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Preparation and application of chitosan biomaterials in dentistry

Chenxi Zhang, Didi Hui, Colin Du, Huan Sun, Wei Peng,
Xiaobing Pu, Zhengyong Li, Jianxun Sun, Changchun Zhou

PII: S0141-8130(20)34999-0
DOI: https://doi.org/10.1016/j.ijbiomac.2020.11.073
Reference: BIOMAC 17236

To appear in: International Journal of Biological Macromolecules

Received date: 27 August 2020

Revised date: 2 November 2020
Accepted date: 11 November 2020

Please cite this article as: C. Zhang, D. Hui, C. Du, et al., Preparation and application
of chitosan biomaterials in dentistry, International Journal of Biological Macromolecules
(2018), https://doi.org/10.1016/j.ijbiomac.2020.11.073

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© 2018 Published by Elsevier.

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Preparation and application of chitosan biomaterials in dentistry

Chenxi Zhang1, §, Didi Hui2, *, Colin Du2, §, Huan Sun3, 4, Wei Peng5, Xiaobing Pu5, Zhengyong Li6, Jianxun
Sun1, *, Changchun Zhou3, 4, *

1
State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan
University, Chengdu 610041, China
2
Innovatus Oral Cosmetic & Surgical Institute, Norman, OK 73069 USA
3
National Engineering Research Center for Biomaterials, Sichuan University, 610064, Chengdu,
China

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4
College of Biomedical Engineering, Sichuan University, 610064, Chengdu, China
5

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West China School of Public Health and West China Fourth Hospital, Sichuan University
Chengdu, Sichuan, 610041, China.
6
Department of Burn and Plastic Surgery, West China School of Medicine, West China Hospital,
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Sichuan University, 610041,Chengdu, China
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Abstract

Chitosan is a biodegradable and biocompatible natural polysaccharide that has a wide range of
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applications in the field of dentistry due to its functional versatility and ease of access. Recent
studies find that chitosan and its derivatives can be embedded in materials for dental adhesives,
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barrier membranes, bone replacement, tissue regeneration, and antimicrobial agent to better
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manage oral diseases. In this paper, we provide a comprehensive overview on the preparation,
applications, and major breakthroughs of chitosan biomaterials. Furthermore, incorporation of
chitosan additives for the modification and improvement of dental materials has been discussed
in depth to promote more advanced chitosan-related research in the future.

Key words

Biomaterials; Chitosan; Oral disease

1. Introduction

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Chitosan is a straight chain cationic polysaccharide (deacetylated polysaccharide), usually refers

to a cationic copolymer composed of 2-amino-2-deoxyglucose (60-100%) and 2-acetylamino-2-
deoxyglucose-D-glucoside (0-50%), which exists naturally or is obtained by deacetylation of
chitin[1, 2]. Chitin is found mainly in the exoskeletons of crustaceans, but also in some fungi[3].
In 1859, Rouget treated chitin with hot potassium hydroxide solution, resulting in the discovery
of chitosan, which also laid the foundation for modern chitosan production[4].

The amino group of chitosan is more acetylated than that of chitin. The free electron pair of
nitrogen on the amino group is responsible for the adsorption of metal cations. The average

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degree of deacetylation determines the proportion of amino groups that can interact with the
metal. Unlike chitin, chitosan is highly soluble and can be dissolved in dilute acid media to form

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cationic polymers, which are then combined with various natural or synthetic anion species, such
as DNA, proteins, lipids, or negatively charged synthetic polymers, such as polyacrylic acid[5].
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The protonation of amino acids in acidic solution is also the cause of anion electrostatic
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attraction.
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Chitosan can be biodegraded to non-toxic residue by lysozyme or chitinase, and it hydrolyzes

glucosamine-glucosamine, glucosamine-N-acetyl-glucosamine, and N-acetyl-glucosamine
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bonds, so it has good biodegradability[6, 7]. Secondly, acetylation increases the interaction
between chitosan and cells by increasing the number of positive charges, thus improving the
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biocompatibility. It has been found to have no antigenic response and even has anti-inflammatory
properties. The hemostatic effect of chitosan is also a major feature, mainly because it can induce
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platelet adhesion and aggregation, and activate endogenous blood coagulation[8]. The chitosan
can also control bleeding by adsorbing plasma and red blood cell coagulation.

Because the chitosan has biodegradability, biocompatibility, hydrophilic, antimicrobial

properties, biological activity and other properties, and have different forms of processing
(solution, blend, sponge, film, gel, paste, tablet, microspheres and micro particles, etc.), it has
many biomedical applications, including effective wound healing, tissue regeneration, dosing,
bone regeneration, anti-infection and so on[9]. Since it comes from natural and renewable
resources, not only it is an economical natural biopolymer, but also cost effective

2. Preparation of chitosan biomaterials

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2.1 Ionic gelation method

Chitosan nanoparticles are usually engineered using ionic gelation method. The method is to
dissolve chitosan in acetic acid aqueous solution, then adjust the pH of the solution by adding an
appropriate amount of NaOH. After that, tripolyphosphate (TPP) is used as ionic cross-linker and
added into chitosan aqueous phases while stirred with magnet stirrer at room temperature to form
chitosan nanoparticles. Finally, the chitosan nanoparticles are washed with distilled water to
remove any impurity. As mentioned above, the temperature, pH, chitosan concentration, TPP
concentration, and reaction time can influence the physical and chemical properties of the

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particle [10, 11].

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Sedigheh Vaezifar et al. [12] found that the optimum chitosan concentration, TPP concentration,
and reaction time are 1.0 mg/ml, 1.0 mg/ml, and 60 min. Further study found that under

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optimum conditions, chitosan nanoparticles had a mean size around 90-100 nm, polydispersity
index around 0.22, and zeta potential close to + 31 mV [13]. Moreover, Chitosan nanoparticles
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obtained by this method are widely used as drug/gene/enzyme carrier systems and play an
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important role in in vitro and in vivo. Currently, many researchers are focusing on how to better
bind drugs or genes to chitosan nanoparticles. Tang et al. [14]found that the optimal conditions
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for enzyme immobilization are as follows: one milligram of neutral proteinase was immobilized
on chitosan nanoparticles for about 15 min at 40°C. Under the optimized conditions, the enzyme
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activity yield was 84.3%.

In addition, Eizatahry [15] found that chitosan nanoparticles containing metronidazole are good
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for colon-specific delivery due to its excellent mucoadhesive properties. Meanwhile, recent
studies showed that the drug is released from the optimized formulation over a period of 12
hours in a sustained controlled manner.

Ionic gelation method has the advantages of mild reaction conditions, no use of organic solvents,
easy operation, etc. Thus, it is developing rapidly in recent years. Numerous researchers focus on
the chitosan and itsn derivatives nanoparticles using ionic gelation method, which can effectively
package the biological macromolecules, transmit the targeted drug in the body, and slowly
release the drug in a controlled manner[16]. At present, the composite preparation technology
combing nanoparticles with other preparation technologies has appeared, so as to combine the

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advantages of other dosage forms and avoid the defects of a single dosage form, which is one of
the future development trends of this technology.

2.2 Solvent evaporation method

First, chitosan solution is added into the aqueous phase to form the emulsion. Then polymer
solvent evaporates and precipitates to form nanospheres. pDNA- Tris buffer is added with
ethanol, the mixture was stirred with magnetic stirrer for 30 min. By applying reduced pressure,
the solvent is removed to yield nanoparticles. Finally, the solvent is removed to produce
nanoparticles [17].

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Jonacir Novaes et al. obtained chitosan and collagen blends with silver nanoparticles by method

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of evaporation of the solvent [18]. The nanoparticles with porous and interconnected structures

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are compatible for medical use. Moreover, nanoparticles derived from PLGA is also prepared by
this method, and further study showed that the encapsulation rate of curcumin with different
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capping agents such as chitosan, glucan and emulsifier is 82%-89%, and the antioxidant activity
is 80%. The in vitro anticancer activity of PLGA nanoparticles coated with curcumin suggests
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that they are more effective in inhibiting cell growth [19].

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However, in order to shorten the preparation time and accelerate the solidification of
microspheres to improve the encapsulation rate, the microspheres are prepared by reducing
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pressure, which makes the operation more complex and may affect the active pharmaceutical
ingredient.
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2.3 Microemulsion method

Reverse micelles are thermodynamically more stable liquid mixtures of water, oil, and
surfactants, which are separated into microdomains of water and oil by surfactant-rich
membranes. Surfactants are amphiphilic molecules that spontaneously form spherical or
ellipsoidal aggregatesin water or organic solvents. Normal micelles exist in water with low
concentration of organic solvents, but reverse micelles are formed in large amounts of organic
solvents [20]. In reverse micelle, the reaction occurs in the water core of the reverse micelle
droplet. Here, the monomers, cross-linking agents, and other aqueous solutions of hydrophilic
compounds are still present in the reverse micelle's water core (the main nano-reactor). In these

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cores, a polymerization occurs through a primary growth process, leading to the formation of
nanoparticles. The reverse micelle droplet is nanoscale. Therefore, any polymerization that takes
place in these droplets produces nanometer-sized polymers. Reversed micelle droplets are
stabilized by an expanded water core with a layer of surfactant molecules and dispersed in the
oil. The nucleation process of the system is continuous and can occur during the whole
polymerization process. Over time, the number of polymer particles increases steadily, but their
size remains the same.

Liu et al. prepared chitosan nanoparticles using microemulsion technology consisting of water,

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Triton X-100, octanol and cyclohexane. Experimental results show that the method which
combined ionic gelation and cross-linking gave uniformly sized chitosan nanoparticles with an

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average diameter of 92 nm, while the cross-linking without ionic gelation produced spindly
chitosan particles with an average length of 943 nm and width of 188 nm [21]. Chitosan
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nanoparticles are obtained by cross-linking chitosan amines with glutaraldehyde and removing
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organic solvents by evaporation at low pressure. Excessive surfactant is removed by CaCl2
precipitation and centrifuged to obtain lyophilized nanoparticles with a size of less than 100
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nanometers. In addition, particle size can be changed by changing the concentration of

glutaraldehyde [22]. You et al. [23] prepared chitosan-alginate core-shell nanoparticles using
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aqueous reversed-phase microemulsion templates in oil. Microemulsion Method can offer a

narrow size distribution of less than 100 nm. However, it consumes lots of time, including
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complex washing steps and use of organic solvents.

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2.4 Self-assembling method

Several chitosan nanoparticles have been introduced into clinical practice. However, the vast
majorities of these traditional nanoparticles either needs complicated fabrication process (such as
high pressure, temperature and long operation duration) or involve the utilization of harmful
chemicals (such as DMSO). The emergence of self-assembly method overcome these problems
mentioned above. [24, 25]

Specifically, chitosan is positively charged natural alkaline polysaccharide and phospholipids are
negatively charged lipid mixtures. The self-assembly between chitosan and phospholipids
formed nanoparticles due to the electrostatic interactions [26]. The whole process did not involve

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any organic solvents or cross-linking agents, and protect the loaded bioactive substances from
toxic damage.

The self-assembled chitosan nanoparticles are simple to prepare, easy to mass produce, and have
high encapsulation efficiency, so it is expected to be widely used in clinic [27, 28].

3. Application of chitosan biomaterials

3.1 Preventive Dentistry

3.1.1 Chitosan-containing mouthwash and toothpaste

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Mouthwash containing water-soluble chitosan exhibits lower toxicity and higher antimicrobial

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activity comparable to that of commercial mouthwashes with or without alcohol. The chitosan

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antibacterial activity demonstrated a significant inhibitory effect on Streptococcus mutans and
Lactobacillus brevis [29]. Due to its great ability to inhibit Streptococcus mutans proliferation,
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chitosan mouthwash effectively interferes bacterial adherence and biofilm formation [30].
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Chitosan-containing mouthwash also have analgesic and anti-inflammatory effect. A study

showed that the experimental group that is treated with carboxymethyl chitosan mouthwash have
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significantly lower concentration of bradykinin than the control group. Thus, chitosan-containing
mouthwash promotes wound healing and have better effect in reducing ulcer size and
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management of recurrent aphthous stomatitis than commercial mouthwash. Its effect is

comparable to Triamcinolone treatment effect on recurrent aphthous stomatitis [31]. With the
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benefit of antimicrobial activity, analgesic and anti-inflammatory effect, chitosan-containing

mouthwash is a natural and efficient alternative to commercial mouthwashes.

In addition to mouthwash, chitosan can be incorporated into toothpaste. A study showed that oral
antibacterial activity released by chitosan-containing toothpaste is effective in penetrating thick,
mature biofilm layer, reducing the plaque index by 70.47% and bacterial count by 85.29%. The
antiplaque and antimicrobial activity in chitosan-containing toothpaste and its efficiency are
comparable to that of chlorhexidine [32, 33]. Chitosan-containing toothpaste can also help
prevent initial enamel erosion and abrasion. A study showed that chitosan-containing toothpaste

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has similar surface microhardness (SMH) as fluoride toothpaste, but significantly reduce enamel
loss from erosion and abrasion more than fluoride toothpaste [34].

3.1.2 Propolis based chitosan varnish, chitosan-containing dentifrice and gum

Propolis based chitosan varnish (PCV) can be an alternative for fluoride varnish in preventive
dentistry. For decades, fluoride has been the most important and popular dental agent for dental
caries prevention; however, the high prevalence of dental fluorosis remains a concern. In vitro
studies, chitosan interfered the process of enamel demineralization by inhibiting the release of
mineral elements from the enamel. Chitosan when combined with propolis exhibited a synergic

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relationship to promote antimicrobial effect. Chitosan-containing dentifrice is also effective in

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preventing enamel demineralization around the dental braces during orthodontic treatment. In
addition, chewing gum containing chitosan is also found to reduce enamel decalcification and

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preserve the bacteriostatic level in the saliva [35, 36].
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3.2 Restorative and Prosthodontic Dentistry
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3.2.1 Direct pulp capping material

Chitosan can be used as direct pulp cap, adhesive agent, and modification in glass ionomer
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restoration to improve the quality in restorative treatment. The purpose of direct pulp capping is
to initiate reparative dentin formation to help protect the pulp, which starts from the
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differentiation of dental pulp stem cells into odontoblast-like cells. It is essential that the pulp
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capping agent be biocompatible, possesses suitable physical and mechanical properties, and
induces the differentiation of pulp stem cells, which is mainly determined by the interactions
between the pulp capping agent and pulp stem cells.

For decades, Dycal has been the gold standard material as pulp capping agent. A study compared
the cellular effects of gypsum-based chitosan material (Gp-CT) as pulp capping agent to that of
Dycal. A study conducted by Subhi in 2018 showed that cell viability is significantly higher in
pulp stem cells treated with (Gp-CT) than the pulp stem cells treated with Dycal. Not only the
cell viability increased, but also no cytotoxic effect is released; unlike Dycal, which had high
cytotoxicity effect due to its high pH level. Wound healing process involves cell adhesion, which
is necessitated in cell growth, differentiation, and proliferation. Results showed that more

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osteoblasts adhered to the surface of gypsum-based chitosan material than the surface of Dycal.
Such results suggested that Gp-CT is a promising direct pulp capping agent that enhanced cell
viability and promote wound healing with no cytotoxic effect [37].

In addition to Gp-CT, calcium phosphate carboxymethyl-chitosan composite (CaP-CMCS)

material can also be used as pulp capping to enhance cytocompatibility, proliferation, and
differentiation on human dental pulp stem cells (Figure 1). Compressive strength is found to be
greater than 600 kPa, which is greater than that of typical pulp capping agent, calcium
hydroxide; swelling was less than 2%; and its degradation was less than 10%. Differentiation of

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pulp stem cells to odontoblastic cells is also evident. CaP-CMCS composite has shown to
possess fast gelation, improved mechanical properties, biological compatibility, and odontogenic

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potential; thus, CaP-CMCS composite achieves the initial essential elements of a potential
regenerative pulp capping agent that is rapidly curing, mechanically stable, and biocompatible
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3.2.2 Restorative material
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Chitosan can be used as an adhesive agent to improve the clinical performance of dental
restorations. Chitosan modified with methacrylic acid (Chit-MA70) was tested on human teeth as
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a primer of an “etch-and-rinse” adhesive system. Chit-MA70 covalently bonded to the

restorative material and interacted with demineralized dentin. Chit-MA70 showed immediate
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bonding strength, and did not decrease bond strength during thermo-mechanical cycling
treatment of dental restorations. Thus, modified chitosan used as a component of the “etch-and-
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rinse” adhesive system can effectively improve the durability of dental restorations [39].

Chitosan can also be incorporated into the dental composite and glass ionomer and used as
alternative restorative material. A study confirmed the antibacterial effect of methacrylated-
modified chitosan (CH-MA) against Streptococcus mutans in low-molecular weight CH-MA,
reduced the formation of Streptococcus mutans biofilm. However, the hardness and flexure
strength of the composite decreased with increasing quantity of CH-MA. Although the amount of
CH-MA in dental composite that is necessary to achieve antibacterial effect compromises the
mechanical properties of the composite material, the value of flexural strength still clinical
acceptable according to the International Organization for Standardization (ISO) standard [40].

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Glass ionomer cement (GIC) has been known for favorable properties such as antibacterial
effects, sustained fluoride release, biocompatibility, and natural affinity for tooth structure in
enamel and dentin. However, GICs have insufficient fracture toughness and flexural strength,
particularly in large filled restorations. Studies showed that microshear bond strength of chitosan
(CH) modified GIC was significantly higher than that of conventional GIC [41, 42]. CH
modified GIC also had the higher compressive and flexure strength and higher antibacterial
activity compared to conventional GIC [43]. It could be concluded that small ratios of 5-10% CH
modified GIC is sufficient to improve antibacterial properties of GIC against Streptococcus
mutans without adversely affecting its bonding ability to dentin surface [44].

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While small amounts of chitosan can improve the flexural strength of glass ionomer restoration

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(GIR) and increase the rate at which fluoride ions are released, a study showed that higher
chitosan concentrated modified GIR showed poor performance of flexural resistance. The same
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study also showed that CH catalyzed the fluoride release from GIR to the medium. Fluoride ions
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were also released in much larger quantity than conventional GIR. With its antibacterial and
mechanical reinforcement effects and ability to release fluoride in greater amount, chitosan
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modified GIC is a viable and promising alternative dental restoration [45].

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3.2.3 Increase bonding strength of lithium disilicate glass ceramic cementation procedure.

Chitosan can also be assimilated in the procedure of lithium disilicate glass ceramic cementation.
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A study analyzed the effect of different chelating agents on microtensile bond strength (MTBS)
of self-adhesive resin cements to dentin. The different chelating agents included chitosan (CH),
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ethylene diamine tetra acetic acid (EDTA), polyacrylic acid (PAA), and a control group with no
dentin conditioning. Results showed that no significant effect on MTBS among the dentin
substrates treated with different dentin chelating agents, but the MTBS in conditioned groups
were twice higher than the control group with no dentin conditioning. Being a more
biocompatible dentin chelating agent, chitosan at low concentration of 0.2% was able to remove
the smear layer with minimal erosive effects on dentin surface and has MTSB results comparable
to EDTA and PAA. This study showed that 0.2% chitosan can reduce dentin microhardness and
have similar demineralization potential to that of EDTA. Hence, chitosan is a promising

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alternative to the traditional dentin chelating agents in conjunction to cementation of lithium

disilicate glass ceramic with self-adhesive resin cements [46].

3.2.4 Dental adhesive for denture base

Chitosan can be used as dental adhesive for acrylic denture base to fight against common fungi
such as Candida albicans. Candida adherence to denture base is the etiology of denture
stomatitis. Infections with drug-resistant Candida have become a more prevalent problem in
elderly and immunocompromised patients; and thus, chitosan is a biocompatible, safe antifungal
agent for oral application. A study showed that high molecular weight chitosan has the highest

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antifungal activity against most Candida species compared to lower molecular weight chitosan

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and carboxymethylcellulose, and completely inhibited Candida albicans adherence to acrylic
denture base with no toxic effect on gingival fibroblast viability and proliferation. This study

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concluded that high molecular weight chitosan is a water-soluble and biocompatible biopolymer
with antifungal properties that can inhibit Candida albicans adherence to acrylic denture and also
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has sufficient retention to be used as denture adhesive [47].
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Another benefit of using chitosan coatings as denture adhesive is to promote blood clotting and
wound healing after alveolar surgical procedures. A study found that 4% chitosan acetate
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solution exhibited the best viscosity to allow a relatively uniform thickness to a 60° angulation
on removable acrylic dentures that is clinically acceptable in serving as a wound dressing or oral
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medicine [48].
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3.3 Endodontic therapy

3.3.1 Root canal treatment

Enterococcus faecalis is the most common bacteria species found in endodontically treated teeth.
The success of root canal treatment is determined by how well the bacteria load is eliminated.
Chitosan can be heavily utilized in endodontic procedures due to its antibacterial and
physiochemical properties. Chitosan has a board spectrum of antibacterial properties, high
chelating ability in acidic conditions, biocompatibility, and biodegradability. A study investigated
antibacterial properties of chitosan-citrate solution against Enterococcus faecalis and its ability to
remove smear layer. The antibacterial effect of chitosan-citrate solution and removal of smear

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layer were achieved at 5 minutes, and the removal of smear layer was significantly more than
10% citric acid. This study showed that chitosan-citrate solution can be a possible root canal
irrigant due to its antibacterial activity and ability to remove smear layer [49].

Sodium hypochlorite (NaOCl) and ethylenediaminetetraacrtic acid (EDTA) are commonly used
irrigants. A study compared chitosan nanoparticles (CNPs) to NaOCl and EDTA in its
antibacterial activity and ability to remove smear layer in dentin. Results show that irrigation
with CNP can remove smear layer and inorganic contents from the dentin effectively. CNP also
resisted biofilm formation significantly greater than NaOCl and EDTA, and has similar chelating

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effect as EDTA. In contrast to EDTA which could cause dentin demineralization, chitosan could
remineralize the demineralized dentin with additional benefit of resistance to bacterial adherence.

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CNPs could be used as an alternative to EDTA or as a final irrigant in root canal treatment due to
its ability to inhibit bacterial recolonization and remove the smear layer on dentin [50].
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Moreover, chitosan can also sustain the release of calcium ions from calcium hydroxide, which is
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the traditionally preferred material for intracanal dressing because of its favorable antimicrobial
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action. However, calcium hydroxide is ineffective in maintaining an alkaline pH and releasing

calcium ions for more than 7 days. Therefore, a study evaluated the calcium ion release and
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measure the pH change in the environment when calcium hydroxide was combined with different
medium, such as distilled water, propylene glycol, calcium hydroxide containing gutta-percha
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points, and chitosan. Chitosan formulation also showed the highest sustained release of calcium
ions and maintained a high alkaline pH up to 30 days compared to other formula mediums.
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Hence, these studies concluded that chitosan can be a promising vehicle for calcium hydroxide in
long term dressing to sustain release of calcium in root canal treatment [51,52].

Chitosan can also be incorporated into zinc-oxide eugenol (ZOE) as temporary restorative
material or as sealers in endodontic procedures. One of most common reasons for root canal
treatment failures is reinfection due to coronal leakage. ZOE is often used as coronal seal to
prevent secondary infection. The antibacterial effect from ZOE is due to the release of eugenol,
but this effect is decreased over time. Since eugenol from ZOE is being released over time and
increasing eugenol content is not recommended due to its cytotoxic effects on human
osteoblastic cells, chitosan is incorporated into ZOE to observe its antibacterial effects against

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Staphylococcus epidermidis, Streptococcus mutans, and Enterococcus faecalis. Results in this

study showed that Streptococcus mutans has the highest susceptibility to eugenol. Incorporating
chitosan into ZOE reduced the compressive strength; however, the compressive strength
requirements in ISO 3017 is still maintained. This study supported that chitosan can be
incorporated in ZOE to increase and sustain antibacterial effects [53].

Enhancing sealers’ antibacterial properties can help improve the prognosis of endodontic
treatment. A study examined the biofilm formation within sealer-dentin interfaces of root
segments filled with gutta-percha and zinc-oxide eugenol (ZOE) sealer incorporated with

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chitosan nanoparticles (CNP). Results showed that incorporating chitosan nanoparticles into
ZOE sealer inhibited Enterococcus faecal biofilm formation within the sealer-dentin interface.

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The inhibitory effect on biofilm formation is maintained in canals that are treated with
phosphorylated chitosan and moderately maintained in canals that are treated with chitosan-
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conjugated Rose Bengal and photodynamic irradiation. This study suggested that chitosan can be
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incorporated into ZOE sealer to inhibit biofilm formation within sealer-dentin interface [54].
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Moreover, chitosan can also be incorporated into RealSeal self-etching primer to eliminate
bacteria from root canals and prevent secondary infection. A study investigated the antibacterial
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activity of a chitosan modified self-etching primer in RealSeal system and examined its bond
strength to radicular dentin. Results exhibited significant antibacterial effects against
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Enterococcus faecal without compromising bond strength using chitosan solution in RealSeal
self-etching primer compared with using unmodified primer. This study confirmed that chitosan
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modified self-etching primer is a promising antibacterial primer in RealSeal system without

affecting the bond strength to radicular dentin [55].

3.3.2 Dental pulp regeneration.

Unlike conventional endodontic treatment where all pulp tissues are removed, regenerative
endondontic treatment targets pulp connective tissue, radicular dentin, vascularization and
innervation to regenerate. Scaffolds are essential to deliver active molecules and cells in the root
canal and is the main determining factor to regenerative endodontic treatment. Cellularized fibrin
hydrogel with chitosan used as a scaffold can prevent endodontic bacteria growth and support
dental pulp formation. Fibrin-chitosan hydrogel exhibited a potent antibacterial effect in the

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fibrin network, as well as similar dental pulp viability, fibroblast-like morphology, and
proliferation of collagen production as normal dental pulp tissue. Incorporating chitosan in fibrin
hydrogel can help promote dental pulp tissue formation without altering the dental pulp cell
viability, morphology, and proliferation in collagen matrix [56].

Studies showed that chitosan-based scaffolds are favorable for pulp regeneration and dentin
formation due to its ability to induce mineralization. Chitosan-based scaffolds contain tricalcium
phosphate that promotes high expression of mineralization markers, such as osteopontin and
alkaline phosphatase, and dentin formation by human periodontal ligament cells (HPLCs).

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Chitosan-based scaffolds also promote proliferation, migration, and odontoblastic differentiation
of dental pulp stem cells. This study suggests that chitosan-based scaffold contributes greatly in

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dental-pulp regeneration [2].

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Another study used optimized chitosan/carbon dot hydrogel and evaluated its effects on
proliferation of dental pulp stem cells. Results showed that chitosan hydrogels exhibited high
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cellular proliferation when compared to calcium hydroxide paste. This study concluded that
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chitosan/carbon dot hydrogel can be used as an alternative to calcium hydroxide or triple

antibiotic paste in regenerative endodontic procedures [57].
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3.4 Periodontal treatment

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3.4.1 Periodontitis treatment

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One of the challenges in local delivery systems of antimicrobial agents in periodontal treatments
is finding the ideal appropriate system to administer drugs. An ideal local delivery system should
be able to deliver antimicrobial drugs at ease in a controlled manner with good retention at the
application site. Chitosan-based delivery systems could be micro-nanoparticles, fibers,
membrane, and gels as demonstrated in figure 2 [58]. These different ways of using local
delivery system to delivery drugs can target against inflammation and infection, and also
promote tissue regeneration. The efficiency of chitosan gel can be determined by the
concentration of chitosan. Chitosan-based gels at 1-4% viscosity can be injected into periodontal
pockets and also used as drug carriers to release active drugs, such as statins, doxycycline, or

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other antibiotics/antiseptics such as tetracycline, into disease sites and can improve periodontal
healing.

Chitosan-based hydrogel can be incorporated with naringin, which is a natural substance that
possesses anti-inflammatory properties. When injected at the lesion site with acute inflammation,
active release of naringin induced an anti-inflammatory response in periodontal tissues. Such
response can be reasoned due to how well-controlled drugs can be delivered by the chitosan-
based drug carrier [2]. Chitosan formulations in gels and film forms as antimicrobial drug
delivery system that has antimicrobial activity against periodontal pathogen, Porphyromonas

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gingivalis. The flow property of chitosan bioadhesive gels is placed in syringe and injected into
the periodontal pocket. This study showed that chitosan has antimicrobial activity against P.

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gingivalis with higher the molecular weight chitosan having higher antimicrobial activity. The
combination of chitosan with chlorhexidine also has higher antimicrobial activity than
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chlorhexidine alone. This study revealed that chitosan films and gels are promising delivery
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system due to its bioadhesive and antimicrobial properties [59].
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Chitosan gel incorporated with metronidazole is used effectively as a drug carrier and an active
agent in adjunctive to scaling and root planning periodontal treatments. Results showed that
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pocket depths were reduced, and no complications were observed in patients. This study
suggested that chitosan is effective in periodontal treatments as an active antimicrobial agent and
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as a drug carrier for metronidazole [60].

However, rapid clearance of the injected biomolecules requires repeated injections, which causes
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complications like infection, fibrous tissue formation, and consequent damage. Such obstacles
are possibly tackled through the use of chitosan nano-microparticles that can deliver therapeutic
molecules, such as anti-inflammatory drugs, and release them in a sustained manner for
periodontal therapy. In addition, nano and microparticles can interact with cells at the intra and
extracellular space depending on their size (Figure 3) [61]. For example, the chitosan-natamycin
microsphere has rough, porous surface and slowly released natamycin, where its drug
concentration is above its minimal inhibitory concentration (MIC) value against Candida
albicans. Hence, this study suggested that chitosan as microsphere drug carrier is effective to
deliver drugs such as natamycin into periodontal pockets [62]. Meanwhile, researchers found that

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self-assembled chitosan/phospholipid nanoparticles (SACPNs) break through the limitation of

drug hydrophobicity on carrier structure as presented in Figure 4. It can improve not only the
encapsulation efficiency, but also the stability of resisting the attack of surrounding enzymes.
The SACPNs is simple to prepare, easy to mass produce, and have high encapsulation efficiency.
Due to its superior gastrointestinal mucosa and transdermal penetration, SACPNs has been
widely concerned and can be used as multi-functional drug delivery systems [63].

In addition to the different ways of using chitosan as drug carrier, one study designed an
injectable and thermosensitive hydrogel made of chitosan, β sodium glycerophosphate (β-GP),

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and gelatine blend to inhibit alveolar bone resorption, anti-inflammation, and regeneration of
periodontitis. This hydrogel is highly biocompatible and biodegradable, and can inhibit

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inflammation by releasing aspirin and erythropoientin, guide tissue regeneration, and treat
intrabony periodontal defects [64].

3.4.2 Periodontal regenerative potential.

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Chitosan can also be used as a suitable treatment for potential periodontal regeneration. One
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study evaluated chitosan ascorbate produced in a gel form and its effect on periodontal pockets.
Chitosan ascorbate degraded in presence of atmospheric oxygen and at pH 6.0, and formed a
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honeycomb structure. Thus, the cells proliferated in the honeycomb structure and reconstructed
the histoachitecture of the periodontal tissue. Results showed that tooth mobility and pocket
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depth are significantly reduced after chitosan asborbate treatment. This study indicates that
chitosan ascorbate can be a promising treatment to reduce pocket depths and teeth mobility [65].
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Another study used poly (D,L-lactide-co-glycolide acid) PLGA-lovastatin-chitosan-tetracycline

nanoparticles as local delivery device to control localized periodontal infection, promote bone
regeneration, and fight against periodontal pathogens. PLGA-lovastatin-chitosan-tetracycline
nanoparticles exhibited effective well-controlled release of drugs, good biocompatibility,
antibacterial activity, superior osteogenic potential, and increased alkaline phosphatase activity.
Micro-CT scans also showed new bone formation found in defects that was filled with
nanoparticles. This study highlighted that PLGA-lovastatin-chitosan-tetracycline nanoparticles is
a useful local drug delivery device in periodontal regenerative treatments [66].

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3.5 Oral Surgery

3.5.1 Bone regeneration

Chitosan can be incorporated with biomimetic calcium phosphate (Bio-CPC) and used in bone
graft procedures. A study showed that Bio-CPC-reinforced chitosan adhere to mouse
odontoblast-like cells with no signs of cytotoxic effect or affecting the odontoblastic cell
viability. In vitro results exhibited that Bio-CPC-reinforced chitosan can promote growth and
differentiation of odontoblasts and enhance strength and properties for bone repair [67].

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Another study examined the effects of chitosan on socket repair after dental extractions. The
density of regenerated bone is measured against the maximum bone density of each individual

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patients. Results showed that in the apical section, regenerated bone reached up to 98.2% of

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normal bone density, and the bone density in apical and middle sections are increased by 29.3%
and 10.8% of normal bone density. This study concluded that chitosan increased bone density
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significantly in apical and middle sections, and can be used as bone grafts to effectively repair
bone in bone defect areas, promote osteogenesis, and improve bone regeneration [68].
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Chitosan can also be used for bone regeneration around dental implants. Human dental pulp stem
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cells (hDPSCs) incorporated in chitosan scaffold is implanted in rabbit models, and the results of
bone healing and implant osseointegration are compared to that of using xenografts in rabbit
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models. The hDPSCs with chitosan exhibited higher mean area percent and lower mean gap
distance than xenografts, confirming that hDPSCs with chitosan is a promising technique to
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regenerate bone formation around dental implants and improve osseointegration [69].

3D printing is a series of material processing technologies based on the dispersion-accumulation

principle of computer-aided manufacturing [70]. In recent years, 3D printing technology has
developed rapidly [71-75], and many advances have been made in biomedical engineering and
artificial organ construction, especially in the field of bone repair, 3D printed biomaterials have
shown a wide range of application prospects [76-81]. Current research shows that calcium
phosphate, carbon nanotubes, and hydroxyapatite can increase the mechanical properties of the
chitosan scaffolds to some degree [82]. For example, Matinfar et al. [83] mixed chitosan and
carboxymethyl cellulose, and reinforced triphasic calcium phosphate fibers as bone repair

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scaffolds. Bi et al. [84] prepared a chitosan-containing composite 3D printing scaffold and

seeded with osteoblasts. It was found that a large number of osteoblasts adhered on the scaffold,
which proved that the 3D printing chitosan scaffolds have good osteogenic properties [85].

3.5.2 Dental membrane barrier

Chitosan membrane has a porous structure that is biodegradable, and effectively contributes in
guided tissue regeneration (GTR) and guided bone regeneration (GBR). Ideal material for GTR
and GBR membrane should achieve wound stability, space maintenance, and ability to exclude
unwanted tissues or cells such as gingival connective tissues and epithelium into the surgical site

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(Figure 5). Not only is chitosan biocompatible, biodegradable, and antimicrobial, but also,

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chitosan acts as a hydrating agent to promote tissue healing and osteoinducing effect [86].
Histological results in one study showed that chitosan collagen sponge inhibited apical migration

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of epithelium, and new bone and cementum formation are increased in one-wall intrabony
defects in beagle dogs [87]. Another study showed that the use of chitosan collagen membrane
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for GTR exhibited a reduction in probing pocket depth and gain in clinical attachment at
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furcation sites, and significant improvements in infrabony and furcation defects. There were also
low incidence of gingival recession, device exposure, and gingival pathology, and no allergic
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reactions depicted from using chitosan collagen membranes [88]. These studies supported that
chitosan collagen membrane is an effective barrier for GTR and GBR procedures due to its
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unique bioproperties, making it a promising membrane for periodontal regeneration.

Chitosan membrane can also be combined with bone morphogenic protein (BMP) to treat buccal
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gingival recession. BMP can promote bone and periodontal regeneration. Results showed that
chitosan with BMP induced more healing progress than chitosan without BMP. This study
indicated that chitosan membrane with BMP is effective to treat buccal gingival recession [89].

3.5.3 Hemostasis in oral surgery wounds

Chitosan is an effective wound dressing after oral extraction procedures. A study assessed the
effectiveness of chitosan-based dressing after extractions on patients on antithrombotic
medications without interruptions. Results showed no incidences of dry socket or pus discharge
in extraction sites with chitosan dressing. Chitosan dressing is a hemostatic agent that can

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significantly reduce post-extraction bleeding with better pain control in patients on oral
antithrombotic medications without interruption [90]. In recent years，the powder hemostatic
materials are increasingly appreciated because of their prolong storage time, wide storage
temperatures, portable properties. Mesoporous silica materials attracted more and more attention
owing to their favorable biocompatibility and outstanding hemostatic performance, but their
hemostatic process is too simple to meet the requirements. Thus, herein, mesoporous silica
nanoparticles modified by chitosan and hydrocaffeic acid (MSN@CS-HCA) is developed for
rapid and safe hemorrhage control. By tissue adhesion, activating the coagulation cascade,
aggregating red blood cells and platelets (Figure 6), MSN@CS-HCA with the porous structure

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exhibited excellent hemostatic effects in both in vivo and in vitro coagulation tests [91].

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HemCon Dental Dressing (HDD), which is composed of freeze dried chitosan derived from
shrimp shell chitin, is an effective hemostatic oral wound dressing. Results showed that HDD
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surgically treated sites, including patients on oral antithrombotic medications without
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interruption, achieved hemostasis in less than 1 minute, and wounds are controlled in 9.53
minutes, which is faster and healed significantly better than negative control sites. HDD is
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proven clinically to be safely used in patients under oral antithrombotic therapy and effective for
hemostasis, which significantly shortened bleeding time, reduced pain, and improved surgical
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wound healing rate and outcome [92-94].

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AXIOSTAT is another chitosan based dental dressing that is composed of freeze dried chitosan
molded into a sponge-like structure, and it has been increasingly popular in dental surgeries. The
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average hemostatic time in all patients with AXIOSTAT dental dressing placed in extracted
sockets is 1.5 minutes. Chitosan stimulated platelet adhesion and aggregation, and the release of
growth factors from platelets. The study also found that chitosan based AXIOSTAT minimizes
the incidences and risks of thromboembolism by allowing the continuation of antiplatelet therapy
when undergoing oral surgeries [95]. In addition to MSN@CS-HCA, HDD, and AXIOSTATan
injectable hydrogel consisting of polylysine (ε-PL) and carboxymethyl chitosan (CMCS), as
demonstrated Figure 7, is an injectable biodegrading hydrogel that also has good mechanical,
antibacterial, and hemostatic properties for hemostatic dressing. It is capable of rapid gelation,
low toxicity, and low irritation. And these chitosan derived wound dressings have good
application prospects in medical hemostatic dressings [96].

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3.5.4 Temporomandibular joint (TMJ) disc repair

In a study conducted in rabbit model, chitosan-based theromosensitive hydrogel is incorporated

with hyaluronic acid (HA) and beta-glycerophosphate and used as intra-articular injectable
vehicles to the TMJ. Chitosan based hydrogel controllably released HA and beta-
glycerophosphate to the inflamed TMJ and stayed in the synovial cavity up to a few months. The
mean concentration of HA in experimental joints is significantly higher than that of the control
after 7 days. It also provided extracellular matrix structure for TMJ regeneration. Chitosan based
hydrogel is a controlled released drug system for HA and beta-glycerophosphate to treat TMJ

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disc repair [61].

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Chitosan can also be an alternative effective treatment for TMJ pathologies, disc malpositioning
or degeneration. Fibrin-chitosan hybrid scaffold can be reinforced with TMJ-synovium derived

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mesenchymal stem cells (SDSCs) as a potential scaffold for cartilage regeneration to repair TMJ
disc perforation. Results exhibited improved cell seeding, proliferation, chondrogenic induction,
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cell viability, and more extracellular matrix deposited in the fibrin-chitosan scaffold. Fibrin-
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chitosan hybrid scaffold incorporated with TMJ-SDSCs can repair TMJ disc perforation,
improve fibrocartilage regeneration, and enhance TMJ disc reparative ability [97].
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Moreover, chitosan-alginate scaffolds can be used to promote fibrochondrogenic differentiation

of dental pulp stem cells (DPSCs) to form fibrocartilage tissue as a replacement to natural TMJ
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disc. A study reinforced chitosan-alginate scaffolds with calcium chloride and glutaraldehyde,
and deposited them with DPSCs, and evaluated the cell attachment, viability, and proliferation of
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DPCSs. DPCSs in chitosan-alginate scaffolds increased fibrocartilaginous gene expressions, and

elastic response is more than cell-free scaffolds. This study indicated that chitosan-alginate
scaffold can induce fibrocartilage tissue formation to be used as TMJ disc replacement [98].
(Figure 8)

3.6 Implant Dentistry

3.6.1 Titanium coating in dental implants

Implant surface treatment and coating, responsible for direct bone to metal surface contact, is a
major factor in determining the success of osseointegration of dental implants. Chitosan has

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excellent metal binding capacity, antimicrobial properties, and biocompatibility. To prevent

infections and improve osseointegration, chitosan can be coated on titanium implants to promote
faster and better wound healing with increased bioactivity. A study showed that Porphyromonas
gingivalis bacteria is inhibited; and fibroblast-cell attachment and proliferation are enhanced
around chitosan coated titanium implants. In gram-positive bacteria, chitosan inhibited food
ingestion into the gram-positive bacteria. In gram-negative bacteria, low-molecular-weight
chitosan passed into the bacterial cells, broke the cell metabolism, and killed the bacteria.
Chitosan coating is an effective bioactive coating on dental implants due to its ability to inhibit P.
gingivalis bacteria adhesion while allowing gingival fibroblast cells to adhere and proliferate

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with high level of cytocompatibility [99, 100].

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Titanium implants coated with chitosan can also improve mechanical strength and increase
durability of titanium implants. One study evaluated chitosan coating on orthopaedic and
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craniofacial implant devices. Deacetylated chitosan is chemically bonded to titanium molecules;
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and bond strength and cytocompatibility are evaluated. Results showed that the chitosan coating
bond strength is less than that of calcium-phosphate coating. However, there are more osteoblast
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cell growth and attachment on chitosan-coated titanium than uncoated titanium. This study
indicated that chitosan is a potential biocompatible and bioactive coating for orthopaedic and
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craniofacial implant devices [101].

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Moreover, chitosan coated titanium dental implants can induce bone formation and
osseointegration. One study coated chitosan on titanium implants and implanted in the tibia of 16
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rabbits. Histological results showed that there is fibrous bone formation, followed by lamellar
bone development with minimal inflammatory response, and exhibited close boney apposition
with dental implants. The bone-implant interface in chitosan-coated implants is comparable to
that of calcium phosphate-coated implants and uncoated implants. This study concluded that
chitosan coating on titanium implants can induce bone formation and improve osseointegration
[102].

3.6.2 Gene carrier to promote ossteintegration

Low bone quality in osteoporosis patient lowers the success rate of osseointegration of dental
implants. C-myb is a transcription factor that supports bone formation. Chitosan-gold

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nanoparticles can be used as a gene delivery vehicle to delivery C-myb gene to enhance dental
implant osseointegration. Plasmid DNA with c-myb gene is conjugated with chitosan-gold
nanoparticles (Ch-GNPs/c-myb) to promote osteogenesis and inhibit osteoclastogenesis. Ch-
GNP/c-myb coated titanium implants are implanted into ovariectomised-induced osteoporotic rat
mandibles. Results demonstrated that volume and density of newly formed bone increased and
osseointegrated with dental implants. There is also upregulation of bone morphogenic proteins,
and downregulation of gene regulator RANKL, which induces osteoclastogenesis. This study
indicated that c-myb gene delivered by Ch-GNPs facilitates osseointegration of dental implants
in osteoporotic conditions [103].

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4. Conclusion and future prospects

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Chitosan, a deacetylated polysaccharid derived from chitin, has been studied extensively for its

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unique characteristics and dental applications ranging from preventative dentistry to bone
regeneration in oral surgery. The characteristics of chitosan biomaterials that are most important
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to dental treatments are their biodegradability, biocompatibility, hydrophilicity, bioactivity,
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antibacterial and antifungal properties. Over the past 50 years, chitosan and its derivatives have
been incorporated in mouthrinse, toothpaste, varnish, denture adhesive gel, pulp capping agent,
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glass ionomer restorative material, and root canal sealer. In recent investigation, chitosan
biomaterials have also been used as titanium implant coating, dental membrane, scaffolds,
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hemostatic dressing, and carrier in drug or gene delivery. The increased use of chitosan in
diverse dental applications is promising in light of treatment success and outcome. Nonetheless,
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more studies are needed to further characterize chitosan biomaterials and to expand their use
effectively in dental treatments.

Declaration of Competing Interest

There are no conflicts to declare.

Acknowledgement

This work was partially supported by the National Key Research and Development Program of

China (2018YFC1106800). National Natural Science Foundation of China (31971251). Sichuan

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Province Science & Technology Department Projects (2019YFH0079, 2016CZYD0004,

2019JDTD0008, 2020YFS0462, 2020YFS0036).

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Figures and Table:

Table 1. Advanced chitosan biomaterials and their applications in dentistry areas.

Dental
specialties
Chitosa
n
applicati
Name
Application
site
o f
Advantages Reference
ons
r o
- p
Inhibit Streptococcus
Compon
ent of
Chitosan gel and
Sorbitol mixture
r e mutans, biofilm
formation, prevent initial 29,30,33

toothpast
l P
Teeth and
enamel erosion and
abrasion
e against
a oral mucosa

Preventive
Dentistry
dental
plaque rn
0.5% chitosan

u
modified Sn2+
mouthwash effectively
interferes bacterial
adherence and biofilm
31,34

Deminer J o toothpaste
formation

analgesic and anti-

alization chitosan-containing
inflammatory, prevent 36
preventio mouth rinse
demineralization
n Teeth
Better taste, promote
Chitosan propolis based
antimicrobial effect than 35
varnish chitosan varnish
fluoride varnish

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Improve bonding
methacrylate- demineralized
strength and durability of 39
modified chitosan dentin
dental restorations

wound
dental
adhesion healing after
good adhesion strength,
Prosthodontic
Dentistry
chitosan coatings as
denture adhesive
alveolar
surgical
o f
promote blood clotting
and wound healing
47,48

procedures
r o
Increase
chitosan modified
enamel and
-phighest antibacterial
bonding
strength
glass ionomer
cement
dentin

r
surface e activity and highest
compressive and flexure
41,42,43,46
of GIC
Gypsum-based
l P strength

chitosan material
a
rn
cell viability increased,
with growth factor promote wound healing 47
Direct
pulp
capping
o u BMP-2 Pulp and
dentin
without cytotoxic effect

Endodontic
therapy
material
J
calcium phosphate
carboxymethyl-
chitosan composite
rapid curing,
mechanically stable, and 38
biocompatible
material

Root High antibacterial

chitosan-citrate smear layer
canal activity and better ability 46
solution
treatment to remove smear layer

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Dentin,
inhibit dentin
smear layer demineralization,
chitosan
improve dental collagen 50
nanoparticles and dental
stability and remove the
collagen smear layer on dentin
Pulp and
increase antibacterial
add chitosan into
ZOE
sealer-dentin
interface
o f
effects, inhibit biofilm
formation
53,54

r o
fibrin- chitosan
hydrogel as scaffolds
-p promote dental pulp
tissue formation
56
Dental
pulp
r
pulp-dentin
e favorable for pulp
regenerat
ion chitosan/carbon dot
l P
complex
regeneration and also
dentin formation due to 58
hydrogel

n a its ability to induce

mineralization

u r
chitosan
formulations in gels
Better bioadhesive and
2,59

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antimicrobial properties
and film forms

Periodon
chitosan film used as Periodontal
Periodontal active antimicrobial
titis drug system for 60
Dentistry tissue agent
metronidazole
treatment

chitosan drug effective to deliver drugs

62
delivery system into periodontal pocket

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highly biocompatible and

thermosensitive biodegradable，
hydrogel （chitosan, periodontal inhibiting alveolar bone
β sodium resorption, anti- 64
pocket
glycerophosphate (β- inflammation, and
GP), and gelatine） regeneration of
periodontitis

Periodon chitosan ascorbate f

a promising treatment to

o
reduce pocket depths and 65
tal
regenerat
periodontal
pocket
r oteeth mobility

ive
potential
enzymatically
- p
highly biocompatible and
solidified chitosan
hydrogens
r e biodegradable， reduced
incidences of ankyloses
66

l P
restoring
tooth defects,
bio-calcium
a non-toxic; adhesive

rn
periodontium
phosphate cement potential to odontoblasts;
67,68
reinforced with and biocompatibility and
Bone
regenerat
o u chitosan
maxillofacial
osteoconductibility

Oral Surgery
ion
J chitosan scaffold
area

around dental
Improving Osteogenesis
69
with hDPSCs implants and osseointegration

Dental Periodontal biocompatible,

membran Chitosan biodegradable, and
and bone 88
e barrier membranes antimicrobial, tissue
in GTR tissue healing and

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and GBR osteoinducing effect

Periodontal new bone and cementum

chitosan collagen
formation and 87
sponge tissue

HemCon Dental
o f
biodegradable

shortened bleeding time,

ro
Dressing (HDD) reduced pain, and
92,93,94
Hemosta （freeze dried improved surgical wound
sis in
oral
chitosan） oral wound
- phealing rate and outcome

surgery
wounds
Axiostat（freeze
dried chitosan
r e hemostatic agent，
antibacterial, improved
molded into a
sponge-like
structure）
l P post extraction healing,
and reduced risk of
thromboembolism
95

chitosan-based
a
Temporo
mandibul
u rn
theromo-sensitive
hydrogel
incorporated with intra-articular
a controlled released
drug system for HA and
61
ar joint
(TMJ) Jo
hyaluronic acid
(HA) and beta-
glycerophosphate
beta-glycerophosphate to
treat TMJ disc repair

fibrin-chitosan
disc improved cell seeding,
hybrid scaffold
proliferation,
repair reinforced with
TMJ disc chondrogenic induction,
TMJ-synovium 96
better maintenance of
derived
cell viability, and more
mesenchymal stem
extracellular matrix
cells (SDSCs)

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chitosan-alginate fibrocartilage tissue

98
scaffolds formation

Titanium
Titanium
coating
Chitosan Coatings Implants prevention of infection or
in dental
implants f
promote osseointegration

o
99,100,101

r o
Implant
Dentistry
Gene
carrier to
- p
promote
Plasmid DNA/c-myb
conjugated with
r
Implants e Promote volume and
density of newly formed 103
ossteinte
gration
chitosan-gold
nanoparticles
l P bone

n a
u r
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Figure 1. Carboxymethyl-chitosan polymer and calcium phosphate composite

na

crosslinking schematic [38].

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Figure 2. Schematic diagram of different biomaterials as injectable hydrogels, micro-

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nanoparticles, natural polymers and natural/synthetic scaffolds for periodontal disease treatment
[58].
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Figure 3. Nano and microparticles have the potential to deliver various biomolecules and drugs
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and act intracellularly or extracellularly depending on the particle size [61].
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Figure 4. Schematic representation of chitosan-phospholipid interaction and the self-assembly of SACPNs

[63].

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Figure 5. The schematic presentation of bone regeneration using the guided bone regeneration
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(GBR). Shows the barrier preventing the contact of “the dentogingival epithelium and gingival
approach [86].
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Figure 6. The hemostatic mechanism of MSN@CS-HCA [91].

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Figure 7 An injectable hydrogel used in dentistry application consisting of polylysine (ε-PL) and
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carboxymethyl chitosan (CMCS) [96].
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Figure 8. Intra-articular stem cell delivery with nano/microparticles for accelerating the
regeneration of damaged TMJ [98].

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