Biomimetics in endodontics - Health Sciences

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 

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 nature’s 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 

Health Sciences 2013;2(1):JS007 1 An Open Access Peer Reviewed E-Journal

Jojo Kottoor 


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 

Figure 1. Tissue engineering triad 

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 

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 


Jojo Kottoor 


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 

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 

Biomimetic approaches for 

regeneration 

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 


Jojo Kottoor 


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 

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) 


Jojo Kottoor 


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 

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 


Jojo Kottoor 


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 

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 


Jojo Kottoor 


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, 

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 


Jojo Kottoor 


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 couldn’t 

regulate the crown width, cusp position, and 

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. 

Conclusions 

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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