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Current applications of in dentistry: a review

Shaeesta Khaleelahmed Bhavikatti, MDS n Smiti Bhardwaj, BDS n M.L.V. Prabhuji, MDS

With the increasing demand for advances in diagnosis and treatment surface modifications. This review provides detailed insights about cur- modalities, nanotechnology is being considered as a groundbreaking rent developments in the field of dentistry, and discusses potential future and viable research subject. This technology, which deals with mat- uses of nanotechnology. ter in nanodimensions, has widened our views of poorly understood Submitted: February 4, 2013 health issues and provided novel means of diagnosis and treatment. Revised: July 1, 2013 Researchers in the field of dentistry have explored the potential of Accepted: August 13, 2013 nanoparticles in existing therapeutic modalities with moderate success. The key implementations in the field of dentistry include local Key words: nanotechnology, dentistry, diagnosis, drug delivery agents, restorative materials, bone graft materials, and implant delivery systems, bone grafts, dental implants

he term nanotechnology is derived Nanotechnology involves the develop- quantum dots, fullerenes, , and from the Greek word nanos, mean- ment of materials, devices, and systems nanocapsules. The top-down approach Ting dwarf. The Nobel Prize winning exhibiting properties that are different deals with the enhancement of existing physicist, Richard P. Feynman, during his from those found on a larger scale. In the materials, where the existing structures 1959 Plenty of Room at the Bottom speech nanodimension range of 1-100 nm, the are contracted and miniaturized into the to the American Physical Society, had lower limit is marked by the size of a hydro- nanorange with their molecules consecu- first projected this dimension of discover- gen atom (0.25 nm) and the upper limit tively rearranged to achieve the desired ies at a billionth meter scale.1 The term commences from a size where phenomena properties.8,9 Research in the medical nanotechnology was introduced by Norio different from larger structures start appear- sector is directed toward the develop- Taniguchi in 1974, when he referred to a ing. In layman’s terms, if a child’s marble is ment and application of nanodevices in “production technique to get extra high compared to a nanometer, a meter would the sphere of diagnostics, drug delivery, accuracy and ultra-fine dimensions.”2 appear as the earth’s diameter. and therapeutics. Later in 1986, K. Eric Drexler contributed This novel scale of technology has The diagnostic discipline emphasizes to its development by introducing the appealed to researchers of various fields the manufacture of new sensing devices, concept of molecular nanotechnology including medicine and dentistry. An and the nanotization of existing devices, in his 1986 publication, Engines of cre- overview of the general applications of to make them more compact and less ation: the coming era of nanotechnology.3 nanotechnology will provide a better invasive. This includes the development Applications in the field started in the understanding of the concept. However, of collection and analyzing platforms 1980s with the invention of the scanning this review will focus on the current for mass identification of diseases and tunneling microscopes and the discovery applications of nanotechnology in their associated markers. Various in vivo of carbon nanotubes and fullerenes.4-6 dentistry, and the novel materials and nanomeric diagnostic devices, which However, major initiatives began at the techniques that have been developed can be easily introduced into the human beginning of this century, thus ushering in using its principles for disease diagnosis, body, have been developed either de the era of nanotechnology. prevention, rehabilitation, and pulp/ novo or as design alterations of existing According to the National periodontal regeneration. devices. Once inside the vascular system, Nanotechnology Initiative, a United States subsequent directions can be provided to government research and development A brief insight into general the devices via specific surface targeting program, nanotechnology involves the developments molecules that can identify the required Current nanotechnological research falls tissue receptors. These proposed novelties …research and technological development under 2 approaches. The bottoms-up are being researched and tested for any at atomic, molecular, or macromolecular approach deals with the creation and secondary fallouts or disadvantages. A list levels, in the length scale of approximately development of new ‘intelligent’ materials of diagnostic devices in Table 1 provides 1-100 nanometer (nm) range, with cre- or devices, wherein various processes are a brief introduction to their functioning ation and use of structures, devices, and utilized to induce nanostructures to self- and application.10-13 systems that have novel properties and assemble at a desired scale and then orga- The in vitro systems act when a sample functions as a result of their small and/or nize into higher macroscale structures.8,9 tissue or fluid has been harvested from intermediate size; and ability to control or Various particles formulated at the the human system. The conventional manipulate matter on the atomic scale.7 nanoscale include nanorods, nanotubes, in vitro diagnostic aids, such as mass

72 July/August 2014 General Dentistry www.agd.org Table 1. A brief description of nanotechnological in vivo diagnostic devices.10-13 Table 2. Drug delivery devices.4,6 Nanodevices Functioning mechanism and applications 6 Special sensor These are nanorobots, which can be inserted through the skin into the blood Nanotubes • First described by Iijima in 1991 nanobots vessels, where they check blood contents and warn of an abnormal variation, such • Sheets of graphene that can be as hyperglycemia.10 rolled into hollow cylinders Quantum dots These are nanometer-sized semiconductor crystals that glow when illuminated Carbon • First described by Kroto et al in by ultraviolet light. Their linkage to against specific fullerenes 19854 enables sensitive detection of cancer cells.11 • Insoluble hollow spheres of Superparamagnetic These are multilayered polymeric shells with an iron oxide core. These shells carbon, also known as buckyballs iron oxide can carry contrast agents with different aqueous . Specific surface Magnetic • Dual core particles acting via nanoparticles anti-nucleosome antibodies help identify targeted tumor sites, where the nanoparticles thermal exchange coupling (SPIONs) compromised mechanisms of the tissues help in their retention and improved MRI imaging.12 • Can be coated with drug particles in a lipid layer Nanopunch This is a paramagnetic biopsy tool consisting of layered copper, nickel, silicon, and chromium, in the shape of a claw. With temperature change, the differing coef- Lipid • Biodegradable drug-filled lipid ficients of expansion cause the claw to open and close to collect the specimen. nanoparticles particles without an outer coating Once tissue is harvested from the site, the punch could be collected from the urine • Can penetrate stratum corneum sample by a magnetic trap.13

spectrometry (MS), have been modified place between the 2 layers, resulting in discussed, and implemented since ancient with the addition of nanomeric particles locally increased temperature which can times. However, there is a constant need on MS planar surfaces (nanotexturing).14 potentially destroy the cancer tissue. for improved tools and techniques. Relatively newer systems include nanopar- Apart from these particles, an innova- Nanotechnology, with its ever-increasing ticle bar codes and nanomechanical tion in existing drug delivery scope, provides dental research new oppo- cantilevers that employ the application of systems is being developed in the form of runities for progress. magnetic field and optical beam deflec- nanostructured lipid carriers. These physi- Biofilms are considered the root cause tion, respectively, in order to interpret ological lipid nanospheres are biodegrad- of most dental and periodontal diseases. biomolecular interactions.15 able, and exhibit both reduced Specific pathogenic microorganisms have Currently, various nanoparticles suit- and increased penetrability. They improve been associated with the development of able for drug and gene delivery are being the shelf life of photosensitive compounds dental caries and plaque-induced peri- designed and tested for safety, control, and by enhancing their chemical stability.19,20 odontal . Technology employ- appropriate use. Drug delivery systems The inclusion of nanospheres encapsulat- ing nanosized quantum dots based on are therapeutic arrangements that can ing local anesthetic agents within carrier immunofluorescence enables the labelling control the release of and deliver the vehicles could help direct the drug to the of specific bacteria, which eases their optimally (Table 2). One such desired delivery site and prolong its effect, identification and removal. This technique agent, nanotubes, are open-ended barrels thereby reducing its toxicity.21,22 The afore- provides excellent single cell resolution for that can carry minute quantities of drugs mentioned systems are only a few of the both in vivo and in vitro labeling of peri- within their 50-100 nm wide drug cell. many currently being researched. odontal pathogens.23 The open ends of these tubes are covered The field of dentistry is receiving Apart from dental caries and plaque- with pH or thermosensitive caps, which unprecedented support from the bio- induced periodontal disorders, the oral break down upon reaching inflamed sites. technological sector, in the form of novel cavity is often afflicted by autoimmune Similarly, carbon fullerenes and innovations that include improvised diag- disorders and carcinomatous changes. polymeric nanoparticles can also be nostic aids and treatment devices. Current Highly sensitive diagnostic techniques formulated as drug delivery vehicles.16,17 dental research involves progressive involving better revelations of autoan- These carriers possess -modified ingress into the preventive, diagnostic, tibodies, dysplastic cells, and salivary surfaces, which enable drug delivery to reconstructive, regenerative, restorative, biomarkers are required for apt diagnosis specific target sites that are inaccessible and rehabilitative domains (Chart). and early treatment. Cost-effecive tech- to carrier-free drugs.17 Recently, 2-layered nological advancements on this front will iron oxide magnetic nanoparticles were Diagnostic dentistry help promote a widespread implementa- used in an animal study for cancer tissue Dental caries and periodontal disease tion of salivary diagnostics. The Oral destruction.18 After these nanoparticles are the most common maladies affect- Fluid Nano Sensor Test (OFNASET, are injected into tumors, and a magnetic ing the human race. Methods to prevent The Wong Lab, University of California, field is applied, exchange coupling takes and combat them have been devised, Los Angeles) is a highly sensitive,

www.agd.org General Dentistry July/August 2014 73 Microbiology Current applications of nanotechnology in dentistry

specific, portable, and automated Chart. Current applications of nanotechnology in dentistry. nanoelectromechanical system, which enables point-of-care detection of sali- vary proteomic biomarkers and nucleic Bone regeneration Disease diagnosis acids specific for oral cancer, including n-HAP composite bone graft scaffolds: Biocompatible Quantum dot-assisted detection of 4 mRNA biomarkers (SAT, ODZ, IL-8, with superior mechanical properties. periodontal pathogens. and IL-1β) and 2 proteomic biomarkers Nanocrystals of CaSO4: Particle size ranging from OFNASET: Point of care detection of (thioredoxin and IL-8).24 200-900 nm. Improve resistance to degradation. Last salivary biomarkers. longer (12-14 weeks).

Preventive dentistry Nanoceramic composite materials: CaPO4 + ZnO Disease prevention (antibacterial) carbon nanotubes (provide flexible and In the sphere of preventive plaque control Dentifrices containing nanosized measures, dentifrices and inert scaffold). CaCO3, HAP, or CAP crystals for form the most widely used products. caries prevention. Dentifrices can be incorporated with Restorative dentistry Mouthwashes containing specific agents that help prevent dental Nanofillers: Particle size ranging triclosan loaded nanoparticles caries, remineralize early carious lesions, from 0.005-0.01 µm. Decrease Nanotechnology and silver nanoparticles for and aid in desensitization of abraded teeth. polymerization shrinkage and in dentistry gingivitis prevention. Biomimetic The process of enamel remineralization thermal expansion. Increase CA-HAP nanocrystals for daily is governed by the local concentration of polishing ability, hardness, and use in implant care. apatite minerals. Nanosized calcium car- wear resistance of composite bonate particles or hydroxyapatite crystals restorative materials. are similar to the morphology and crystal Tissue regeneration structure of enamel.25 In a study of a test GTR membranes incorporated with dentifrice containing nanosized calcium Dental implants nCHAC/PLGA: Show improved flexibility, carbonate particles, Nakashima et al found Implant surface nanotextured with titanium. HAP , and osteoconductivity. 48.8% improvement on the remineraliza- or bisphosponates induce and promote celluar dif- Gene-activated matrix: Collagen scaf- tion of artifically produced subsurface ferentiation and proliferation. Silver nitrate modified fold with /plasmid nanoparticles implant surfaces exhibit antimicrobial properties. encoding for PDGF. enamel lesions.26 Dentifrices for dental hypersensitivity that incorporate nano- hydroxyapatite (n-HAP) or nanocarbonate Abbreviations: CaCO3, calcium carbonate; CA-HAP, calcium hydroxyapatite; CAP, carbonate apatite; CaSO4, calcium sulphate; GTR, guided tissue regeneration; HAP, hydroxyapatite; nCHAC/PLGA, nanocarbonated hydroxyapatite/ apatite (n-CAP) particles are currently collagen/polylactic-co-glycolic acid; NHAP, nanocrystalline hydroxyapatite; OFNASET, Oral Fluid Nano Sensor Test; being tested. n-CAP is similar to the inor- PDGF, platelet-derived growth factor; ZnO, zinc oxide. ganic component of teeth and is known to have a high and a more neutral pH. When compared to conventional agents, n-CAP has proven to be an effica- Apart from regular dental care, there shrinkage and thermal expansion, and cious short-term desensitizing dentifrice.27 has been nanotechnology research into enhance the polishing ability, hardness, Mouthwashes containing nanoparticles implant care and the prevention of peri- and wear resistance of composites.32,33 loaded with triclosan and silver nanopar- implant diseases. Mouthwashes containing The size of these particles range from ticles have demonstrated plaque control biomimetic carbonate-hydroxyapatite 0.005-0.01 µm. At this size, the optical potential. The colloidal suspensions of nanocrystals have been shown to pre- properties of the resin and the filler parti- triclosan nanoparticles have shown high serve the implant titanium oxide layer cles become a fraction of the wavelength of substantitvity due to the use of bioad- by protecting it against surface oxidative light. Consequently, these particles cease to hesive polymers in the system.28 This processes. These nanocrystals also reduce reflect back light, resulting in a more physi- technology is based on a polyanhydride implant surface roughness by depositing ologic color expression by the material. nanoparticulate platform, hydroxyapatite into the streaks present The bottoms-up approach is required for which ensures high mucoadhesive capac- on the titanium surface. This decrease in the production of nanofiller particles. Two ity for 8 hours, increased encapsulation surface roughness provides better preven- different types of nanofillers, nanomers capacity, a more homogenous particle size tion against plaque accumulation and peri- (5-75 nm) and nanoclusters (2-20 nm) (250 nm), and longer shelf life (2 years).29 implant pathologies.31 have been synthesized. Their incorporation This creates a controlled-release system into an existing resin matrix system has with bioadhesive properties due to the Restorative dentistry been shown to improve the optical and presence of a positively charged surfactant The incorporation of nanofiller particles polishing properties of microfill composites on the microparticle surface. This system in composite resins has given rise to a new and the strength of hybrid composites.32 can be incorporated into gels, , class of materials with improved properties An improvement has also been made and mouthwashes for the treatment and over micro- and macrofilled composites. to resin-modified glass ionomer cement prevention of periodontal diseases.30 Nanofillers reduce the polymerization (RMGIC) with the addition of nanosized

74 July/August 2014 General Dentistry www.agd.org fillers. This has been reported to improve from 200-900 nm, while the conventional to form a highly flexible, biocompatible, the polishability and esthetic properties of CaSO4 bone graft particle size ranges from osteoconductive, and biodegradable com- the RMGIC.34 The inclusion of nanofilled 30-40 µm. These nanoparticles are further posite membrane. When osteoblastic cells resins in posterior restorative GIC self- condensed into pellets of 425-1000 µm. were cultured on this membrane, they adhesive coatings has also demonstrated This nanotization of particles results in a showed a more positive response compared high hydrophilicity and protection against graft material which is more resistant to to a pure PLGA membrane.51 abrasive wear.35 The low viscosity of the degradation and lasts longer (12-14 weeks) coating provides an optimal seal and glaze than conventional CaSO4 (4-6 weeks). Tissue engineering to the GIC surface, which gives time for This rate of degradation matches the rate Recent events have generated research on the restoration to mature and increases of bone growth in the intrabony defects, new approaches to tissue engineering and its esthetic properties.35 Thus, it could resulting in better treatment outcomes.47 local gene delivery systems in periodontal be stated that these improvements in An antibacterial nanoceramic composite tissue regeneration. A gene-activated matrix filler technology can be used to develop material has recently been developed by (GAM) provides a platform to combine new resin-based dental restoratives with impregnating nanocalcium phosphate, these 2 techniques. GAM provides a struc- enhanced mechanical properties.36,37 walled carbon nanotubes, and zinc oxide tural template for therapeutic gene expres- (ZnO) nanoparticles into an alginate poly- sion and fills the defects for cell adhesion Regenerative dentistry mer matrix.48 Carbon nanotubes provide and proliferation, as well as the synthesis Bone grafting a strong, flexible, and inert scaffold on of extracellular matrix. A recent develop- Bone grafting has been the primary which cells could proliferate and deposit ment in this aspect is a GAM composed component of periodontal regenerative new bone, while the ZnO nanoparticles of chitosan/collagen scaffold acting as a dentistry since 1923, when Hegedus suc- provide the antibacterial properties. This 3-dimensional carrier, incorporated with cessfully attempted the use of extraoral material enhances HAP formation in chitosan/plasmid nanoparticles that encode autogenous bone in the oral cavity to bone defects.48 The use of nanoparticulate platelet-derived growth factor. This matrix treat advanced pyorrhea.38 Artificial bone bone grafts show promise in postextrac- demonstrated a sustained and steady release substitutes were concomittantly developed tion ridge preservation, intrabony defects of condensed plasmid DNA over 6 weeks, in order to avoid the drawbacks of second regeneration, root perforations, sinus-lift which resulted in a high in vitro prolif- site surgery and inconsistent graft quantity. procedures, implant dehiscence, and fenes- eration of cultured periodontal ligament Different alloplastic bone grafts are being tration corrections. fibroblasts, thus demonstrating potential developed with nanoscale particles. The Nanoparticles can also be designed— for periodontal tissue engineering.52 most popular ones to date are nanoHAP using ultrasonic assessment of the bone (n-HAP) bone grafts, which are available quality and structure—to simulate bone.49 Nerve regeneration in crystalline, chitosan-associated and tita- Current research is focused on generating Nanoparticles can also be applied to recon- nium-reinforced forms.39-41 These n-HAP nanoparticle composite and nanofiber struct damaged nerves, with self-aggregat- composite bone graft scaffolds are highly scaffolds to increase mechanical strength ing rod-like nanofibers called amphiphiles. biocompatible, have superior mechani- and support cell growth and differen- Aggregated amphiphiles may reach up to cal properties, and induce better cellular tiation in required osseous architectures. several micrometers in length and can be responses compared to ‘plain’ chitosan Genetic material delivery systems that will utilized in vivo to bridge tissue defects in scaffolds.42,43 A clinical study comparing encode for osteogenic growth factors are the spinal cord.53 This application holds the use of nanocrystalline HAP (NHAP) also being developed.50 huge potential in the oral surgical arena, vs open flap debridement (control) in such as the possible reconstruction of intrabony defects demonstrated clinically Guided tissue regeneration a damaged inferior alveolar nerve after significant outcomes in the NHAP group, The concept of guided tissue regeneration extensive oral surgical procedures. with a clinical attachment level gain of 3.6 (GTR) is being researched to replace earlier ± 1.6 mm vs the control group’s gain of 1.8 functional graded membranes with novel Pulp regeneration ± 1.2 mm.44 This indicated that the use of 3-layered membranes.51 The former system Nanotechnology has potential in the an NHAP paste significantly improved the included bilayered GTR membranes with region of dental pulp regeneration. The clinical outcome when compared to open a porous surface on one side (for cellular development of tissues to replace diseased flap debridement. ingrowth), and a smooth surface on the or damaged dental pulp can provide a Apart from HAP, the use of calcium opposite side (for cellular occlusion). A revolutionary alternative to pulp removal. sulphate (CaSO4) as a biodegradable novel system has come up with a 3-layered The α-melanocyte-stimulating hormone and osteoconductive bone substitute has GTR membrane composed of an inner- (α-MSH) is known to possess anti- 45,46 been utilized since 1892. As CaSO4 most layer made of 8% nanocarbonated inflammatory properties. Recently, it has degrades, calcium phosphate forms, which hydroxyapatite/collagen/polylactic-co- been suggested that nanofilms containing helps in the attachment of osteoblasts and glycolic acid (nCHAC/PLGA) porous α-MSH could help revitalize damaged new bone deposition. Nanosized crystals of membrane, a middle layer of 4% nCHAC/ teeth.54 Further research is needed to conventional CaSO4 bone grafts have now PLGA, and an outer layer of PLGA non- evaluate these proposed therapeutic and developed, with particulate sizes ranging porous membrane. These 3 layers combine regenerative approaches.

www.agd.org General Dentistry July/August 2014 75 Microbiology Current applications of nanotechnology in dentistry

Rehabilitative dentistry Each new technology brings forth its Bangalore, Karnataka, India, where The introduction of dental implants has share of specific advantages and disadvan- Dr. Bhardwaj is a postgraduate student, revolutionized the rehabilitative dental tages. Although nanotechnology is more and Dr. Prabhuji is a professor. procedures. Various implant surface mod- than a decade old, no ecologic or toxic ifications are now being tested to improve effects were reported before 2005.63,64 Disclaimer the bone-to-implant contact ratio, mimic Nanotoxicology is defined as a science The authors have no financial, economic, the cellular environment, and favor the that deals with the adverse effects of engi- commercial, and/or professional interests process of osseointegration.55 Surface neered nanodevices and nanostructures in related to topics presented in this article. characteristics determine the biocompat- living organisms.65 ibility and biointegration of implants by Techniques promising major break- References regulating their surface energy, composi- throughs in medical and dental sectors 1. Feynman RP. There’s plenty of room at the bottom. Eng 56 Sci. 1960;23:22-36. tion, roughness, and topography. A might also have a downside, and hence, 2. Taniguchi N. 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76 July/August 2014 General Dentistry www.agd.org Published with permission of the Academy of General Dentistry. © Copyright 2014 by the Academy of General Dentistry. All rights reserved. For printed and electronic reprints of this article for distribution, please contact [email protected].

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