Nanoparticles in dentistry

Abstract

Objective

Nanoparticles having a size from 1 to 100 nm are present in nature and are successfully used in many products of daily life. Nanoparticles are also embedded per se or as byproducts from milling processes of larger filler particles in many dental materials.

Methods and Results

Recently, possible adverse effects of nanoparticles have gained increased interest with the lungs being a main target organ. Exposure to nanoparticles in dentistry may occur in the dental laboratory, by processing gypsum type products or by grinding and polishing materials. In the dental practice virtually no exposure to nanoparticles occurs when handling unset materials. However, nanoparticles are produced by intraoral adjustment of set restorative materials through grinding/polishing regardless whether they contain nanoparticles or not. Nanoparticles may also be produced through wear of restorations or released from dental implants and they enter the environment when removing restorations. The risk for dental technicians is taken care of by legal regulations. Based on model worst case mass-based calculations, the exposure of dental practice personnel and patients to nanoparticles through intraoral grinding/polishing and wear is low to negligible. Accordingly, the additional risk due to nanoparticles exposure from present materials is considered to be low. However, more research is needed, especially on vulnerable groups (asthma or COPD). An assessment of risks for the environment is not possible due to the lack of data.

Significance

Measures to reduce exposure to nanoparticles include intraorally grinding/polishing using water coolants, proper sculpturing to reduce the need for grinding and sufficient ventilation of treatment areas.

Introduction

Nanotechnology is the application of scientific knowledge to manipulate and control matter predominantly in the nanoscale to make use of size- and structure-dependent properties and phenomena distinct from those associated with individual atoms or molecules, or extrapolation from larger sizes of the same material . Nanomedicine is the controlled use of nanotechnologies in healthcare leading to new pathways for diagnosis and treatment of human diseases .

Nanoparticles are present in nature and are used to a large extent in our daily life; e.g. in cosmetic products like sun screens (e.g. TiO 2 or ZnO particles used as UV filter) or in tooth pastes, here mainly titanium dioxide or silicates. But nanoparticles are also present in daily food, dietary supplements and sprays used for coating, cleaning and impregnation . They are able to improve e.g. the stability of food, its taste and consistency. Silicon dioxide, magnesium oxide or titanium dioxide are tested and licensed food additives in some countries .

In dentistry nanoparticles are playing an increasing role: they are intentionally embedded into products, e.g. to improve material properties of resin-based composites like polishability and gloss stability but also as components for tissue engineering scaffolds . Dental materials, which intentionally release nanoparticles are rather seldom, like scanning sprays for CAD/CAM or occlusion indicator foils. On the other side, nanoparticles can be byproducts from milling processes for fillers. As many dental materials like resin-based composites, cements, or impression materials contain such fillers, it is estimated that nanoparticles are present in about 3500 dental materials (Verband der Deutschen Dental-Industrie (VDDI)—Personal Communication, June 2017).

Use of nanotechnology has a great potential for daily life and worldwide research groups and national/international agencies are putting much effort into this new and highly promising technology (e.g. Refs. ). More recently, nanoparticles have also become a matter of public and scientific concern and national and international agencies are dealing with nanomaterials and their safety aspects; e.g. WHO, ISO , EU Commission , or the FDA . These activities are not only directed to better understand the biological actions of nanoparticles (scientific aspects) but also to control market access of products containing nanoparticles and thus ensuring an acceptable risk level (regulatory aspects). In doing so, it should be kept in mind that nanoparticles are widespread in nature, e.g. in high concentration on sand beaches, in desserts and after volcanic eruptions.

The aim of this brief survey is to provide basic information for the dental community on problems of nanoparticles, which then can be used for further discussions within the community and for patient communication. Cosmetic products like tooth pastes or dental instruments like air abrasion devices are not covered. For more detailed information on the whole field of health risk from nanoparticles the reader is referred to the literature . As this is a rapidly developing area, regular revision/reconsideration of this review is mandatory.

Definitions 1

1 In this review literal citations e.g. from ISO, EU and other documents are used without quotation marks in each case for better readability; respective references are provided.

In order to facilitate communication, definitions of the terms are needed. Unfortunately, as will be delineated below, generally accepted or legally binding definitions are often missing and it may happen that the same terms are used with different meanings . Here we concentrate on definitions from ISO , which had been developed for broad use and on those recommended by the EU , which had been developed for regulatory purposes being important for market access of dental products. The definition of the EU, however, is a recommendation and – according to the new EU Medical Device Regulation – a dynamic definition, which means that it can be changed, if new scientific information justifies it (see also below).

Nanoscale

According to ISO, the term nanoscale is defined as the length range approximately from 1 nm to 100 nm . In the EU definition the term “approximately” has been deleted, because it is not clearly defined as is needed for regulatory purposes. Although this definition seems to be rather arbitrary, especially concerning the upper limit, the above range is widely accepted . However, it should be kept in mind that particles in a slightly higher size range may also display typical nanoparticle properties.

Nanoparticles

Here, different definitions are used e.g. concerning the amount of dimensions of particles which are in the nanoscale range. According to the EU, nanoparticles have one or more external dimensions in the size range from 1 nm to 100 nm . More detailed definitions are provided by ISO . Here, nanoparticles are nano-objects with all external dimensions at the nanoscale, where the length of the longest and the shortest axes of the nano-object do not differ significantly. If the dimensions differ significantly (typically by more than 3 times), terms such as nanofibres, nanorods or nanoplates (see below) may be preferred to the term nanoparticle. Hence, according to ISO nanoparticles are a subgroup of nano-objects. Similar to the EU definition of a nanoparticle is the ISO definition for a nano-object: this is a discrete piece of material with one, two or three external dimensions in the nanoscale. The second and third external dimensions are orthogonal to the first dimension and to each other.

Nanofibres are nano-objects with two similar external dimensions in the nanoscale and the third dimension significantly larger. A nanofibre can be flexible or rigid. The two similar external dimensions are considered to differ in size by less than three times and the significantly larger external dimension is considered to differ from the other two by more than three times. The largest external dimension is not necessarily in the nanoscale. Nanorods are solid nanofibres; nanoplates are nano-objects with only one external dimension in the nanoscale .

Single nanoparticles, aggregates and agglomerates

Single particles are those, “which cannot be dissociated (de-agglomerated or de-aggregated) into smaller constituent particles under the dispersion conditions” . Nano-sized single particles may, however, readily form clusters. These can be subdivided into aggregates and agglomerates. Aggregates are particles comprising strongly bonded or fused particles where the resulting specific external surface area is significantly smaller than the sum of calculated surface areas of the individual components. The forces holding an aggregate together are strong forces, for example covalent bonds, or those resulting from sintering or complex physical entanglement. Aggregates are also termed “secondary particles” and the original source particles are termed “primary particles” . Agglomerates are collections of weakly bound particles or aggregates or mixtures of the two where the resulting external surface area is similar to the sum of the surface areas of the individual components. The forces holding agglomerates together are weak forces, for example van der Waals forces, or simple physical entanglement. Agglomerates are also termed secondary particles and the original source particles are termed primary particles .

In the EU recommendation for a nanomaterial definition the presence of aggregates, agglomerates and single particles determine the nanomaterial (see below) and no difference is made between the three conditions. However, from a biological point of view, the potential of single nanoparticles and agglomerates to cause particle related reactions is assumed to be more pronounced compared to aggregates, because the latter have a stable and considerably larger particle size (i.e. therefore a significantly smaller specific surface area) than the involved nanoparticles, as has been delineated above.

In the literature, the terms free, fixed and embedded nanoparticles are used . Unfortunately, no definitions have been provided in this document, but nanoparticles strongly bound to implant surfaces were named “fixed”, and those in cured materials (like in resin-based composites) are “embedded nanomaterials” (here in non-degradable materials). Nanoparticles in pastes (like uncured resins) were termed “free nanoparticles”. This will be discussed in more detail later.

Nanomaterials

Here, more basic differences in the definitions are apparent, especially between those from the EU and those from other organizations, like ISO. According to the definition for the EU, the term “nanomaterial” means a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm–100 nm. In specific cases and where warranted by concerns for the environment, health, safety or competitiveness the number size distribution threshold of 50% may be replaced by a threshold between 1 and 50% . This definition is also included into the new EU Medical Device Regulation . In short, nanomaterials are defined as containing nanoparticles. However, in article 3 it is stated that the definition may be changed according to new scientific evidence. In 2015 the EU definition thus has been challenged by a scientific committee installed by the EU stating amongst others that the definition makes it very difficult to prove that a material is not a nanomaterial. This could be addressed by adding an additional criterion .

According to ISO nanomaterials are materials with any external dimension in the nanoscale or having internal structure or surface structure in the nanoscale. This generic term is inclusive of nano-object and nanostructured material. In short, nanomaterials are nano-objects. The following terms for subgroups are often used:

  • Engineered nanomaterials: nanomaterials designed for a specific purpose or function,

  • Incidental nanomaterials are generated as an unintentional by-product of a process,

  • Manufactured nanomaterials are intentionally produced to have selected properties or composition.

In some documents like the Guidance on the Risk assessment of the Application of Nanoscience and Nanotechnologies in the Food and Food Chain from the European Food Safety Authority (EFSA) , only manufactured/processed nanomaterials are addressed. Furthermore, Health Canada also specially addresses manufactured nanomaterials when defining them from a regulatory point of view .

Dose metrics of nanoparticles: numbers or mass/volume

As common in chemical toxicology, for measuring nanoparticle exposure and for risk analysis/assessment the biological effective dose needs to be determined. For nanoparticles this presents a number of problems, because the biological effect is based not only on masses or concentrations – as in chemical toxicology – but also on the nanoparticle as such . One way is to take the (relative) number of nanoparticles (e.g. Ref. ) or the total surface of applied nanoparticles as dose. The other method is based on the mass or volume . While it is plausible that for biologic effects, which are based on the sole presence of a nanoparticle, the particle number is the appropriate dose, it must be considered that particle sizes and their distribution are difficult to measure . Therefore, although involved masses or volumes are small, there is also a tradition of mass being used for risk assessment e.g. for dust exposure . Furthermore, the only presently available limit values (for fine dust exposure) are given as mass values and this is why the present risk analysis used mass values. However, for the time being, no final decision both in the scientific and regulatory field has been taken, which dose metrics will be used .

Medical devices

This term had been introduced for regulatory purposes and is also used in the discussion on nanomaterials. Definitions worldwide vary, but basically it means “any instrument, apparatus, appliance, software, material or other article, … and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.” This means that all dental materials which have contact with the human body are medical devices. According to the EU definition of a nanomaterial, medical devices containing nanoparticles are nanomaterials. According to the ISO definitions, medical devices may contain or release nanomaterials.

Conclusions

A main problem when dealing with nanoparticles/materials is that generally accepted definitions are often lacking, which complicates communication. Especially when using the term “nanomaterial” caution is required, because there are essential differences in the use of this term, which may have severe implications e.g. concerning the allocation to risk groups and thus to market access. Furthermore, the conditions, in which nanoparticles occur should be taken into account, as single particles and agglomerates (loosely bound nanoparticles) may have different biological (and technical) properties as aggregates, which exhibit a much lower surface than the involved nanoparticles.

In following text for the sake of simplicity only the term nanoparticle will be used and the – ambivalent – term “nanomaterial” will be avoided. The term nanoparticle will be used as in the EU-document for particles with one or more dimensions in the range from 1 nm to 100 nm. Dental materials thus are materials (medical devices), which may contain such nanoparticles.

Definitions 1

1 In this review literal citations e.g. from ISO, EU and other documents are used without quotation marks in each case for better readability; respective references are provided.

In order to facilitate communication, definitions of the terms are needed. Unfortunately, as will be delineated below, generally accepted or legally binding definitions are often missing and it may happen that the same terms are used with different meanings . Here we concentrate on definitions from ISO , which had been developed for broad use and on those recommended by the EU , which had been developed for regulatory purposes being important for market access of dental products. The definition of the EU, however, is a recommendation and – according to the new EU Medical Device Regulation – a dynamic definition, which means that it can be changed, if new scientific information justifies it (see also below).

Nanoscale

According to ISO, the term nanoscale is defined as the length range approximately from 1 nm to 100 nm . In the EU definition the term “approximately” has been deleted, because it is not clearly defined as is needed for regulatory purposes. Although this definition seems to be rather arbitrary, especially concerning the upper limit, the above range is widely accepted . However, it should be kept in mind that particles in a slightly higher size range may also display typical nanoparticle properties.

Nanoparticles

Here, different definitions are used e.g. concerning the amount of dimensions of particles which are in the nanoscale range. According to the EU, nanoparticles have one or more external dimensions in the size range from 1 nm to 100 nm . More detailed definitions are provided by ISO . Here, nanoparticles are nano-objects with all external dimensions at the nanoscale, where the length of the longest and the shortest axes of the nano-object do not differ significantly. If the dimensions differ significantly (typically by more than 3 times), terms such as nanofibres, nanorods or nanoplates (see below) may be preferred to the term nanoparticle. Hence, according to ISO nanoparticles are a subgroup of nano-objects. Similar to the EU definition of a nanoparticle is the ISO definition for a nano-object: this is a discrete piece of material with one, two or three external dimensions in the nanoscale. The second and third external dimensions are orthogonal to the first dimension and to each other.

Nanofibres are nano-objects with two similar external dimensions in the nanoscale and the third dimension significantly larger. A nanofibre can be flexible or rigid. The two similar external dimensions are considered to differ in size by less than three times and the significantly larger external dimension is considered to differ from the other two by more than three times. The largest external dimension is not necessarily in the nanoscale. Nanorods are solid nanofibres; nanoplates are nano-objects with only one external dimension in the nanoscale .

Single nanoparticles, aggregates and agglomerates

Single particles are those, “which cannot be dissociated (de-agglomerated or de-aggregated) into smaller constituent particles under the dispersion conditions” . Nano-sized single particles may, however, readily form clusters. These can be subdivided into aggregates and agglomerates. Aggregates are particles comprising strongly bonded or fused particles where the resulting specific external surface area is significantly smaller than the sum of calculated surface areas of the individual components. The forces holding an aggregate together are strong forces, for example covalent bonds, or those resulting from sintering or complex physical entanglement. Aggregates are also termed “secondary particles” and the original source particles are termed “primary particles” . Agglomerates are collections of weakly bound particles or aggregates or mixtures of the two where the resulting external surface area is similar to the sum of the surface areas of the individual components. The forces holding agglomerates together are weak forces, for example van der Waals forces, or simple physical entanglement. Agglomerates are also termed secondary particles and the original source particles are termed primary particles .

In the EU recommendation for a nanomaterial definition the presence of aggregates, agglomerates and single particles determine the nanomaterial (see below) and no difference is made between the three conditions. However, from a biological point of view, the potential of single nanoparticles and agglomerates to cause particle related reactions is assumed to be more pronounced compared to aggregates, because the latter have a stable and considerably larger particle size (i.e. therefore a significantly smaller specific surface area) than the involved nanoparticles, as has been delineated above.

In the literature, the terms free, fixed and embedded nanoparticles are used . Unfortunately, no definitions have been provided in this document, but nanoparticles strongly bound to implant surfaces were named “fixed”, and those in cured materials (like in resin-based composites) are “embedded nanomaterials” (here in non-degradable materials). Nanoparticles in pastes (like uncured resins) were termed “free nanoparticles”. This will be discussed in more detail later.

Nanomaterials

Here, more basic differences in the definitions are apparent, especially between those from the EU and those from other organizations, like ISO. According to the definition for the EU, the term “nanomaterial” means a natural, incidental or manufactured material containing particles, in an unbound state or as an aggregate or as an agglomerate and where, for 50% or more of the particles in the number size distribution, one or more external dimensions is in the size range 1 nm–100 nm. In specific cases and where warranted by concerns for the environment, health, safety or competitiveness the number size distribution threshold of 50% may be replaced by a threshold between 1 and 50% . This definition is also included into the new EU Medical Device Regulation . In short, nanomaterials are defined as containing nanoparticles. However, in article 3 it is stated that the definition may be changed according to new scientific evidence. In 2015 the EU definition thus has been challenged by a scientific committee installed by the EU stating amongst others that the definition makes it very difficult to prove that a material is not a nanomaterial. This could be addressed by adding an additional criterion .

According to ISO nanomaterials are materials with any external dimension in the nanoscale or having internal structure or surface structure in the nanoscale. This generic term is inclusive of nano-object and nanostructured material. In short, nanomaterials are nano-objects. The following terms for subgroups are often used:

  • Engineered nanomaterials: nanomaterials designed for a specific purpose or function,

  • Incidental nanomaterials are generated as an unintentional by-product of a process,

  • Manufactured nanomaterials are intentionally produced to have selected properties or composition.

In some documents like the Guidance on the Risk assessment of the Application of Nanoscience and Nanotechnologies in the Food and Food Chain from the European Food Safety Authority (EFSA) , only manufactured/processed nanomaterials are addressed. Furthermore, Health Canada also specially addresses manufactured nanomaterials when defining them from a regulatory point of view .

Dose metrics of nanoparticles: numbers or mass/volume

As common in chemical toxicology, for measuring nanoparticle exposure and for risk analysis/assessment the biological effective dose needs to be determined. For nanoparticles this presents a number of problems, because the biological effect is based not only on masses or concentrations – as in chemical toxicology – but also on the nanoparticle as such . One way is to take the (relative) number of nanoparticles (e.g. Ref. ) or the total surface of applied nanoparticles as dose. The other method is based on the mass or volume . While it is plausible that for biologic effects, which are based on the sole presence of a nanoparticle, the particle number is the appropriate dose, it must be considered that particle sizes and their distribution are difficult to measure . Therefore, although involved masses or volumes are small, there is also a tradition of mass being used for risk assessment e.g. for dust exposure . Furthermore, the only presently available limit values (for fine dust exposure) are given as mass values and this is why the present risk analysis used mass values. However, for the time being, no final decision both in the scientific and regulatory field has been taken, which dose metrics will be used .

Medical devices

This term had been introduced for regulatory purposes and is also used in the discussion on nanomaterials. Definitions worldwide vary, but basically it means “any instrument, apparatus, appliance, software, material or other article, … and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.” This means that all dental materials which have contact with the human body are medical devices. According to the EU definition of a nanomaterial, medical devices containing nanoparticles are nanomaterials. According to the ISO definitions, medical devices may contain or release nanomaterials.

Conclusions

A main problem when dealing with nanoparticles/materials is that generally accepted definitions are often lacking, which complicates communication. Especially when using the term “nanomaterial” caution is required, because there are essential differences in the use of this term, which may have severe implications e.g. concerning the allocation to risk groups and thus to market access. Furthermore, the conditions, in which nanoparticles occur should be taken into account, as single particles and agglomerates (loosely bound nanoparticles) may have different biological (and technical) properties as aggregates, which exhibit a much lower surface than the involved nanoparticles.

In following text for the sake of simplicity only the term nanoparticle will be used and the – ambivalent – term “nanomaterial” will be avoided. The term nanoparticle will be used as in the EU-document for particles with one or more dimensions in the range from 1 nm to 100 nm. Dental materials thus are materials (medical devices), which may contain such nanoparticles.

Biological relevance of nanoparticles—why care?

Compared to bulk materials the surface area/volume ratio (volume specific surface area, VSSA) is highly increased in nanoparticles and therefore the elution/release of potentially toxic substances is enhanced compared to bulks of the same material. Such a release is for a given material dependent upon the size of the exposed surface and the physical and chemical stress/conditions. Biological effects are due to the nature and the amount of released substances, but also to released particles as such without any elution of potentially toxic substances. Of course, combinations of both mechanisms (via eluates and particles) are possible.

Passage/translocation of nanoparticles through intestines into the lymphatic system seems possible . It has been shown that nanoparticles can be transported to local lymph nodes. This has also even been shown for particles from dental implants surfaces . As a consequence of cellular uptake an upregulation of reactive oxygen species with consecutive DNA damage and an impaired DNA repair has been reported . Contamination of nanoparticles surfaces is possible, because they can be coated with all kinds of reactive chemicals including biological compounds such as endotoxins . The shape of nanoparticles is also likely to be an important factor although there is little definitive evidence . Fibers play a role especially for inhalation, where the physical parameters of thinness and length appear to determine respirability and inflammatory potential . Certain nanotubes show carcinogenic effects like asbestos fibers . Multi-walled carbon nanotubes are carcinogenic to the lungs of F344 rats . However, IARC (International Agency for Research on Cancer) , considered the evidence to be not strong enough to alter its evaluations (possibly carcinogenic to humans—Group 2B). An in-depth examination of the in vivo and in vitro studies affirmed those of the original evaluation on the inadequate or limited evidence of carcinogenicity for most types of carbon nanotubes and carbon nanofibers. Key evidence gaps need to be filled by further research .

Studies specifically dealing with harmful effects of nanoparticles are emerging in the literature , although comprehensive studies on defined nanoparticle exposure related to biological or clinical effects, the latter with sufficient statistical power, are still rare . Nanoparticles can be used as drug delivery system or for gene transfer. This is not covered here, because for the time being this application does not play an essential role in dentistry.

After inhalation of nanoparticles effects on lungs have been reported . Chronic inflammation, especially in patients with asthma or chronic obstructive pulmonary disease (COPD) were demonstrated. Large epidemiological studies in the United States have shown a statistical association between air concentration of the fine dust fraction PM(2.5) (particle diameter of 2.5 μm or less) in the general environment and increased risk of lung cancer . Whether this is of any relevance for dental personnel or for patients has to be studied in future investigations. Also cardiovascular diseases may be triggered by the exposure to nanoparticles through inhalation . Again, the relevance of these findings in dentistry is unknown. Nanoparticles in the air may increase allergic reactions in the atopic patients . The influence on the environment remains unclear. The relevance of BPA released from particles produced by removing resin-based composite fillings (with BPA) is also unclear. More details on the BPA release and on biological implications of nanoparticles in general can be found in the literature . Apparently, different nanoparticles exhibit largely different biological properties depending not only on the fact that they are nanoparticles or not but also due to a number of other factors like composition, morphology or contamination.

Nanoparticles in/from dental materials

A large number of dental materials (see above) intentionally or unintentionally contain nanoparticles. Here we concentrate on the important groups of resin based composite materials, cements, impression materials and implant materials.

Nanoparticles in set dental materials

Dental resin-based composites contain anorganic filler particles of different sizes, ranging from supra-micron, to sub-micron and nano-sized . To fill the space between larger filler particles, and thus to reduce the resin content of resin-based composites, nano-sized filler particles are added. As they contain both large and very small particles, these resin-based composites are called hybrid composites, or nano-hybrid composites. Only so-called nano-composites contain solely nano-sized particles, even though the filler particles are mostly clustered into larger secondary particles . The formerly used resin-based microfiller composites used solely nanoparticles aggregates.

Filler particles in resin-based composites may vary significantly in composition. In the past, restorative resin-based composites used to contain quartz particles (so-called ‘macro-filler’) . As quartz is not radio-opaque, resin-based composites used for restorative purposes contain today radio-opaque glass-filler particles with high atomic-mass elements, such as barium, zirconium, strontium or ytterbium. These amorphous particles are usually between 400 nm–1 μm, or even larger, but to optimize filler packing nano-sized particles are added. Typically, pyrogenic silica (SiO 2 ) is added, but also mixed oxides, such ZrO 2 –SiO 2 . Furthermore, nanoparticles are generated inadvertently during the milling process.

The filler particles in resin-based composites are embedded in the resin matrix. Moreover, manufacturers usually try to functionalize the particle surface with a silane coupling agent to chemically attach the particles to the methacrylate resin matrix.

Zinc phosphate cements contain ZnO or MgO (nano-)particles in the powder. Glass ionomer cements contain finely ground glass particles in the range of 4–25 μm (e.g. calcium and/or strontium and sodium fluorophospho alumino silicate), but during the milling process unintentionally also nanoparticles will be obtained and some products may contain also pyrogenic silica as nanofillers. Bioactive cements like hydraulic calcium silicate cements may contain powders e.g. from Portland cement, which primarily consists of tricalcium silicate, dicalcium silicate, tricalcium aluminate and tetracalcium aluminoferrite . For cements, nanoparticles may be added or included unintentionally as byproduct of the grinding process for the powder. The same is true for impression materials. They have a base of silicone or other polymerizing or otherwise setting materials, into which a variety of fillers, e.g. ZnO or TiO 2 are embedded to improve product rheology.

Nanoparticles in un-set dental materials

The above mentioned materials are delivered to the dentist in an un-set (plastic) state and are placed as such or after mixing into the mouth of the patient, where they harden (set).

Premixed

Most resin-based composites are delivered as premixed pastes, which are cured by light activation. The particle content is the same as for the set materials (see above). These yet un-set materials normally set in the oral environment within less than one minute depending on the manufacturer’s recommendation.

Paste/paste

These are e.g. resin-based composites, which are mixed and cured by chemical activation. Other examples are impression materials. These yet unset materials normally set in the oral environment within a maximum of 5 min.

Powder/liquid

These are e.g. cements (and also resin-based composite materials), where the powder is mixed with a liquid and which set by a chemical reaction. These yet unset materials normally set in the oral environment within a maximum of 5 min.

Nanoparticles on surfaces (implants)

Such nanoparticles are strongly bound to the surface of a material, typically an implant. The term “fixed” nanoparticles has also been used in the literature in this context. Nanoparticles on these surfaces are used for coating a medical device to prevent infection (e.g. silver nanoparticles) or to improve biocompatibility (e.g. apatite or Ti particles ).

Chemical nature of nanoparticles in dental materials

In summary, intentionally or non-intentionally incorporated nanoparticles into dental materials mainly have the following chemical nature:

  • SiO 2 , ZrO 2 –SiO 2 (e.g. resin-based composites),

  • Silicate glasses (in GIC and Composite resins) but particle size mainly >400 nm,

  • ZnO (e.g. cements),

  • Ag-nanoparticles (e.g. in some adhesives),

  • TiO 2 (e.g. tooth pastes, certain resin-based composites, impression materials or in scanning sprays for digital impressions),

  • Apatite and Ti nanoparticles (on dental implants) ,

  • Pigments, used as coloring agents in dental materials, also containing nanoparticles (e.g. in resin based composites). Typical coloring agents are: iron oxides (red, yellow, black), TiO 2 (white), and rare earth oxides (fluorescents). Ceramic materials contain pigments that are mixtures of different oxides.

Further to these incorporated substances, the following nanoparticles are generated by grinding/polishing or removing dental materials like resin based composites:

  • Nanoparticles of unknown composition arising from grinding resinous materials mainly through heat generation .

  • Nanoparticles containing the incorporated nanoparticles together with substances of unknown composition derived from the resinous matrix through heat generation .

Nanoparticles in/from dental materials—release and exposure

Release of nanoparticles, exposure and exposure calculation/estimation are the basis for any risk assessment. In the dental environment, potential exposure may occur in different places (laboratory or dental office) and under different circumstances (e.g. processing a variety of materials in the dental laboratory; placing, removing, wear and removal of restorations in the dental office). In the following the different places/circumstances are described separately.

Occupational exposure in the dental laboratory

Nanoparticles are released during processing, grinding and polishing of materials in the dental laboratory, e.g. in the context of processing powdered materials like gypsum or investment materials or grinding and polishing alloys, resins or ceramics. The route of exposure and the prime target are the lungs of dental laboratory personnel. It is well-known that – under adverse and old-fashioned technical conditions – dental technicians are prone to pneumoconiosis, a chronic lung condition marked by fibrosis and mixed restrictive-obstructive lung disease . However, the exposure to nanoparticles is – as far as we know today – is not known to induce increased rates of lung diseases, especially lung cancer to dental laboratory personnel. Special legal regulations for occupational safety are available for different countries (e.g. Refs. ). Therefore, this aspect is not further dealt with in detail in this review.

Occupational exposure in the dental office (dentist, dental auxiliaries)

Material application/unset materials

For premixed pastes (e.g. resin-based composite pastes) in the literature nanoparticles in such pastes were described as “free” nanoparticles and a high potential for systemic exposure was estimated. The term “free” might give the impression that nanoparticles can easily escape from the paste surface. However, the release and thus the availability of such nanoparticles from the unset paste during application have not been shown nor is it plausible. On the contrary, for improving filler compatibility with the resin matrix, filler surfaces are silane treated. This not only provides chemical bonds between fillers and the resin matrix, but it also improves the wettability of the filler by the resin matrix. Due to this good wettability of the filler particles are covered by the resin. In physical terms, the movement of particles in dental pastes is limited by a phenomenon called “capillary transverse pressure” . This pressure exits between liquids and opposing solid surfaces that are wetted by the liquid and where the solid surfaces are at a distance of some micrometers. The pressure is directed to keep opposing walls or particles in a liquid at an equilibrium distance. This distance depends on interfacial properties of the materials involved and on their size and shape. This means that above the equilibrium distance attractive forces exist and below the equilibrium distance repulsive forces exist. Calculations show that equilibrium distances and pressures between particles are the higher the smaller the particles are. It has also been shown that the capillary transverse pressure keeps wetted particles away from the surface of a paste like material. This means that nanoparticles in dental pastes are normally not available on the surface (Dermann K.—Personal Communication, March 2017). Also for paste/paste systems, release/availability of nanoparticles form the unset mix can be assumed to be the same as for premixed resin-based composites pastes.

For powder/liquid systems (e.g. dental cements or temporary materials) during dosing and mixing part of the powder may reach the air and may be inhaled by the dental personnel. For the mix itself, which is brought into the mouth of the patient, the same is true as for resin based materials. In summary, for mixing/applying unset materials, only the mixing of powder/liquid materials may lead to a short term exposure of dust from the powder to dental personnel, but not for the patient. However, for better handling a number of powder/liquid materials are delivered in capsules without any exposure for the dental personnel. Therefore, when handling premixed pastes, past/paste mixtures or powder/liquid mixtures, exposure is not likely or extremely low (see above). Actual data on release of nanoparticles from unset dental materials are, however, missing.

Set materials

Processing of set dental materials may generate nanoparticles: set materials are adjusted (occlusion, margins) by grinding and polishing. This mainly applies to direct restorations but also to indirect (ceramic and metal) restorations and with tungsten carbide or diamond grinding tools and polishing disks/points. More than two decades ago, Collard et al. showed that crystalline silica could be released upon abrading traditional quartz-containing resin-based composites, which are nowadays not used anymore for restorative purposes, due to their high surface roughness and lack of radio-opacity. More recently, Van Landuyt et al. reported that contemporary resin-based composites may also release high concentrations of respirable dust (<5 μm) . The in-vitro part of the study was performed in an enclosed box, in which the released particles were collected. In such an environment with a small volume, it was logical that high concentrations of respirable dust were observed, and all tested resin-based composites (both conventional hybrid composites, nano-hybrid composites and a nano-composite) resulted under these conditions in concentrations above 3 mg/m 3 (after measuring for 10 min). In a clinical setting, peak concentrations of respirable dust could be observed each time the dentist was finishing or polishing the restoration. Transmission electron microscopy revealed that resin-based composite dust varied significantly in size: coarse dust (particle size up to 10 μm), fine dust (up to 5 μm), super-fine dust (up to 3 μm) und nanoparticles (<100 nm). These studies were performed under dry conditions in order to avoid artefacts by water droplets.

Whereas the large particles never become airborne, it was observed in a further investigation that the airborne fraction of composite dust is mainly nano-sized. To investigate the airborne fraction of composite dust in more detail in vitro and in vivo, sophisticated equipment was used . For the in-vitro part, a scanning mobility particle sizer was used to evaluate the released particle number size distributions. Surprisingly, the airborne fraction consisted mainly of particles in the nano-range. The mean diameter of the particles varied between 38 and 70 nm and concentrations typically were above 10 6 #/cm 3 . The dust particles had a high tendency to agglomerate. These experiments corroborated the in-vivo experiments, this time carried out with a miniature diffusion size classifier (MiniDiSC, University of Applied Sciences North-Western Switzerland). In vivo, high peak concentrations of nanoparticles between 10 5 and 10 6 #/cm 3 could be observed in the breathing zone of both patient and dentist, especially during finishing and polishing large esthetic resin-based composite build-ups in front teeth. Transmission electron microscopy of the airborne fraction revealed the presence of single nanofiller particles and pieces of resin-based composite dust that consisted of filler particles still embedded in resin. There were also indications for the presence of very small pieces of dust particles consisting of only resin, but more research is necessary to confirm this as transmission electron microscopy and elemental analysis only allow accurate analysis of high-atomic mass elements.

It has been suggested that nanoparticles are also produced by grinding resin based materials, which per se do not contain nanoparticles , as a result of thermal degradation . More research is necessary whether such thermal degradation also occurs with grinding other dental biomaterials. The route of exposure for these nanoparticles is inhalation and the prime target organ is considered to be the lung.

For a risk assessment, information on the number of fillings placed worldwide is necessary. However, such data are not available; therefore figures were taken from Germany, and the number of fillings in the recent years has been used as an example. In the year 2015, ca. 5 Mio fillings and inlays were billed for privately insured patients and for patients with statutory insurance ca. 52 Mio fillings adding up to a total of around 57 Mio fillings. In the same year 71.425 dentists practiced in Germany, which means 800 fillings per dentist and year or 15 fillings per week or 3 per day. It can further be assumed that ca. 80% of these fillings are made from resin-based composites. However, in these figures all dentists are included, also those, which normally do not place fillings, like orthodontists or oral surgeons, which may increase the number of placed restorations per dentist. Furthermore the annual decrease of fillings over the last 25 years was 2.3%, estimating that in 2017 ca. 54 Mio fillings will be placed instead of 57 Mio in 2015. Therefore, it can be estimated that 3–6 fillings are placed per dentists per day. Taking possible variations into account, for a risk assessment 10 resin-based composite fillings per dentists and day are taken here as a worst case scenario.

Exposure of patients

Patients may be exposed to nanoparticles from dental materials during the application of the unset materials, and during processing of the set materials (mainly adjusting for correct occlusion and for optimizing the margins) both by grinding and polishing. Finally, exposure to nanoparticles may occur during the usage period of the material in the mouth of the patient, mainly due to wear and during removal.

Application of the unset materials

As has been outlined above (dental personnel), no release of nanoparticles from unset restorative materials is expected. There is a chance that minute amounts of material deriving from material sculpturing may be swallowed. However, realistically only minor amounts are ingested and very little – if any – as nanoparticles from of unset materials. Actual data on release of nanoparticles from unset dental materials are, however, missing.

Processing of set materials

A number of materials, mainly for direct restorations, but also materials for indirect restorations are adjusted intraorally by grinding and polishing as has been outlined above. Exposure to nanoparticle dust is likely and has been documented (see occupational exposure). Again, this was also observed when grinding resin materials, which did not contain nanoparticles . The main route of exposure is inhalation and prime target organ is the lung. Exposure through swallowing is possible but considered to be negligible.

The frequency of exposure for the patient was estimated based on the above mentioned figures of placed fillings for Germany. According to these data and a population of 82,175,684 inhabitants (31.12.15), 0.67 fillings per inhabitant were placed per year (2015). As this calculation covers the whole population and also those without teeth like small babies or (edentulous) elderly, an exposure of 1–2 fillings on the average per patient and year can be assumed. Taking into account possible variations, for risk assessment here a worst case scenario of 5 fillings per year is assumed.

Wear of dental restorative materials

Nanoparticles from dental restorative materials may be generated by wear during the usage period of the restoration. Such wear depends on a number of non-material related variables; e.g. bruxism/non bruxism, the tooth (molars wear more than premolars), the size of the restoration, the area of measurement (occlusal contact areas are more prone to wear than the whole restoration), patient factors (age and gender) and the method of evaluation . Furthermore, material-related factors are surface hardness, filler size and filler volume, modulus of elasticity, flexural strength or surface roughness . The average wear of enamel is reported to be 54 μm to 91 μm for acclusal contact areas, 41 μm for all occlusal areas after two years .

For resin-based composites the mean occlusal contact wear was reported in a review from 2006 to range from 60 to 200 μm and for non-occluding areas: 20–100 μm in two years . However, in this review also data from resin-based composites from the 80 s of last century with comparatively large sized filler particles were included, which resulted in increased wear. In a more recent series of studies in human molars less wear was measured for modern resin-based composites (hybrid and nano-hybrid composites) with particles sizes around or less than 1 μm . After 3 years in situ, average vertical losses for nano/microhybrid composite fillings of 40 μm–67 μm (0.2770 mm 3 –0.368 mm 3 ) were measured , which was less than the ADA requirements from 2001 being 100 μm in three years . For hybrid composite materials after 3 years 99 μm–125 μm (0.8–1.2 mm 3 volume) loss was reported with no statistical difference to enamel .

In a follow-up of these studies after five years, the generalized vertical wear rate/month were 1.4 μm–1.8 μm and volume wear rate/month were 0.017 μm 3 –0.018 μm 3 ) . A more detailed analysis revealed for 0–6 months: 5.6 μm–7.0 μm, 6 months–3 years: 0.97 μm–1.3 μm and over 5 years: 0.87 μm–0.93 μm, all data per month.

Taken together, the annual loss in occlusal contact areas was 100 μm for older materials and for new materials (worst case, initial data up to 6 months used) 7 μm × 12 = 94 μm or for the whole period (initial and later period) 0.93 μm × 12 = 10.2 μm.

For amalgam wear data are sparse. An annual wear rate of 120 μm in 2 years was reported . For ceramic materials , generally lower wear rates are reported than for resin-based composites . A topic of concern is the wear of opposing natural teeth. In a study from 2008 the mean occlusal wear of ceramic crowns for molars were 29 μm–69 μm (0.34 ± 0.08 mm 3 volume) after one year and thus not statistically different from a contralateral tooth . For other restorative materials like glass ionomer cements or combinations of resin based materials with cements data on wear are sparse. Generally, the wear of glass ionomer cements and RMGIC is regarded to be greater than those of resin-based composites. However, these materials are only recommended for Class I and Class V cavities and not for larger cavities and are thus not prone to strong occlusal load. Glass ionomer cements showed in Class V situations an in vivo wear on the average of 25 μm after two years compared to a composite resin with 18 μm . However, in Class V situations no occlusal load occurs. In general the occlusal wear rate of restorations (vertical loss) in the initial months/years may be higher compared to later years. Support of enamel reduces the load on the fillings and may reduce wear.

Approximal wear of restorations has been shown, but the contact surface and hence the wear volume is usually quite small and there are no recent clinical data indicating the amount. It can be assumed that all generated wear particles are embedded in saliva and swallowed and reach the intestinal tract.

In summary, for all dental restorative materials a general loss of up to 50 μm per year seems a reasonable assumption. However, taking into account variations, for risk assessment beside 50 μm also 100 μm per year and based on a recent study 250 μm per three years are taken.

Release of nanoparticles from dental implants

Ti particles could be observed in peri-implant tissues and in newly formed bone . It was suggested that those Ti particles might be detached during the insertion of the implant or released after insertion .

Although Ti based implants have been considered to be biological inert, it has been found that non-dental implants in the body can undergo corrosion and release particulate debris over time . It has been reported that the metallic debris from Ti based implants might exist in several forms including particles (micrometer to nanometer size), colloidal and ionic forms (e.g. specific/unspecific protein binding) , organic storage forms (e.g. hemosiderin, as an iron-storage complex), inorganic metal oxides and salts . According to a previous study , the degradation of implants in the human body is primarily induced by wear and corrosion . Ti particles released from implants have been found in the regenerated bone and peri-implant tissues in animals . It has been shown that also Ti ions can be released from embedded implants in animals . Ti particles/ions are able to enter the circulation of blood and lymph . Ti particles detached from hip, knee and mandible implants have been detected in organs such as liver, spleen, lung, and lymph nodes . Increased levels of elementary Ti have also been detected in the blood of patients with poorly functioning implants .

In a recent study the release of Ti and other metallic elements was measured from dental jawbone implants through detailed post-mortem studies of human subjects. The highest Ti content detected in human mandibular bone was 37,700 μg/kg-bone weight at a distance of 556–1587 μm from implants, and the intensity increased with decreasing distance from implants. Particles with sizes of 0.5–40 μm were found in human jawbone marrow tissues at distances of 60–700 μm from dental implants .

Release of silver nanoparticles (AgNPs)

As has been mentioned above, AgNPs are used in dental materials to prevent or decrease bacterial colonization. AgNPs have been applied in different areas of dentistry, such as endodontics , dental prostheses , implantology , and restorative dentistry . Data on the release of silver nanoparticles from dental materials in the oral cavity are rare. However, resin-based composites containing silver ion-implanted fillers that release silver ions have been found to have antibacterial effects on oral cariogenic bacteria (e.g. streptococcus mutans) . It could also be demonstrated that metallic implant coatings (silver and bismuth) released particles after 168 h in culture medium in amounts of AgNPs (550 μg/L) or bismuth (80 μg/L) . Therefore, from all these studies it can be assumed that either silver nanoparticles as such are released or silver ions from those particles.

Environment/waste generation

Obviously, during the removal of dental restorations nanoparticles are produced. As such procedures are generally performed under water cooling and vacuum suction, dust formation is unlikely to occur. However, these particles end up in the effluent of the dental office and thus into the environment if not removed from the effluent by the separator of the dental unit. Such separators are available for amalgam waste with a 95% efficiency , but they are not available so far for other particles, especially those from resin-based composites.

It has been repeatedly shown that BPA and several resin monomers are eluted from resin-based composites over a long period (here up to one year) . Nineteen compounds were identified as elution products: e.g. BPA and Bis-EMA. The highest concentration of Bis-EMA was measured for deuterated methanol on day 90 at 36.993 mmol/L and in deuterated water on day 90 at 0.031 mmol/L. The highest BPA concentration was measured in deuterated methanol on day 90 at 1.469 mmol/L and in deuterated water on day 180 at 0.007 mmol/L. Examination of time-related elution indicates that various elution products (e.g. Bis-EMA, BPA) were only released in small quantities during the first 90 days, but in higher quantities between day 90 and day 180 .

These data are derived from bulk samples of resin-based composites. As elution processes are (amongst other factors) dependent upon the available material surface and as this surface is much larger in (nano)particles than in bulk materials of the same mass, it can be concluded that the above mentioned substances will also be eluted from resin-based composite particles, which reach the environment after restoration removal, and probably even in a higher amount than measured for bulk materials. However, data are missing.

In a recent study, the release of monomers and BPA from composite dust was indeed confirmed . In this in-vitro study, composite was ground in a small box and respirable airborne dust was collected on a filter, which was immersed in either water or ethanol. In both extraction media, monomers and a minute amount of BPA could be determined. The highest amounts could be quantified in ethanol: up to 970 μg/m 3 TEGDMA, 360 μg/m 3 UDMA and 180 μg/m 3 BisGMA, depending on the composition of the composite. Elemental analysis confirmed that the particles on the filters originated from the composite dust.

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Nov 22, 2017 | Posted by in Dental Materials | Comments Off on Nanoparticles in dentistry
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