoleonic wars, collecting the choicest teeth from the
fallen soldiers in the hopes of using them in other mouths. 19
It continued for many centuries till in the late 18th century,
physicians observed that contagious diseases, especially
syphilis, spread among the recipients of tooth transplants,
which caused allotransplantation of teeth to wane. 18,20,21
The autotransplantation of teeth is moving a tooth from
one site to another in the same individual. However, auto
transplantation, has reported three to five-year success
rates of 75 percent or more. Third molars and premolars
extracted for orthodontic reasons are most commonly
used as the donor teeth for auto transplantation 18 and
is an economically feasible clinical therapy, and teeth
exhibiting two-thirds root formation are considered to
be ideal for reimplantation. 22 Another advantage of tooth
transplantation is the possibility for pulp regeneration,
revascularization, and reinnervation. The limited supply
of available donor teeth restricts the practical use of this
technique. 21,23
Tooth autotransplantation, allotransplantation, substituting
the lost physiological tissue/organ with a nonbiological,
artificial material and dental implants have existed for
many years, but have never been totally satisfactory 24
and pathological repeats are common. 25,26 Therefore, an
ambitious dream of numerous dentists is to be able to
substitute the artificial material with a biological, cell-based
one that is able to form a genuine replica of the damaged
tooth part or the entire lost tooth. 3
Charles Lindbergh was one of the first persons to begin
to think about culturing organs. 27 By the early 1970s, the
term "biomaterials" became prominent. Despite continual
discussions about refocusing the field of biomaterials, the
greatest impetus for change did not arrive until the decoding
of the human genome at the end of the last century. 8
TISSUE ENGINEERING:
In the late 1980s, a polymer chemist (Robert Langer) and
the organ transplant surgeon (Joseph Vacanti) proposed that
it might be possible to generate a tissue or organ by seeding
the cells that make this tissue into a biodegradable scaffold.
This approach to regenerative medicine was named tissue
engineering, which is defined as an interdisciplinary field
that applies the principles of engineering and the life
sciences toward biological substitutes that restore, maintain
or improve tissue function. 5
PARTIAL TOOTH TISSUE REGENERATION:
Over the last few years, dental researchers started to explore
the potential of tissue engineering to repair lost tooth
structures and, perhaps, even for complete replacement of
an entire tooth. 28 The point of interest is that various animal
species (e.g., mice) can replace physically worn teeth parts
of varying teeth types with stem cells 29,30 and numerous
animals are endowed with the ability to continually replace
lost teeth throughout life via de novo formation of tooth
germs (polyphyodonty). 31 Normally, humans do not have
such abilities; however, it is possible that the regenerative
potential in humans is underestimated and some of
components might be able to be reactivated under certain
circumstances. 3,27,32
Nearly every organ harbors in particular niches specific
cells that are known today as somatic stem cells. 3,29,33-35 The
ability of human teeth to form reparative dentin in response
to deep caries and mild trauma suggests that progenitor
cells present in fully developed tooth pulp retain the ability
to form functional odontoblasts, which can produce dentinlike
hard tissues. 36 This line of research seeks to reactivate
existing but latent reparative capabilities and/or use teethrelated
stem cells to repair the damaged part of the tooth
by cell multiplication and production of the missing
material, 17 in attempts to repair the damaged tissues like
pulp and dentin. 7,37 In an effort to restore periodontal tissues,
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Tooth Tissue Replacement
Guided tissue regeneration was successfully used. 38
To increase bone at a specific site, including sites for
implantation of teeth, various barrier membranes often
coupled with grafts/polymers/factors, etc. have been used
with varying success. 7
dissociated from both the epithelium and the mesenchyme,
and the correct placement of cells is a major issue 46
(fig.1).
The more long-term branch of research involves using
stem cells and applying conventional tissue engineering
techniques to create a replica of the desired missing
tooth. 7
WHOLE TOOTH REGENERATION:
Numerous studies in the early twentieth century developed
techniques for culturing both isolated dental tissues and
whole teeth, establishing the basis for future experimental
manipulation of dental tissues. 7 The emergence of wholetooth
tissue was made possible by the marriage of biological,
developmental and material sciences. 12,39 Regenerating a
whole tooth is no less complicated than rebuilding a whole
heart, says Songtao Shi of the University of Southern
California. 40
In considering the future, several lines of evidence need to
be considered: A.Enamel organ epithelia and dental papilla
mesenchyme tissues contains stem cells during postnatal
stages of life, B.Late cap stage and bell stage tooth organs
contain stem cells, C.O dontogenic adult stem cells responds
to mechanical as well as chemical signals , D. Adult bone
marrow as well as dental pulp tissues contain odontogenic
stem cells and Epithelial-mesenchymal interactions are
pre-requisite for tooth regeneration. 41
Several populations of dental stem cells have been
identified and characterized: 12 (DPSCs) Human dental pulp
stem cells, 42,43 (SHED) Stem cells harvested from human
exfoliated deciduous teeth, 12 (SCAP) Stem cells isolated
from human teeth at the tooth root apex called DSCs of
the apical papilla .
At present the only human source is the tooth germ of
young children. 3 Recently, dental tissue stem/progenitor
cells, which can differentiate into dental cell lineages,
have been identified in both impacted and erupted human
teeth, and these cells can be used to regenerate some dental
tissues. Using a patient’s own stem cells avoids issues of
histocompatability. 44
Key elements:Regenerative treatments require the three
key elements; an extracellular matrix scaffold, progenitor/
stem cells, and inductive morphogenetic signals. 9
Recent breakthroughs in single cell manipulation methods
for the reconstitution of bioengineered tooth germ and the
investigation of in vivo development of artificial tooth
germ in the adult oral environment have been reported. 45
Reconstitution of bioengineered tooth germ, like that for
other organs, requires that single cells are completely
Fig. 1: Single cell manipulation (Courtesy. 2009 Takashi
Tsuji Laboratory) 53
Fig. 2: Strategies for building a bioengineered tooth from
dissociated single cells. (Courtesy of Kazuhisa Nakao,
Takashi Tsuji November 2008) 44
APPROACHES FOR RECONSTRUCTION OF
TOOTH:
Currently, two approaches are being investigated for
reconstructing teeth using cell culture procedures. One
approach is to seed tooth germ cells into tooth-shaped
scaffolds made of bio degradable materials. The other
approach is to reconstitute teeth by reaggregating tooth germ
from dissociated single epithelial cells and mesenchymal
cells. 46
SCAFFOLDING METHOD:
One of the three-dimensional tissue engineering methods
is scaffolding, in which a complex cell mixture and a
prefabricated biodegradable scaffold are employed to
grow a tissue of a desired form 47 (fig.2). The importance
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Sahana N S et al.
of scaffold materials and design for tissue engineering has
long been recognized. Scaffold porosity, biocompatibility
and biodegradability, the ability to support cell growth,
and use as a controlled gene and protein delivery vehicle
are all highly significant properties. 48 The different
scaffold materials used are collagen sponge, hydrophilic
polymers, poly-L-lactic acid and poly lactic co-glycolic
acid co-polymers, alginate, and agarose and natural silk
47, 49-51
proteins.
Tissue engineering methods using scaffold should be
utilized for the formation of differentiated tooth or tooth
germ in late stages of differentiation which has cell
polarization of mineralized tissue, and in odontoblast/
ameloblast cell lineages in organ architecture, because
they can manipulate a spatial configuration of several
types of cells and scaffolds 47 .Arranging epithelial cells
and mesenchymal cells within the scaffold by seeding
them sequentially, instead of the conventional method of
seeding a mixture of epithelial cells and mesenchymal
cells, improved the tissue arrangement in bioengineered
teeth. 52
Yelick’s 12 group examined explants containing dissociated
cells isolated from porcine unerupted third molars or rat
molar tooth buds. These contained both epithelial cells and
mesenchymal cells that were plated onto a tooth-shaped
scaffold. The explants were capable of generating a tooth
crown containing both dentin and enamel. 38
CELL AGGREGATE METHOD:
The cell aggregate method is a technique for creating
undifferentiated tooth germ using tooth germ cells.
The approach for the reconstitution of a bioengineered
tooth germ is the cell reaggregation method. The first
step in multi-cellular aggregation of epithelial cells and
mesenchymal cells is multi-cellular assembly by selfreorganization
of each cell type. This occurs through cell
migration and selective cell adhesion until cells reach an
equilibrium arrangement. Next, reciprocal interactions
among epithelial cell layers and mesenchymal cell layers
initiate organogenesis that regulates differentiation and
morphogenesis 47 (fig.2). To create a bioengineered tooth
germ, dental epithelium is reassociated with a cell pellet
of dissociated mesenchymal cells; the resulting artificial
germ is then used to grow a tooth with a proper structure
by transplantation in vivo. 44
During tooth development, the properties of cells vary,
depending upon the developmental stage. Different cell
manipulation techniques are thus required according to
the target stage of the tooth germ. The cell aggregation
method and the tissue engineering method using scaffolds
may be useful for regeneration of tooth germ in the early
developmental stages and in the late developmental
stages. Using cell aggregate methods layers of epithelial
and mesenchymal tissues can be reproduced in a manner
similar to the initial stages of the tooth germ, such as from
the bud to cap stages. Tissue engineering using scaffold
reproduces the proper anatomical arrangements for both
undifferentiated cells and committed odonto-forming or
enamel forming progenitor cells based upon maturation
events. 44
BIOENGINEERED ORGAN GERM METHOD:
A bioengineering method for forming a three-dimensional
organ germ in the early developmental stages is termed the
‘bioengineered organ germ method’. To precisely replicate
tooth organogenesis in the early developmental stages, a cell
aggregation method using cap-stage tooth-germ-derived
epithelial cells and mesenchymal cells was chosen. This
method has the distinctive feature that the bioengineered
tooth germ is reconstituted between epithelial cells and
mesenchymal cells using cell compartmentalization at
a high cell density in a collagen gel solution. 44 In one
experiment Nakao used the novel bioengineered method
and could generate plural teeth in alveolar bone of the
mice. 53
CONCLUSION:
With today’s 21st century technological advancements, it
is expected that individuals will either retain their natural
teeth or obtain functional tooth replacements throughout
their entire life. As adult tissue derived cell sources are
anticipated to be useful in clinical applications for tooth
regeneration, several stem cells/progenitor cells have
been found, which were isolated from adult dental/nondental
tissues. Even though the tooth regeneration looks
exiting many hurdles must be overcome to develop tooth
regenerative therapy.
Conflicts of Interest: The authors declare no conflicts of
interest.
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CORRESPONDENCE:
Dr. Sahana N S
Department of Oral and Maxillofacial Pathology
Government Dental College and Research Institute
Fort, Bangalore-560002
Karnataka, India.
E-mail: drsrinathsk@yahoo.co .in
Mobile No: +91-9480489690
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