Drug Delivery NanoPlatforms For Oral and Dental Ap
Drug Delivery NanoPlatforms For Oral and Dental Ap
Drug Delivery NanoPlatforms For Oral and Dental Ap
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1. Introduction
The oral cavity and oropharynx are complex environments that are susceptible
to physical, chemical, and microbiological insults. They are also common sites For a long time, systemic administration
for pathological and cancerous changes. The effectiveness of conventional has been the most important route for
delivery of drugs for treating oral dis-
locally-administered medications against diseases affecting these oral milieus
eases. This pathway of drug administra-
may be compromised by constant salivary flow. For systemically-administered tion produces problems such as drug re-
medications, drug resistance and adverse side-effects are issues that need to sistance and dysbiosis, as well as adverse
be resolved. New strategies for drug delivery have been investigated over the side effects on tissues and organs unre-
last decade to overcome these obstacles. Synthesis of nanoparticle-containing lated to the targeted tissue. Because of these
catches, much effort has been devoted to
agents that promote healing represents a quantum leap in ensuring safe,
the development of more effective local-
efficient drug delivery to the affected tissues. Micro/nanoencapsulants with ized drug delivery strategies.[1] The most
unique structures and properties function as more favorable drug-release significant advantages of using drug carri-
platforms than conventional treatment approaches. The present review ers are the possibility to control and target
provides an overview of newly-developed nanocarriers and discusses their drug release, improve pharmacokinetics,
potential applications and limitations in various fields of dentistry and oral increase drug bioavailability and selectivity,
and thence, treatment effectiveness.[2,3] The
medicine.
use of drug carriers also improves the safety
of administration and limits the interaction
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Figure 1. Schematic of nanoscopical drug delivery systems employed in dentistry and for treatment of oral cancer.
2. Antibiotic Delivery
Eradication of microbial biofilms is a major area of concern in
the field of oral health. Bacterial biofilms are derived from a con-
sortium of bacterial clusters that produce an extracellular matrix
known as extracellular polymeric substance (EPS) around indi-
vidual cells. The EPS consists of different proteins and polysac-
charides which provide binding sites. The microenvironment Figure 2. The antibacterial mechanisms of antibiotics are broadly classi-
created by the EPS enables the bacteria to stick to one another and fied into: inhibition or regulation of enzymes involved in cell wall synthe-
adhere to biological or non-biological surfaces. Drug tolerance sis, interference with nucleic acid metabolism, inhibition of protein syn-
of dental biofilms increases when they mature. Some bacteria thesis, and disruption of bacterial cell membrane structure. Reproduced
such as Streptococcus mutans and lactobacilli also create an acidic with permission.[16] Copyright 2017, CMB Association.
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Figure 3. A) Top and bottom right: Schematic of an adhesive nanoparticle-hydrogel (NP-gel) hybrid system for localized antibiotic release to inhibit
bacterial growth under flow conditions. Bottom left: Photographs of freshly prepared and lyophilized samples; a scanning electron microscope image of
the lyophilized sample is included (bar = 1 µm). B) The release profile of ciprofloxacin (Cipro) from NP-gel, in which Cipro was loaded into the embedded
nanoparticles (left panel). Quantification of bacterial load of the Escherichia coli biofilm samples (right panel). C) Photographs of E. coli biofilms after
treatment with phosphate-buffered saline (PBS), blank gel (without nanoparticles or Cipro), free Cipro, Cipro-loaded nanoparticles ((NP(Cipro), without
hydrogel), and Cipro-loaded NP−gel (NP−gel(Cipro)). Reproduced with permission.[18] Copyright 2016, American Chemical Society.
dental applications. Whereas active antibiotics are mixed with eradicated. A novel antimicrobial strategy that takes advantage of
dental materials in conventional delivery methods, antimicrobial the existing shear forces in living organisms has been proposed
agents are immobilized on the micro- and nanomaterials for im- and investigated. Figure 3 shows the mechanism of action of a
proved stability, localized delivery, and sustained release.[17] nanoparticle-hydrogel hybrid system and its effective release of
The oral cavity is a complex environment in which shear forces antibiotics under shear stresses. Although tested on mouse skin,
are constantly present as a consequence of the action of the this drug delivery method represents a potential strategy for oral
tongue against the palate and the oral mucosa against the teeth. application because it did not introduce any toxic effect on the
The shear rate depends on the viscosity of the bolus and the tissue and was able to prevent bacterial biofilm formation.[18]
level of lubrication.[19] Changes in shear stress can influence the Infections have always been challenging in the surgical place-
characteristics of oral biofilms, such as their morphology, thick- ment of orthopedic and dental implants. One of the possible
ness, and diversity.[20] This, bacterial infections in areas with high reasons for dental implant failure is post-surgical osteomyelitis,
shear forces are challenging to be managed and difficult to be which invariably necessitates implant removal. Osteomyelitis,
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the infection of the bone, is caused mostly by three types of bacte- geotrichosis, and coccidioidomycosis. Among these, the most
ria, Staphylococcus, Enterobacteriacea, and Pseudomonas, in which common oral fungal infection is candidiasis, which is also the
S. aureus and S. epidermis are the main pathogens.[21–23] The ma- least hazardous. Candida infections may be identified by the ap-
jority of implant-related infections are caused by bacterial adhe- pearance of a white cottage cheese-like film (i.e., thrush) in the
sion, although biofilm formation at the implantation sites may oral cavity.[35] Hyperplastic candidiasis, known previously as can-
also trigger infection. One of the most effective steps in pre- dida leukoplakia, is the most widespread variant of candidiasis
venting implant-related infections is the inhibition of bacterial caused mostly by Candida albicans, and is manifested by the
adhesion.[24] Conventional treatment of osteomyelitis involves appearance of white patches on the commissures of the oral
antibiotic therapy and debridement of the infected tissues.[22,25,26] mucosa; if the lesions are untreated, a small portion of those
However, systemic antibiotic delivery is associated with increas- lesions may undergo dysplasia and develop carcinoma.[36] The
ing renal and liver toxicity due to ineffective penetration of the an- second most common fungal infection is aspergillosis caused by
tibiotics into the cells and excessive antibiotic intake.[24,27] Thus, Aspergillus species such as A. fumigatus and A. flavus.[37] Deaths
targeted release of antibiotics directly to the infected tissues is from invasive aspergillosis have significantly increased.[38] This
more desirable than conventional treatment. type of fungal infection may spread from the primary oral mu-
Treatment of osteomyelitis with targeted antibacterial deliv- cosa infection site to the maxillary sinus.[39]
ery is a novel therapeutic method that increases the amount Different antifungal drugs have been used to combat the
of antibiotics delivered to the infected sites without causing aforementioned infection, the best-known examples being the
systemic toxicity. Drug-loaded calcium phosphate-based coat- azole class of drugs such as clotrimazole, miconazole, econa-
ings (e.g., hydroxyapatite) have been experimentally investigated zole, oxiconazole, tioconazole, and sertaconazole. The mech-
for the treatment of osteomyelitis. Hydroxyapatite is biocom- anism of action of azole antifungals is summarized in Fig-
patible, non-toxic, non-immunogenic, and possesses relatively ure 5. Azoles inhibit C-14 𝛼-demethylase (a cytochrome P450
potent antibacterial activity as well as bioactivity toward bone enzyme) and block the demethylation of lanosterol to ergos-
regeneration.[28–30] Hydroxyapatite has high adsorption capac- terol, the principal sterol of fungal membranes. Disruption of
ity because its positively-charged surface interacts with depro- the fungal membrane structure and function inhibits fungal cell
tonated carboxyl groups and other negatively-charged groups growth. However, the hydrophobic nature of these azole anti-
present in the antibiotic molecules.[31] fungal drugs render them sparingly water-soluble, resulting in
Hydroxyapatite coatings loaded with antibiotics are used as poor oral bioavailability.[40–42] There are two additional drawbacks
bone implant coatings to prevent bacterial adhesion. A tech- that hinder the clinical applications of these antifungal agents:
nique was used to coat titanium implants by a single-stage toxicity and drug-drug interactions.[43] For example, although
electrophoretically-driven deposition of hydroxyapatite nanopar- amphotericin-B is a potent antifungal drug, its use may cause
ticles loaded with antibiotics (Figure 4A). In this approach, pris- infusion-related reactions and nephrotoxicity. In addition, the si-
tine hydroxyapatite nanoparticles are loaded with gentamicin multaneous use of amphotericin-B with other drugs such as cy-
sulfate or ciprofloxacin, followed by single-step electrophoretic closporine and aminoglycosides increases its nephrotoxicity.[44]
deposition to create osteoconductive and antibacterial-coated This example illustrates the need for the design and creation of
nanoparticles that are capable of sustained release of the two an- efficient drug delivery platforms.
tibiotics. A bioactivity study was performed on a commercially Some of the obstacles of antifungal drug delivery have been
available dental titanium implant coated with gentamicin sulfate- overcome by the introduction of drug delivery nanoparticles. For
hydroxyapatite using scanning electron microscopy (Figure 4B). example, lipid-based formulations of amphotericin-B consisting
According to the microscopy images, the nanoparticle coating of amphotericin-B lipid complex, amphotericin-B colloidal dis-
covered the titanium implant homogenously. Microscopy images persion, and liposomal amphotericin-B demonstrate significant
of the coated implants after 4 weeks of immersion in simulated reductions in amphotericin-B-induced nephrotoxicity without
body fluid at 37 °C showed excellent retention of the hydroxyap- compromising their antifungal activities.[45] Many novel drug de-
atite coating by the titanium implant (Figure 4B). Examination livery nanocarriers have since been introduced. These nanopar-
of the kinetics of antibiotic release as a function of time (Fig- ticles may be categorized into different classes based on their
ure 4C,D) indicated a burst release profile for the two antibiotics composition: phospholipid vesicles, non-phospholipid vesicles,
during the first day and a slower sustained release profile that polymeric nanoparticles, polymeric micelles, solid lipid nanopar-
continued for 10 days for ciprofloxacin and 25 days for gentam- ticles, nanostructured lipid carriers, nanoemulsions, and den-
icin sulfate.[32] drimers. The most practical class of nanocarriers is the phospho-
lipid vesicles, which include liposomes, deformable liposomes,
3. Antifungal Delivery ethosomes, transfersomes, and transethosomes.[46]
Denture stomatitis caused by C. albicans frequently occurs in
Human involvement with fungal diseases has escalated expo- patients wearing removable dentures. It is an erythematous in-
nentially in recent years. Fungal infections can cause mortality flammatory disease that is accompanied by burning sensation,
in case of neglect, particularly for habitants in tropical countries unpleasant taste, and disturbance in masticatory function.[47–49]
where the weather plays a key role in fungal growth. The oral cav- Factors such as age, smoking, systemic diseases affect the sever-
ity, the genital organs, skin, hair, and nails are the most common ity of denture stomatitis.[50,51] Strategies to control denture stom-
sites for superficial fungal infections.[33,34] atitis include oral hygienic education,[52] phytotherapy,[53] as well
Oral fungal infections include candidiasis, mucormyco- as controlling the predisposing factors.[54] Denture adhesives
sis, histoplasmosis, blastomycosis, aspergillosis, cryptococcosis, are common materials used for enhancing the retention and
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Figure 4. A) Schematic of the synthesis and deposition of antibiotics-loaded hydroxyapatite (HAp) nanoparticles. B) Scanning electron microscopy
images of a dental implant surface coated with gentamicin-HAp nanoparticles I) before and II–IV) after 4 weeks of immersion in simulated body fluid at
37 °C. C,D) The release profile of gentamicin sulfate-loaded HAp (solid lines) and ciprofloxacin-loaded HAp (dashed lines). C) Total amount of antibiotic
release. D) Cumulative release percentages. Reproduced with permission.[32] Copyright 2017, Royal Society of Chemistry.
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Figure 5. The mechanism of action of azole group antifungal agents: 1) inhibition of the conversion of lanosterol to ergosterol, 2) inhibition of ergosterol
production, and 3) destabilization and disruption of the fungal cell membrane.
stability or removal of oral prostheses. They are commercialized compounds.[68,70] Because of its side effects such as headache,
in the form of creams, strips, powder, and cushion formulations nausea, liver disease, drug interaction, and the risk of drug re-
and can be included in mucoadhesive compositions.[55] Mucoad- sistance, it is necessary to utilize a suitable drug delivery system
hesion may be used to enhance antifungal activity by increas- for its dispensary.[69] Mucoadhesive nanoparticles have been syn-
ing the duration of drug release and bioavailability of antifungal thesized to deliver fluconazole.[71] Chitosan was used to coat the
formulations.[56–58] mucoadhesive nanoparticles to enhance their efficacy. Chitosan
Miconazole nitrate has been used extensively to treat superfi- possesses many desirable properties, including its biocompatibil-
cial mucosal candidiasis.[59] This antifungal agent is usually in- ity, non-toxic nature, antifungal property, mucoadhesive property
corporated in oral gel formulations. When applied to the oral via attachment to negatively-charged mucosal surfaces for exten-
mucosa, these formulations have short contact times with the in- sion of drug release duration.[72,73] In addition, the side effects
fected mucosa. This necessitates the use of high initial concentra- of fluconazole were reduced considerably. Improved bioavailabil-
tions of the antifungal agent. In addition, these formulations do ity of chitosan-coated nanoparticles has been demonstrated in in
not have sustained release properties and frequent applications vitro and in vivo experiments, with negligible manifestation of
are necessary.[60] Polymer-based microscopical and nanoscopical cytotoxicity.[71]
delivery platforms have been designed to address the aforemen-
tioned deficiencies.[61] 4. Antiviral Delivery
Different pH-sensitive, mucoadhesive polymer-based mi-
croparticles have been used to encapsulate miconazole nitrate. Antiviral drugs are active molecules used for treating viral
The pH-sensitive microparticles release their cargo in a pro- infections.[74] Although most of these agents are designed to tar-
longed manner (Figure 6). The composition is capable of improv- get specific viruses, it is still possible to find drugs that are effec-
ing the solubility of miconazole nitrate, with potent antifungal tive against a wide range of viruses.[75] The mechanism of antivi-
activities.[59,62,63] Other antifungal drugs such as chlorhexidine ral drugs is presented in Figure 7.
(CHX) and nystatin have also been incorporated in resilient den- Viral infections can involve the skin of the mouth as well as
ture liners to inhibit the growth of C. albicans.[64–66] These two the oral mucosa, an example of which is represented by oral her-
antifungal agents demonstrated good biocompatibility and neg- pes infection. Oral herpes is caused by human herpes simplex
ligible toxicity in vivo, rendering promising candidates for treat- virus 1 (HHV-1) and causes pain on the lips, tongue, and the
ment of denture stomatitis.[67] roof of the mouth.[76] Other human herpes infections include
Fluconazole is another antifungal agent that is used for site- the HHV-2 virus that causes genital herpes, the HHV-3 virus
specific treatment of infections caused by C. albicans.[68,69] It is that causes chickenpox and herpes zoster, the HHV-4 (Epstein-
a synthetic antifungal agent derived from the group of triazole Barr) and HSV-5 (cytomegalovirus) viruses that cause infectious
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Figure 6. Antifungal delivery systems for treatment of oral candidiasis. A) Miconazole nitrate-encapsulated liposome and hydrogel. B) Modified denture
materials with prolonged miconazole nitrate release.
Figure 7. Schematic of the mechanisms of antiviral drugs. Reproduced with permission.[78] Copyright 2018, ISFCP.
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mononucleosis, the HHV-6 and HHV-7 viruses that cause rose- manner that helps to maintain an optimized concentration of
ola (a viral disease causing high fever and a skin rash in small the ions and exert their protective effect over a longer period of
children), and the HHV-8 virus that causes Kaposi’s sarcoma in time. In this context, nanoparticulate carriers are more effective
people with acquired immunity deficiency syndrome.[77] To date, than microparticulate carriers. In a recent study, NaF/chitosan
systemic administration of antiviral drugs is still the most com- microparticles were prepared by spray-drying in the presence of
mon strategy for treating oral virus infections.[77] Very few local glutaraldehyde as cross-linker. The microparticles demonstrated
administration strategies are available in the literature and top- continuous release of fluoride ions up to 360 min at pH 4 and pH
ical administration of antiviral agents, such as creams for labial 7.[80] Fluoride ion-containing ethylcellulose and gelatin micropar-
herpes, is the only class of local drug delivery strategy available ticles with different sources of NaF, monofluorophosphate, and
commercially.[1] aminofluoride were prepared by hardening emulsion and spray-
The use of nanoparticles for the delivery of antiviral drugs is an drying methods; the in vitro results reported sustained release of
exciting field of research.[75] Nanoparticles can tune the release the fluoride ions over a period of 8 h. Such a strategy presents a
kinetics of antiviral drugs, increase their bioavailability, control potential tool for the delivery of fluoride ions to dentin.[86,87]
their dissolution rates, reduce their side effects, and lower the The use of nanoparticles is a more efficient delivery ap-
cost of treatment. Adoption of nanoparticle delivery platforms proach than the use of larger-sized particles because of the
provides the possibility of targeting specific biological sites either higher surface-to-volume ratio of nanoparticles. Calcium fluo-
passively or actively.[74] ride nanoparticles are 20 times more effective than traditional
glass ionomer cement on remineralizing dentin.[88] The anti-
cariogenic effect of CaF nanoparticles on S. mutants biofilms has
5. Ion Delivery been reported.[89] In an in vitro study, chitosan/fluoride nanopar-
ticles were prepared in the presence of sodium tripolyphosphate
Carbohydrate fermentation by S. mutants and S. sobrinus bacte- as a cross-linking agent, with sustained release of fluoride ions
ria produce organic acids. The increased acidity triggers the re- from the nanoparticles. Fluoride release from the nanoparticles
lease of calcium and phosphate ions from enamel and mineral- was increased in an acidic pH. The results suggest that these
ized dentin. This demineralization process is counteracted by the nanoparticles are capable of releasing fluoride ions in an acidic
activity of saliva, which contains bicarbonate ions for buffering environment and expedite hard tissue remineralization.[90] Cal-
the acidic changes and restoring the oral environment of normal cium fluoride and lignocaine nanoparticles have been loaded in
pH value, as well as mineral ions that replenish the demineral- thiolated chitosan bioadhesive films for prolonged release of flu-
ized tooth surfaces with calcium and phosphate ions (reminer- oride ions over 8 h.[85] Recently, NaF nanoparticles have been pre-
alization). If this dynamic physiological balance is shifted such pared in the presence of surfactant and loaded on a polylactic acid
that the rate of demineralization is higher than that of reminer- nanoscaffold using electrospinning for delivery of fluoride ions
alization, it will result in dental caries with consequential enamel to dentin (Figure 8A). The nanoparticles ranged between 80 and
dissolution.[79–81] Ion delivery in the form of calcium, phosphate, 110 nm with the polylactic acid scaffold (Figure 8B,C). Sustained
and fluoride to suppress demineralization in the oral environ- release of fluoride ions from the polylactic acid nanoscaffolds was
ment has been a major challenge for dental researchers for over observed, at a concentration of 5.0% mg mL−1 , up to 4 h.[91]
a century. The following sections deal with delivery of different Calcium and phosphate ions are depleted during bacterial
ions for dental applications. acid-induced hard tissue demineralization. Calcium phosphate
nanoparticles doped with fluoride ions have been shown to form
fluorapatite salts in water faster than undoped nanoparticles. In
5.1. Fluoride Delivery an in vitro dentin caries model, these nanoparticles can deliver
calcium and fluoride ions to occlude dentinal tubules.[92]
Fluoride is a mineral-source ion that prevents the growth One of the most practical applications of fluoride ions is their
of caries-related bacteria and further acidification of the oral incorporation in mouthwashes. In people with a high risk of
environment.[80,82,83] It has been shown that hard tissue dem- caries, these mouthwashes protect the teeth from acid demineral-
ineralization is reduced with increasing concentration of fluoride ization via the production of fluorapatite.[93] The use of fluoride-
ions present in the saliva.[84] By reacting with relatively more sol- containing mouthwashes enables demineralized tooth surfaces
uble hydroxyapatite, fluoride ions are incorporated in the hydrox- to be exposed intermittently to fluoride for long time periods
yapatite lattice structure to produce more acid-resistant fluorap- to inhibit dental caries. In another study, mouthwashes contain-
atite. Fluoride ions also interfere with the metabolism of organic ing different concentrations of chitosan nanoparticles were de-
acid-producing bacteria and prevent caries progression.[80,82,83] A signed for sustained release of fluoride ions. Addition of 40 µg
daily intake of 200 ppm of fluoride has been shown to prevent mL−1 chitosan to the mouthwash increased its viscosity and re-
dental caries.[85] To maintain the concentration of fluoride ions sulted in prolonged fluoride release to artificial salvia. The chi-
in the salvia, researchers have resorted to designing novel ion de- tosan nanoparticles had no interaction with the rosins utilized in
livery systems that offer sustained ion release. the mouthwash.[94] 𝛽-tricalcium phosphate nanoparticles func-
The use of microparticles and nanoparticles as delivering tionalized with fluoride has been shown to be more effective than
agents for fluoride ions have received much attention in recent the traditional fluoride ion solution in remineralizin dentin.[95]
years. The large surface-to-volume ratios of these particulates en- Bioactive glass (Bioglass) is a synthesized glass composition
able them to increase the amount of loaded ions. These particu- with controlled degradation that has demonstrated successful re-
lates also possess the ability to release fluoride ions in a controlled sults in bone and tooth tissue engineering.[96] In a pilot study, the
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Figure 8. A) Synthesis of NaF nanoparticles followed by their loading into a polylactic acid scaffold via electrospinning. B) Scanning electron microscopy,
and C) transmission electron microscopy images of the prepared NaF nanoparticles. D) Cumulative fluoride release from the polylactic acid scaffold
compared to NaF in both free and micelles at 37 °C, pH: 7.4. CMC: critical micelle concentration, NaF: sodium fluoride, PLA: polylactic acid. (B–D)
Reproduced with permission.[91] Copyright 2020, Springer Nature.
levels of fluoride ions in the gingival crevicular fluid and saliva tigated using nano silicate platelets in the presence or absence of
were significantly increased after 3 months of using fluoride- fluoride ions. Results of bone regeneration indicated that nanosil-
containing bioglass in human volunteers.[97] In a more thorough icate platelets doped with fluoride enhanced osteogenic cell dif-
study, the bioavailability of fluoride ions from F-containing bio- ferentiation compared with platelets that did not contain fluoride
glass was found to be equivalent to those present in high concen- ions.[104] In another study, the effect of low-level sodium fluo-
trations of sodium fluoride and amine fluoride.[98] ride on bone marrow mesenchymal stem cells was evaluated for
Layered double hydroxides (LDHs) are ionic layers with the extent of wound healing and stem cell differentiation into os-
positively-charged metal plates. The layered structure provides teoblasts after traumatic dental injury. The results indicated that
space for ion exchange and is used extensively in drug delivery 50 µm of sodium fluoride induced cell motility after 12 h stimu-
systems.[99–101] Positive metal plates are usually made up of M+2 lated osteoblast differentiation after 21 days.[105]
and M+3 cations, which can also be loaded with negative ions
such as fluoride ions. Fluoride-incorporated LDH structure can
be used as buccal mucoadhesive strips. An in vivo study con-
ducted on 8 human volunteers showed that these structures are 5.2. Ca and P Delivery
safe and efficient for prolonged release of fluoride ions to prevent
dental caries via an ion-exchange mechanism.[84] Calcium ions make up 99% of bone tissue. Administration
Another application of fluoride is its differentiating effect on of calcium carbonate, calcium lactate, or calcium gluconate
stem cells into bone and hard tissues. Previous studies have helps to prevent osteoporosis and bone loss. The bulk of the
shown that the effect of fluoride ions on stem cells is dose- minerals present in enamel is carbonated apatite, which com-
dependent.[102,103] The toxicity of fluoride ions and their effects prises 10 calcium ions and 6 phosphate ions.[106,107] Hydroxya-
on differentiation of human dental follicle stem cells were inves- patite, being biologically compatible, has been used in various
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Figure 9. Synthesis of PAA-ACP@MSN and its role in remineralization of demineralized enamel. PAA: polyacrylic acid, MSN: mesoporous silica, ACP:
amorphous calcium phosphate, WSLs: white spot lesions. Reproduced with permission.[121] Copyright 2020, Springer.
formulations as a biomimetic agent against dental caries[108] and porous silica (PAA-ACP@aMSN) has also been shown to in-
dentin hypersensitivity.[109] hibit tooth decay by preservation of the microhardness and min-
Calcium and phosphate-based ion delivery systems such as eral content of the remineralized enamel. The structure of PAA-
hydroxyapatite,[110] tricalcium phosphate,[95,111] and amorphous ACP@aMSN is illustrated in Figure 9.[121]
calcium phosphate (ACP) are promising agents for preven- Enamel contains long narrow nano-channels that facilitate
tion of dental caries by increasing saturation of these ions in ion infiltration. Nanofluidic transport of fluoride, potassium, cal-
the oral environment.[112–114] Polyamidoamine (PAMAM) den- cium, and sodium ions into these enamel nano-channels was in-
drimers are a group of hydrophilic polymers with an ethylene- duced by electrokinetic flow. Ion infiltration was confirmed using
diamine core and amidoamine branching structure that enable fluorescence and ion-selective electrodes. Briefly, two enamel rod
them to absorb calcium molecules.[115] PAMAM dendrimers ends were exposed to two reservoirs, one filled with a solution
loaded with calcium and phosphate ions and have been used ex- containing a fluorescence probe, and the other with pure ionic
perimentally to prevent tooth decay. The loaded PAMAM den- solution (Figure 10A). By applying an electric current, the ions
drimer was effective for prolonged release of calcium and phos- are transferred from the left reservoir into the right reservoir by
phate at low pH, with neutralization of the acidic environment infiltrating into the enamel non-channels.[122] In another study,
and inhibition of dental caries.[107] CPP-ACP nanocomplexes were coupled with stannous fluoride
ACP nanoparticles do not have sufficient stability in the oral to increase the stability of the nanocomplexes and ion release ef-
environment and are readily transformed into a crystalline form. ficiency for the treatment of dental caries (Figure 10B).[119]
This results in reduced bioavailability of calcium and phosphate
ions for remineralization of tooth enamel. Polyacrylic acid has
been used to increase the stability of ACP. Polyacrylic acid-ACP 5.3. Sr Delivery
was incorporated into mesoporous silica nanoparticles (MSNs)
via electrostatic interaction. The system demonstrated sustained Strontium (Sr2+ ) is a cation that stimulates the differentiation of
release of calcium and phosphate ions for remineralization of mesenchymal stem cells to develop into bone tissue by suppress-
collagen fibrils in demineralized dentin.[116] Casein phosphopep- ing the activity of osteoclasts as bone resorption cells.[124,125] In
tide (CPP) is a cluster protein similar to salvia-related stabilizing presence of Sr2+ , mesenchymal stem cells have been shown to
proteins. The phosphopeptide improves the bioavailability of cal- secrete bone-related markers.[126,127] Strontium acetate has the
cium and phosphate ions by increasing the stability of ACP. CPP- potential to occlude dentin tubules and also improve dentin me-
ACP has been shown to reduce tooth decay by releasing calcium chanical properties.[128] Strontium ranelate (SrRn; the binding of
and phosphate ions into the oral environment.[117] CPP-ACP two Sr2+ ions to ranelic acid) is a relatively novel anti-osteoporotic
has been used as an anti-cariogenic electroneutral nanocom- drug[129] that has been used for bone reconstruction.[130,131] The
plex to promote remineralization in many commercial products capacity of SrRn to replace calcium hydroxide and mineral triox-
such as toothpaste.[118–120] Apart from CPP-ACP, polyacrylic acid- ide aggregate as a pulp-capping agent to induce mineralization in
stabilized ACP incorporated into amine-functionalized meso- the dental pulp was investigated. The results indicate that SrRn
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Collagen sponges Sr2+ Produce spongious drug delivery systems Enhanced effect of Sr on degradation time [ 133]
bioactive glass structures of strontium-doped bioglass The presence of Sr leads to sustained drug
without using porogens release
SrBG is a promising drug delivery system for
dental tissue engineering
Mesoporous phosphate-based Sr2+ Synthesis of an effective drug delivery Enhanced effect of Sr on degradation time [ 134]
glass system using different Sr Sustained release of loaded drug for bone
concentration regeneration
10% (w/w) strontium acetate Sr2+ Dentin hypersensitivity Increased tubule occlusion for normal root dentin [ 128]
Abbreviations. DPSC: dental pulp stem cells, IL-1𝛽: interleukin-1 beta, IL-6: interleukin-6, TNF-𝛼: tumor necrosis factor-alpha, COX-2: cyclooxygenase-2, iDPSCs: inflamed
dental pulp stem cells, CaF2 : calcium fluoride.
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Figure 11. Release of Sr derived from SrRn into the cytoplasm of dental pulp cells stimulates osteogenic/odontogenic differentiation via the I3K/AKT
signaling cascade. SrRn: Strontium ranelate, PIP2: phosphatidylinositol biphosphate, PI3K: phosphoinositide 3-kinase, Akt: serine/threonine-protein
kinase B, mTOR: mammalian target of rapamycin.
scaffold, and bioactive cues in the form of growth factors or cy- ing of gelatin/methacrylate and a synthetic BMP-2-mimicking
tokines. Human dental pulp stem cells are a specific group of molecule. A short amino acid sequence derived from natural
mesenchymal stem cells harvested from the tooth pulp. They BMP-2 was synthesized in vitro. The purpose of using this
are multipotent and have the capacity to differentiate into bone, molecule was to accelerate the differentiation of encapsulated
teeth, blood vessels, adipose tissues, and neurons.[159] Regular re- MSCs within the printed structure into tooth-forming cells. Such
lease of growth factors is essential for the natural healing of tissue a system holds promise for dental tissue engineering.[168] Stro-
after injury. Direct injection of growth factors into a defect site mal cell-derived factor 1 𝛼 (SDF-1𝛼) is a chemokine that causes
has resulted in effective healing. However, the high cost associ- mesenchymal stem cells to migrate from specific stem cell niches
ated with the use of growth factors, structural limitations, and the to the site of injury.[169,170] An in vivo study demonstrated that
adverse effects of high doses have limited the direct use of these SDF-1𝛼 promoted differentiation of dental pulp stem cells, which
molecules for clinical studies.[160] To promote dental differenti- was followed by pulp regeneration.[171] The synergistic effect of
ation, growth factors delivered by specific vehicles may be used BMP-2 and SDF-1𝛼 on human stem cells from the apical papilla
to control the specific signaling pathway and gene expression of was demonstrated by incorporating the growth factor and the cy-
stem cells within a site of injury and stimulate them to differen- tokine into an injectable hydrogel and implanted into a necrotic
tiate into bone or dentin forming cells.[161] tooth. Hard tissue regeneration was confirmed in vivo.[172]
BMPs are a group of growth factors that are of particular im- Fibroblast growth factor (FGF) plays a hemostatic role in post-
portance in bone tissue engineering.[162,163] The effects of BMP- injury tissue repair and has been extensively studied in dental tis-
4[164] and BMP-9[165] on stem cell differentiation has been well sue engineering.[173,174] FGF8, a member of the paracrine-acting
reported in dental tissue engineering. BMP-2 has been shown FGF family, has been shown to orchestrate the migration, pro-
to induce bone/tooth differentiation.[159] The use of BMP-2 in liferation, and differentiation of dental pulp stem cells.[175] FGF8
dental implants has been reported to stimulate the migration has the potential to induce the earliest dental markers such as
of dental follicle stem cells.[166] Despite their highly-inductive Lhx6 and Lhx7.[176] Recently, it was reported that early delivery of
properties, growth factors are unstable at 37 °C with short exogenous FGF2 to dental pulp resulted in accelerated odonto-
shelf lives. Hence, it is necessary to utilize smart delivery sys- blast differentiation.[177]
tems to control their release and increase their effectiveness. Integrated regeneration of tooth tissue requires the creation
BMP-2 had been loaded into calcium silicate scaffold for sus- of an angiogenic network for the transfer of nutrients and oxy-
tained release to stimulation the induction of mesenchymal gen between cells and the removal of by-products. It has been
stem cells.[158] In another study, BMP-2 was loaded into a tita- shown that amplification of the Wnt signaling pathway leads to
nium structure with poly(lactic-co-glycolic) acid layers and used the vascularization of human dental pulp stem cells.[178] Vas-
in dental implants for controlled release of the growth factor.[167] cular endothelial growth factor (VEGF) is another growth fac-
A printable 3D hydrogel was prepared with a bio-ink consist- tor in which its differentiation and angiogenic properties have
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Figure 12. A) A drug-ion codelivery system consisting of mesoporous bioglass nanoparticles loaded with phenamil and Sr2+ ions activates the BMP-
2/SMAD signaling pathway and stimulates differentiation of dental pulp stem cells into odontoblasts. B) Alizarin red S staining to show the formation
of mineralized nodules in the cell culture plates. C) SMAD expression in the different experimental and control groups. BMP: bone morphogenetic
protein; Trb3: tribbles homolog 3; Smurf1: smad ubiquitin regulatory factor 1, DSPP: dentin sialophosphoprotein, DMP1: dentin matrix protein 1, OS:
osteoodontogenic, PNM: phenamil, Sr-PNM: Sr-doped phenamil, PCNA: proliferating cell nuclear antigen. Reproduced with permission.[135] Copyright
2017, Elsevier.
been extensively studied on dental pulp stem cells.[179,180] In an factor to stimulate angiogenesis.[181] The positive effect of the syn-
in vitro study, VEGF was loaded into a temperature-sensitive chi- ergistic use of BMP-2 and VEGF on the simultaneous effect of
tosan/glycerol phosphate hydrogel and its effect on dental pulp differentiation of dental pulp stem cells and angiogenesis has
stem cells was compared with the use of VEGF alone. The VEGF- been reported.[182] Controlled release of growth factor-encoding
loaded hydrogel was capable of controlled release of the growth plasmids (nanoplexes) instead of the use of free growth factors
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represent more efficient approaches. Nanoplexes consisting of canal infections. The effect of ciprofloxacin loaded with the
electrostatic interactions between phosphate in the plasmids and polymeric nanocarriers was evaluated against E. faecalis, as a
polyethyleneimine groups have been extensively studied in gene type of bacteria that is usually found in teeth with apical pe-
delivery systems.[183,184] Polyethyleneimine nanoplexes and plas- riodontitis that do not heal after root canal treatment. The an-
mids encoding BMP and FGF had been incorporated into a col- tibacterial and anti-biofilm capability of this nanosystem ren-
lagen scaffold for use as dental cement. Ex vivo results indicate ders it potentially useful for use as an interappointment intracal
that the aforementioned system can compete with mineral triox- medicament.[193]
ide aggregate in stimulating the differentiation of human dental Nanoparticle-based photosensitizers have been found to aug-
pulp stem cells in endodontics.[185] All these reports confirm the ment the antimicrobial effect of photodynamic therapy. In an
importance of using growth factor delivery system for tooth re- in vitro study, methylene blue dye-loaded poly(lactic-co-glycolic)
generation. acid nanoparticles were used in combination with photodynamic
Beyond pharmacological activity and studies on possible toxic therapy to eradicate E. faecalis biofilms, with improved bacte-
products derived from nanomaterials key importance should also rial phototoxicity.[194] Similarly, the use of chitosan functional-
be given to technological issues and in particular manufacturing ized with rose bengal stain resulted in significant elimination of
method, that up to now represents one of the main challenges biofilms with reduced cytotoxicity to fibroblasts.[195]
in nanoparticles translation to clinic.[186] Indeed scale-up from a Obturation of the root canal space with gutta-percha and a
few grams produced in the laboratory to several kilos on an in- sealer is intended for sealing of the debrided canal and pre-
dustrial setup is required. Therefore reproducible, easily scalable vent bacterial infection/re-infection of the periapical tissue.[196]
processes following the good manufacturing practice principles Attempts have been made to improve the antibacterial proper-
are important prerequisites.[187] Strongly connected to this is the ties of root canal sealers by incorporating different nanoparti-
thorough characterization of the final product. In the case of poly- cles, but without adversely affecting the mechanical properties
mer NPs, the therapeutic outcome is indeed related to the com- of the sealer. An interesting approach was proposed by syn-
plex interactions of composition and microstructure. Therefore, thesizing a sealer that contained propolis incorporated in poly-
it is essential to gain information about the physical characteriza- meric nanoparticles. The polymeric nanoparticles provided sus-
tion, the size distribution through dynamic light scattering, the tained propolis delivery without fluctuations in its rate of re-
surface zeta-potential, and the NP shape or morphology via mi- lease. The experimental sealer demonstrated cytotoxic properties
croscopy techniques. From this detailed analysis, few key param- that are comparable to a commercially available sealer, and pos-
eters should be considered as reporters for formulation efficacy, sesses antimicrobial activities against E. faecalis, S. mutans, and
in order to develop a robust quality control procedure necessary C. albicans.[197] Likewise, silver nanoparticles were incorporated
for NPs translation to clinics.[188] into dimethylaminohexadecyl methacrylate to create a root canal
sealer with good sealing, flow, and anti-biofilm properties.[198]
Good antibacterial properties have also been obtained by directly
7. Applications adding 2.5% dimethylaminohexadecyl methacrylate and 0.15%
Nanomaterials may be used in different dental specialties (Fig- silver nanoparticles into a commercially available epoxy resin-
ure 13). Some of these applications will be covered in the follow- based root canal sealer.[199]
ing sections. Root canal treatment is challenging because of the complex
anatomy of the root canal system and the difficulty involved in
complete destruction of biofilms from the canal walls. Accord-
7.1. Endodontics ingly, advanced techniques involving nanotechnology have been
developed to overcome the shortcomings of conventional proce-
The objective of root canal treatment is to eliminate microorgan- dures. The application of nanoparticles in the field of endodontics
isms and their by-products from the infected root canal system. has potential to eradicate persistent endodontic pathogens.
Achieving this goal involves cleaning and shaping of the canal
space to eradicate bacterial and fungal biofilms, disinfecting the
root canal system with antimicrobial and hard and soft tissue dis- 7.2. Restorative Dentistry
solving irrigants, and the placement of intracanal medicaments
and subsequently permanent plastic fillings to inhibit bacterial Dental caries is by far the most frequent reason for tooth loss and
re-growth and to prevent microleakage.[189] Nanoparticles have is caused by bacterial biofilm. After teeth brushing, the early col-
been introduced for advanced disinfection of the root canal sys- onizers that can be found on tooth surface are non-pathogenic
tem owing to their broad-spectrum antibacterial and anti-biofilm bacteria such as S. sanguinis and S. gordonii. However, poor oral
activities.[190] One of the frequently investigated nanoparticles hygiene and inadequate diet can cause dysbiosis and lead to the
in endodontics is chitosan nanoparticles because of their in- formation of pathogenic biofilm, within which S. mutans plays
trinsic antimicrobial properties and their capability to encapsu- an important role in production of glucan matrix, making the
late drugs/bioactive molecules.[191] Adherence of Enterococcus fae- biofilm a solid formation difficult to remove. The production of
calis to canal walls was significantly reduced when root canal acid within biofilms causes disruption of enamel integrity and,
dentin was treated with chitosan nanoparticles for root canal within time, leads to the formation of caries lesion.[200] Treatment
disinfection.[192] of dental caries involves removal of the infected carious tissue.
Chitosan has also been used as a coating for poly(lactic-co- This is followed by replacing the lost tissue with a metal, resin
glycolic) acid for the delivery of ciprofloxacin for treating root composite, or ceramic restoration that is bonded to the remaining
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Figure 13. Oral applications of nanomaterials. HA: hydroxyapatite, NACP: nano-sized amorphous calcium phosphate.
tooth structure using a dental adhesive system.[201] Currently, two However, the application of adhesives results in incomplete hy-
different strategies can be used on dentin tissue during resin bridization of the dentin substrate, leaving behind unprotected
bonding procedures: etch-and-rinse and self-etch technique. Re- collagen fibrils surrounded by water, that are prone to hydrolytic
gardless of the approach used, the application of adhesive sys- degradation by endogenous enzymes. Consequently, as a result
tem results in the formation of hybrid layer (HL) – a structure of degradation of the HL’s components, micro-cracks and sec-
that is composed of demineralized collagen fibrils reinforced by ondary caries can occur after tooth restoration.[202] Hence, it is
resin matrix. The key to successful and long-term bonding lies imperative to develop dental materials with antibacterial prop-
in the stability and integrity of collagen fibrils within the HL. erties that show good clinical results.[203,204] For this purpose,
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different nanoparticles with antibacterial and self-healing prop- 7.3. Oral Surgery and Implantology
erties have been incorporated into dental adhesive systems. One
of the approaches to reduce biofilm formation on restorations Dental implants are commonly used in dentistry to replace miss-
is to apply commercially available dentin adhesives that con- ing teeth, with a 90–95% success rate. Failure of dental implants
tain 10-methacryloyloxydodecylpyridinium bromide.[205] Newly occurs because of inaccurate planning, improper surgery, and
developed dental adhesives containing microcapsules, dimethy- prosthesis application, material failure, and lack of maintenance.
laminohexadecyl methacrylate, and ACP nanoparticles demon- Infection is the most serious complication among the reasons
strated optimal results in terms of phosphate ion recharge, for dental implant failure. The incidence of peri-implant mu-
protein-repellent, and antibacterial properties.[206,207] cositis and peri-implantitis infections characterized by bacterial
Similar results have been achieved by combining ACP accumulation on the implant surface is increasing dramatically.
nanoparticles with 2-methacryloxylethyl dodecyl methyl ammo- Hence, different strategies have been developed to enhance the
nium bromide,[208] as well as combining ACP nanoparticles with antibacterial effect of implants. One promising strategy for pro-
2-methacryloyloxyethyl phosphorylcholine[209] in dentin adhe- viding strong fixation and low failure of dental implants is sur-
sive systems. Experimental adhesive systems containing 50–80% face coating with nanoparticles to disrupt bacterial colonization,
(v/v) of nitrogen-doped titanium dioxide nanoparticles displayed so that osseointegration may be successfully induced in the ab-
satisfactory antibacterial properties against S. mutans biofilms sence of bacterial infection.[191,217,218]
which are responsible for secondary caries.[210] Attempts have Bone mineral density and bone formation were enhanced by
also been made to incorporate silver nanoparticles into com- embedding silver nanoparticles on the implant surface, with-
mercially available dentin adhesive systems. Addition of Ag NPs out causing damage to tissues surrounding the dental implants.
in concentrations of 250 ppm into an adhesive produced su- Furthermore, no toxicity to the viability and differentiation of
perior antibacterial results, with dentin bond strength that are bone marrow mesenchymal stem cells was observed with this
at par with commercial adhesive even after 6 months of water coating method.[219] Another study reported that implant coat-
storage.[211] ings consisting of silver nanoparticle-filled hydrogen titanate
Apart from adding nanoparticles to adhesive systems, re- (H2 Ti3 O7 ) nanotubes demonstrated more potent antibacterial
cent studies have also investigated the possibility of integrat- activity, stronger osteogenetic potential, and low toxicity for
ing nanoparticles into restorative materials. ACP nanoparticles stem cells.[220] Similarly, silver nanoparticle-doped Ti6 Al4 V alloy
with and without addition of dimethylaminohexadecyl methacry- surfaces exhibited significant antibacterial activity against Por-
late have been incorporated into resin composite materials. phyromonas gingivalis and Prevotella intermedia, with excellent
Their anti-bacterial effect, potential of remineralization, and me- biocompatibility.[221]
chanical properties were evaluated. The resin composite pos-
sessed mechanical properties that were similar to commercially
available composites. With respect to remineralization poten- 7.4. Prosthodontics and Orthodontics
tial, high levels of Ca and P were released over time. Incorpo-
ration of dimethylaminohexadecyl methacrylate into the ACP Prosthodontics is crucial for replacement of lost teeth, restora-
nanoparticle-containing composite did not impair its mechani- tion of oral function, and facial appearance. Treatment options
cal or remineralization properties; its incorporation significantly include removable partial or complete dentures, fixed tooth-
improved the anti-bacterial potential by reducing the number of supported or implant-supported prostheses. Nanoparticles have
bacteria and production of lactic acid.[212,213] gained attention in prosthodontics and have been incorporated
CHX, an antimicrobial agent used extensively in dentistry, can into ceramics, resins, and metals.[222] Polymethyl methacrylate
be successfully blended within adhesive systems.[214] The devel- (PMMA) is commonly used as denture base material because
opment of an adhesive with CHX-containing nanoparticles is of its esthetic properties, biocompatibility, lightweight, low-cost,
an interesting strategy for combating secondary caries in the and stability. On the other hand, PMMA-based dentures are eas-
future. ily colonized by bacterial and fungal biofilms and suffer from fre-
A nanocomposite indicated for restoring class V lesions (lo- quent fractures.[223] Several PMMA modification strategies have
cated in the root part of the tooth and in close contact with pe- been developed to overcome these drawbacks.
riodontal tissues) was synthesized with the addition of not only Nanoparticles have been used to enhance the surface hy-
ACP nanoparticles and dimethylaminohexadecyl methacrylate, drophobicity of PMMA-based dentures to provide antimicro-
but also silver nanopaticles and 2-methacryloyloxyethyl phospho- bial activity. Incorporation of silver nanoparticles into a den-
rylcholine. The goal of adding silver nanoparticles was to en- ture base acrylic resin was reported and it had no effect on
hance antimicrobial properties. 2-methacryloyloxyethyl phospho- the adherence of C. albicans and biofilm formation.[224] How-
rylcholine with protein-reliant characteristics was incorporated ever, it has been shown that silver nanoparticles had antifun-
with the intention of reducing bacterial adhesion to the implant gal activity and reduced C. albicans formation.[225,226] Incorpo-
surface. The new composite possessed potential antibacterial ration of poly(diallyldimethylammonium) chloride nanoparticles
effect against periodontitis-related pathogens, with satisfactory into PMMA produced antibacterial effect against E. coli, Staphy-
bond strength values.[215] Silver nanoparticles embedded within lococcus aureus, and C. albicans.[227] Similarly, PMMA denture
lactose-modified chitosan demonstrated reduced the formation acrylic containing platinum nanoparticles had a significant bac-
of mature S. mutans biofilms and such an ability was found to terial anti-adherent effect.[228]
be dependent on the concentration of silver nanoparticles within Improving the antibacterial capacity of fixed orthodontics ap-
the coating layer.[216] pliances has been crucial in dentistry to prevent development of
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white spot lesions, which is the most common side effect associ- on the defect site as new bone grows, and self-dissolving without
ated with placement of orthodontic brackets. An orthodontic ad- any toxic effects.
hesive incorporating curcumin-doped poly(lactic-co-glycolic acid) Polytetrafluoroethylene (PTFE) membranes for GTR are com-
nanoparticles was evaluated for its anti-biofilm efficacy against S. monly used because of its porous microstructure that allows
mutans biofilms. The effectiveness of the drug-loaded nanocarri- connective tissue ingrowth. Some studies reported that ePTFE
ers was confirmed and may be used as an antibacterial and anti- membranes provide superior regeneration of periodontal tissues
biofilm orthodontic adhesive.[229] after healing.[236] Antibiotics and metal/metallic oxide such as
silver, zinc, copper, and zinc oxide nanoparticles have been in-
corporated into the GTR membranes to improve periodontal
healing. Incorporation of metronidazole into polycaprolactone
7.5. Periodontics nanofiber membranes produced clear inhibition zones around
the GTR membranes.[237] In a study, electrospun composite
Periodontal disease is a common inflammatory disorder in- fibers prepared from mixing poly(DL-lactide-co-e-caprolactone)
duced predominantly by Gram-negative anaerobic bacteria such and poly(D,L-lactide) with gelatin were loaded with hydroxyap-
as P. gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella atite nanoparticles to enhance osteoconductive activity. Metron-
forsythia, and Treponema denticola. If left untreated, periodon- idazole was used to eliminate periodontal pathogens. This novel
tal diseases destroy the tissues surrounding and supporting the functionally-raded membrane possessed better potential to over-
tooth, eventually causing the loss of tissue, bone, and finally the come the disadvantages of currently available membranes.[238]
tooth. Treatment of periodontal diseases is crucial for the main- Poly(𝜖-caprolactone)–poly(ethylene glycol)–poly(𝜖-
tenance of oral and general health of the patient.[230] caprolactone) (PCL–PEG–PCL) is linear triblock copolymer
The periodontal pocket provides a natural reservoir that is used for guided bone regeneration because of its biocom-
easily accessible to accommodate a dispensing device. Gingi- patibility and biodegradability. Nanohydroxyapatite had been
val crevicular fluid is an exudate discharged by the periodon- incorporated into electrospun PCL-PEG-PCL membranes. The
tal pocket that provides a medium for drug release and for its tensile strength decreased with increasing mineral content but
spreading to adjacent tissues. Intra-pocket drug delivery systems there was no adverse effect on the viability of osteoblasts. Devel-
have gained attention because of their superior features such as oping of a 3-layer scaffold that a chitosan/poly(lactic-co-glycolic
maintaining effective concentrations of antibiotics in the gingi- acid)/nano-sized bioactive glass layer loaded with cementum
val crevicular fluid for an extended time and causing more be- protein 1, a chitosan/poly(lactic-co-glycolic acid) layer loaded with
nign side effects. Several polymers have been investigated as FGF 2, and a chitosan/poly(lactic-co-glycolic acid)/nano-sized
drug carriers because of their biocompatibility, stability, non- bioactive glass layer loaded with platelet-rich plasma expedited
toxicity, and biodegradability.[231] Triclosan-loaded nanoparticles periodontal healing and new alveolar bone deposition.[239] A
prepared from poly(D,L-lactide-co-glycolide), poly(D,L-lactide), novel membrane consisting of CaP nanoparticles incorporated
and cellulose acetate phthalate have been used to develop a in a silk fibroin-PCL-PEG-PCL electrospun layer and a PCL
novel delivery system for the treatment of periodontal dis- membrane layer has been developed for guided bone regen-
ease. These triclosan-loaded nanoparticles behaved as a homoge- eration. The membrane demonstrated better cell adhesion
neous polymer matrix-type delivery system in reducing gingival and proliferation of dental pulp stem cells, with remarkable
inflammation.[232] improvement in tensile strength.[240]
Another method of intra-pocket delivery is films that Silk fibroin is another polymer frequently employed for guided
are formed by solvent-casting or direct milling. Solvent-cast bone regeneration. It has superior features such as biocompati-
poly(lactic-co-glycolic acid) films were used in a layer-by- bility, biodegradability, as well as oxygen and water vapor perme-
layer technique to develop a localized and controlled drug ability. Silver fibroin membranes were useful for guided bone re-
delivery system. This system exhibited antibacterial activity generation of several types of bone defects.[241] Nanofibrous silver
against P. gingivalis, with exhibiting in vitro biocompatibility.[233] fibroin membranes developed by electrospinning demonstrated
Polymeric PolymP-n Active nanoparticles combined with sil- better new bone regeneration, reduced inflammatory reaction,
ver and doxycycline exhibited enhanced antimicrobial activity and improved mechanical stability compared with unfilled con-
against Streptococcus oralis, Actinomyces naeslundii, Veillonella ventional collagen membranes.[242]
parvula, Fusobacterium nucleatum, P. gingivalis and Aggregatibacter
actinomycetemcomitans.[234]
Regenerative procedures such as guided tissue regeneration
(GTR) have taken advantage of the novel technologies based on 7.6. Regenerative Dental Medicine
tissue engineering. Bone grafting materials derived from biologi-
cal tissues or from synthetic origins are used to augment the alve- Several branches of dentistry have already combined regenerative
olar bone and maintain space for future implants. Biocompatible medicine with existing dental practices such as socket preserva-
materials have been investigated due to the drawbacks of osseous tion, scaffolds, dental implants, and PRGF (protein-rich growth
grafts, such as the need for a second surgery, limited availabil- factor) techniques. Scaffolds have a crucial role in regenerative
ity (autografts), disease transmission, high resorption risks (al- dental medicine. Many bone graft materials and substitutes are
lografts), antigenicity, and unpredictable results (xenografts).[235] composed of scaffolds. Studies have focused on finding the ideal
Biocompatible materials for grafting should have superior fea- scaffold type to facilitate growth, cell spreading, adhesion, and
tures such as being osteoconductive, sustaining the load applied differentiation of mesenchymal stem cells.[243]
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Ref.
[ 289]
[ 290]
[ 291]
[ 292]
[ 293]
scientists to apply low levels of these agents. Consequently, at-
tention has been directed toward the use of nanoparticles for
therapy.High internalization.
eficial for local delivery. The Cat-NPs release doxorubicin in
Remarks
species.High cytotoxicity
a prolonged-release manner and significantly reduce the half
release.
of cisplatin. Nanoparticles augment the efficacy of cisplatin
in apoptosis induction of oral cancer cells due to increased
internalization.[285] Nanoparticles not only enhance intracellular
accumulation of chemotherapeutic agents. They also provide a
platform for co-delivery of other anti-cancer agents. For exam-
Encapsulation efficacy
ple, curcumin is a phytochemical derived from rhizome of Cur-
11.8–28.3
cuma longa. Curcumin possesses potent high anti-cancer activ-
89.1
[%]
-
-
ity against oral cancer cells. This plant derived-natural product
can suppress epithelial-to-mesenchymal transition and prolifer-
ation (apoptosis) via affecting molecular pathways such as c-Met
and ERK.[286,287] Nanoemulsions have been used for co-delivery
of curcumin and 5-fluorouracil. The release of these anti-cancer
agents occurs at 4 days with higher release in acidic pH, similar to
Zeta potential
44.8
−50
and down-regulating Bcl-2, curcumin sensitizes oral cancer cells
-
-
to 5-fluorouracil chemotherapy. Nanoemulsions provide targeted
delivery and sustained-release that are of importance in promot-
ing anti-cancer activity of both curcumin and 5-fluorouracil.[288]
Table 2. Representative examples of the use of nanovehicles as agents for oral cancer therapy.
96.2–189.1
150
188
48
marizes the recent progress in using nanoaprticles for therapy
against oral cancer.
SCC-9 cells
SCC-9 cells
Oral mucositis is one of the most common side effects during
cells
In vitroEx vivo
In vitroIn vivo
greatest flaw is the transient presence in the oral cavity and, con-
In vitro
In vitro
In vitro
Chitosan nanoparticle
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promising results in treating induced oral mucositis in hamsters against degradation, elevate their internalization and enhance
were achieved using 250 µg kg−1 gold nanoparticles.[297] their efficiency in gene silencing. The potential of nanoparticles
in targeted delivery can be boosted using surface modification,
for example, by the use of hydroxyapatite. Such benefits have
7.9. Oral Medicine made nanoparticles an inevitable part of oral cancer therapy.
The increasing number of scientific papers that report the syn-
Oral ulcers (commonly known as canker sore or recurrent apht- thesis of different nanoparticles and their application in the den-
hous stomatitis) are generally painful lesions that affect oral cav- tal field is a clear indicator of how promising the obtained results
ity and have various etiologic factors. They are often associated are. In the future, it would be of great interest to conduct clini-
with infections, immune disorders, trauma, or neoplasms.[298] cal trials that would confirm the beneficial effect that nanopar-
The treatment of oral ulcers can be challenging and depends on ticles provide in treating pathological conditions affecting the
the etiologic factor, but in most cases consists of reducing or elim- oral cavity. Beyond the advantages listed above some challenges
inating the pain and preventing secondary infections. Promising must be solved in order to make feasible the translation to the
results in healing of radiation-induced oral ulcers in mice have clinic and subsequent commercialization. First, deeper investi-
been obtained by applying a combination of Aloe vera and sil- gations should be done on possible toxic effects of nanoparti-
ver nanoparticles on the affected sites.[299] In clinical trials involv- cles in order to improve their biocompatibility. Because of this
ing human subjects, a new therapeutic approach, that lies within many preclinical studies are needed, investigating the immune
the range of nanoparticles, was introduced by applying oromuco- system interactions and unanticipated toxicities. Second, their
adhesive films containing propolis extract. This drug delivery sys- target activity is a pivotal point, and improving the specificity
tem was able to prolong the duration of pain relief and enhance of functional nanoparticles-based formulation is essential. Then,
the healing processes.[300] the preservation of the pharmacological activity of nanoparticles
when binding with target should be maintained. In this frame-
8. Conclusion and Outlook work, nanodrug structure design and fabrication protocol are es-
sential, considering that many biological mechanisms related to
As the reader may have already perceived, the use of micro and nanoparticle effects on the human body are still largely unknown
nanosystems as drug delivery carriers is readily expanding in and because of this clinical efficacy studies are required. Last, the
dentistry and the oral health sector. In the future, more and facility of scale-up production, the control over critical design fea-
more products will be approved and be available on the mar- tures, and the final cost, are also extremely important and they
ket. Nanoparticles present exceptional features such as a tunable make a big difference between dental applications and other dis-
structure and intelligent properties such as bio-adhesive behavior eases where the cost factor is less important.
or stimuli-responsive ability. These properties may be harnessed
during drug formulation, particularly for treating diseases such
as antiviral therapy in which relatively few treatment techniques Acknowledgements
are available. This is for sure one of the main challenges ad-
dressed by today’s world of scientific research in this field. The P.M., U.J., M.D., and F.P. share the first authorship of this review article.
M.D. was supported by PON CCI 2014IT16M2OP005 from the Italian Min-
development of smart nanomaterials represents a pivotal point
istry of University and Research.
for many applications and various treatments such as gene and
peptide delivery; because the exceptional improvements can be
obtained working with precise and timely drug release. Internal
or external functionalization, the tuning of the core formulation Conflict of Interest
or the conjugation of the nanostructures with specific molecules The authors declare no conflict of interest.
enable to impose to the whole systems specific chemical or phys-
ical properties. In this direction, they represent good examples
of effective strategies to obtain precise features in terms of drug
release properties for these impending technologies.
Keywords
Oral cancer possesses high morbidity and mortality. A large antibacterial, antiviral, drug delivery, oral cancer, tissue regeneration
number of new cases are diagnosed with oral cancer annually. It
is beneficial to provide effective treatment. Conventional thera- Received: October 20, 2020
pies are no longer effective in oral cancer treatment because of Revised: December 12, 2020
the side effects of anti-cancer drugs and the emergence of a new Published online: February 5, 2021
phenomenon known as chemoresistance. Nanoparticles can pro-
mote the anti-tumor activity of chemotherapeutic agents via pro-
viding targeted delivery and enhancement of cellular uptake. The
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Pooyan Makvandi holds two Ph.D. degrees, one in polymer chemistry from the University of Mazan-
daran in Iran, and the second in biomaterials science and Eengineering from the University of Naples
Federico II, Italy. Currently, he works at the Center for MicroBioRobotics (CMBR), Istituto Italiano di
Tecnologia, Pisa, in Italy. His work focuses on smart materials, 3D printing, antimicrobial compounds,
and nanostructures for biomedical applications.
Adv. Sci. 2021, 8, 2004014 2004014 (27 of 28) © 2021 The Authors. Advanced Science published by Wiley-VCH GmbH
www.advancedsciencenews.com www.advancedscience.com
Franklin Tay received his Ph.D. from the University of Hong Kong in China and his endodontic training
from the Medical College of Georgia, USA. He is currently professor and chair of the Department of
Endodontics, College of Dental Medicine, Augusta University, Georgia, USA. His research interests
include biomineralization of collagen scaffolds antimicrobial sol-gel chemistry, mesoporous silica,
and endodontic materials. He is a fellow of the Academy of Dental Materials.
Adv. Sci. 2021, 8, 2004014 2004014 (28 of 28) © 2021 The Authors. Advanced Science published by Wiley-VCH GmbH