Interaction of

nanomaterials with
tissues
By: Nehal Gamal
Contents:
1- Introduction
2-Classification of nanomaterials.
3-Advantages and disadvantages.
4- Biocompatibility of nanomaterials on tissues.
5-Recommendations for workers’ protection in the
handling and use of nanomaterials.
Introduction
• Nanotechnology is now being used in a wide range of scientific
fields since it offers a variety of practical solutions to scientific and
medical problems.
• Nanotechnologies work at dimensions smaller than 100 nm.
• The numerous dental uses of nanotechnology have led to the
development of the field of nanodentistry
 Classification of nanomaterials used in dentistry on the
basis of shape and composition:
A)Nanoparticles B)Nanotubes
Conventional or unconventional
(metallic& metal oxide) 1-Carbon nanotubes
1-Nanodiamonds
1-Metallic nanoparticles (CNTs)
2-Quantum dots
2-Silver nanoparticles(AgNPs) 2-Halloysite nanotubes
3-Nanoshells
3-Gold nanoparticles(AuNPs)
4-Quaternary ammonium (HNTs)
4-Copper nanoparticles(CuNPs)
methacrylate (QAM) NPs. 3-Nanoplatelet-based
5-Metal oxide nanoparticles.
5-Quaternary ammonium nanomaterials.
6-Zinc oxide nanoparticles(ZnO NPs).
polyethyleneimine (QPEI) NPs 4-Graphene oxide
7-Titanium dioxide nanoparticles(TiO2 NPs).
6-Amorphous calcium phosphate
8-Zirconium dioxide nanoparticles (ZrO2 NPs). nanoplatelets
nanoparticles (ACP NPs)
9-Aluminum oxide nanoparticles (Al2O3 NPs).
7-Hydroxyapatite(HAp).
10-Silicon dioxide nanoparticles (SiO2 NPs).
A)Nanoparticles
Nanoparticle-based nanomaterials can be either
conventional or unconventional.
• Metal NPs and metal oxide NPs are examples of
conventional nanoparticles, and the uses of metallic
and metal oxide NPs have been studied for decades.

• The latest generation of fillers for innovative dental

materials include unconventional NPs
(nanodiamonds, Nanoshells, and quantum dots) that
can easily be customized for different purposes
1-Metallic nanoparticles
1-Metallic nanoparticles are
made by reducing larger
particles to smaller ones
and then sputtering the
resulting nanoparticles
onto a surface (Fig. 3).

2-Metal nanoparticles with

antibacterial characteristics
have the potential to
combat bacteria as well as
microorganisms in the
treatment of dental
problems
 2-Silver nanoparticles(AgNPs):
Used in dental restorative material, dental implants and
dental prostheses, are all examples of antimicrobial
agents.
 2-Silver nanoparticles(AgNPs):
Advantages
1-It has been shown to reduce bacterial
colonization and improve dental health.
Because of its tiny size, it may easily
penetrate bacterial membranes.
2- It is biocompatible and has long-lasting
antibacterial activity.
3-When utilized as a filler, AgNPs improve
dental composites’ mechanical qualities,
minimize the development of lactic acid and
the growth of biofilms on teeth, preventing
secondary caries
disadvantages
1-AgNPs are poisonous. Chronic silver
exposure can cause argyria.
2-AgNPs are toxic because they generate
reactive oxygen species (ROS). Silver ions
along with silver nanoparticles both
contribute to the toxicity.
3-AgNPs are implicated in the generation of
genotoxicity and oxidative stress,
activation of lysosomal AcP(acid
phosphatase), actin disruption, stimulation
of hemocyte phagocytosis, and inhibition
of Na-K-ATPase.
 3-Gold nanoparticles(AuNPs)
1. Gold’s inert, biocompatible, and antibacterial qualities
have captivated scientists for decades.
2. AuNPs have been investigated as a possible nano-drug
delivery system for treating and detecting cancers (ttt.
would involve a targeted, nanoparticle-mediated
localized hyperthermia) in recent research
investigations. In these investigations, gold
nanostructures such as nanospheres and nanorods
were synthesized for usage as photothermal agents,
contrast agents, and nanodrug delivery carriers.
1. AuNPs were utilized as
osteoinductive agents to immobilize
the titanium surfaces of dental
implants. gold nanoparticles on
dental implant surfaces helped to
stimulate bone growth and preserve
nascent bone formation around
dental implants.

2. AuNPs can be made in a variety of

ways, including chemical
functionalization, which renders them
less dangerous than other metal
nanoparticles
 4-Copper nanoparticles(CuNPs)
1. Copper appears to be an important component in the metabolic activity of
plant and animal cells. This is a necessary component of over 30 proteins
and is found in practically every cell.
2. When copper creates hydroxyl radicals, it upsets the cellular membrane
equilibrium, resulting in membrane leakage and cell death in bacteria and
other microbes.
3. Cell membrane destabilization is caused by CuNPs binding to amine and
carboxylic groups on the microorganism’s surface, which results in cell
death.
4. Free radicals produced by copper ions can alter microorganism DNA
replication and protein synthesis.
 4-Copper nanoparticles(CuNPs)

• According to a recent study, the inclusion of

CuNPs provided good antibacterial activity
against S. mutans, preventing the adhesive
interface from degrading without a significant
change in the formulation’s mechanical
qualities.
• Metal nanoparticles with antibacterial
characteristics have the potential to combat
microorganisms and bacteria in the treatment of
dental problems.
 5-Metal oxide nanoparticles
• In their oxide, Metal particles are
more stable form than as metal
particles alone.

• Metal oxide nanoparticles have

recently been the subject of
extensive research into their
potential as antibacterial agents
and dental fillings .
(CVS)=Chemical Vapor Synthesis
 6-Zinc oxide nanoparticles(ZnO NPs).
• The antibacterial efficacy of zinc at the nanoscale is greatly increased
compared to that at the macroscale.
• In the presence of zinc ions, the bacterial cell membrane becomes more
permeable, leading to the cell’s death. An increase in oxygen radical
production and Zn2+ ion production by zinc nanoparticles (ZnNPs) causes
an increase in oxidative stress, which inhibits the growth of
microorganisms.
• Antibacterial activity against Lactobacillus and Streptococcus mutans has
been demonstrated in dental composite resins comprising nanoparticles
of ZnO and nanoparticles of Ag.
Dental resin composites have been found to benefit from the
mechanical and antibacterial features of cellulose nanocrystal
and zinc oxide nanoparticle (ZnO NP) nanohybrids.
 7-Titanium dioxide nanoparticles(TiO2 NPs).
• The exceptional features of titanium alloys, like their
1. high strength
2. corrosion resistance
3. excellent biocompatibility make them widely employed in dentistry.
• UV rays cause TiO2 to produce reactive oxygen (OH and H2O2) radicals
that cause bacterial cell lysis by interfering with their phosphorylation and
creating an imbalance in the micro-osmotic organism’s pressure.
• Streptococcus mutans and Streptococcus sanguinis colony counts were
reduced significantly when TiO2 nanoparticles were added to composite
resins.
 7-Titanium dioxide nanoparticles(TiO2 NPs).
Advantages
• Long-term effect on dental
implants, surface
modification resulted in
additional benefits such as
decreased bacterial
adherence and increased
hardness.
Disadvantages
 Nanoparticles provide a greater risk than
smaller particles. They enter the body via
the nose or mouth.
 Cancer is prevalent among workers in
TiO2 manufacturing plants (as revealed in
epidemiological studies).
 In the hippocampus and cortex, TiO2
nanoparticles that have crossed the
blood–brain barrier may aggregate.
 TiO2 exposure activates microglia,
produces reactive oxygen species (ROS),
and activates signaling pathways involved
in cell death and inflammation
 Microglia
1. They are a type of neuroglia (glial cell) located throughout the brain and spinal cord.
2. Act as the resident macrophage cells, they act as the first and main form of active
immune defense in the central nervous system (CNS) .
3. Microglia are key cells in overall brain maintenance.
4. they are constantly scavenging the CNS for plaques, damaged or unnecessary
neurons and synapses, and infectious agents.
5. microglia are extremely sensitive to even small pathological changes in the CN In
the case where infectious agents are directly introduced to the brain or cross the
blood–brain barrier, microglial cells must react quickly to decrease inflammation
and destroy the infectious agents before they damage the sensitive neural tissue.
6. Due to the lack of antibodies from the rest of the body (few antibodies are small
enough to cross the blood–brain barrier), microglia must be able to recognize
foreign bodies, swallow them, and act as antigen-presenting cells activating T-cells.
 8-Zirconium dioxide nanoparticles (ZrO2 NPs).
Advantages Disadvantages

1-Similar to the tooth in terms of mechanical
properties (fatigue resistance, good wear
resistance,great fracture resistance.
(sometimes known as ‘‘ceramic steel”) and it is
close resemblance in characteristics and color to cellular oxidative stress, resulting in cell
the natural tooth, it is an excellent choice for
cosmetic purposes,
2-They are exhibit low cytotoxicity, good
biocompatibility.
3-In terms of dental implants and prosthetics,
they have been demonstrated to have
biocompatibility, osteoconductivity
1-cause considerable DNA damage in human
T cells, induce apoptosis, and decrease cell
proliferation in rodent fibroblast cell lines.
2-zirconia was discovered to promote
death.
3-These NPs have been shown in studies to
be capable of halting the cell cycle and
crossing numerous physiological barriers,
resulting in detrimental effects.
Conclusion: Incorporation of nano-ZrO2 into the repair resin improved the flexural
strength of repaired denture bases, whereas it decreased impact strength, especially with
high nano-ZrO2 concentrations
Gad MM, Rahoma A, Al-Thobity AM, ArRejaie AS. Influence of incorporation of ZrO 2 nanoparticles on the repair strength of polymethyl
methacrylate denture bases. Int J Nanomedicine. 2016 Oct 27;11:5633-5643.
Conclusions: Nanostructured ceramics can show improved properties
because of the reduction of the grain size to the nanoscale. This is also
true for zirconia-based nanoceramics, where these improvements can be
used to develop highly reliable and aesthetic dental restorations
 9-Aluminum oxide nanoparticles (Al2O3 NPs).
• Alumina ceramics have better aesthetics, a more polished surface, wear
resistance, hardness, and good biocompatibility with the surrounding oral
tissues compared to other materials.
• Low flexural strength and impact strength are two drawbacks of
polymethylmethacrylate (PMMA). Adding Al2O3 NPs to a PMMA matrix
significantly improved the resin’s mechanical and thermal properties and
reduced water absorption and solubility.
 10-Silicon dioxide nanoparticles (SiO2 NPs)
1. using silicon dioxide NPs as filler can improve the mechanical qualities of dental
restorative materials.
2. As a general dental polishing agent, silica fine powder is used to smooth rough surfaces
on teeth to avoid food collection or plaque buildup and thus keep teeth clean.
3. A silicon oxide with the chemical formula SiO2, usually referred to as silica, is most widely
distributed in nature as quartz, a form of SiO2 NPs.
4. It is possible to seal dentinal tubules, which cause hypersensitivity when exposed, with
mesoporous SiO2.
5. When HA (hydroxyapatite) nanoparticles and silica nanoparticles were combined, they
increased calcium phosphate compounds’ concentration in the dentin as well as the
volume of mineral in the dentin that had been demineralized
 10-Silicon dioxide nanoparticles
(SiO2 NPs)
advantages
1. It is biocompatible,
2. It has a minimal toxic effect
3. low density
4. high adsorption capacity
5. it is, most significantly,
cost-effective.
6. When used as a polishing
agent, the roughness of the
tooth surface is reduced.
disadvantages
1. Toxic effects are dependent on the route of entry and
the physiochemical characteristics of the substance.
2. Recent studies have shown that silica nanoparticles,
like crystalline particles, may cause lung cancer and
silicosis.
3. SiNPs are cytotoxic.
4. they can cause oxidative stress and mediate
apoptosis, depending on the size and dose.
5. Research shows that SiNPs are genotoxic (DNA
damage, regulation of genes that control apoptosis
and autophagy) and immunotoxic (immunotoxicity).
 Unconventional nanoparticles in
dentistry
Nanoparticles have been getting investigated for their special
characteristics in the advent of sophisticated dental nanomaterials.
Nanoparticles can be used to create dental materials that are robust,
nontoxic, and antimicrobial, among other things. In this regard,
nanotechnology allows the exploration of numerous nanoparticles for
dental applications and testing. Different approaches to integrating
nanoparticles in dental materials have been implemented depending on
the particle characteristics.
 1. Nanodiamonds

1. The hardest natural substance on the

planet, diamond, is well known to the
general public. Small diamonds, known
as nanodiamonds (NDs), are less than
100 nm in diameter.
2. Their outstanding surface and chemical
nature in dental nanocomposite
manufacturing make them an excellent
filler choice.
In the field of restorative dentistry, nanodiamonds can be used in a
wide variety of ways.

The main applications of NDs in dentistry include :

1-directed tissue regeneration,
2-polymer reinforcement,
3-drug administration to treat infections and cancer.
4-It also used as bioactive or antibacterial dental implant coatings.
 2. Quantum dots
• A quantum dot is a semiconductive
nanoparticle like indium sulfide, zinc sulfide,
or lead sulfide, that may emit light when
exposed to a specific amount and
wavelength of light.
• Exposure to an external magnetic light or
field can alter the dots’ semiconductive
characteristics.
• In addition, these materials can be employed
as nanocarriers for drug or genetic treatments.
 2. Quantum dots
Uses:
1-Through conjugation with photosensitizers and cancer-targeting
medicines, quantum dots could be used for cancer treatment.
2-It also used in therapeutic purpose and in diagnostic imaging.
3-Cancer cells can be more easily attached if they are coated with particular
chemicals and UV light is emitted, the diagnosis of oral malignancies is
improved.
4-quantum dots can be employed to treat head and neck illnesses by
delivering drugs and correcting genetic errors.
5-They can also help to prevent oral cancer
 3. Nanoshells
An inner dielectric core is encased in a thin metal shell to form
nanoshells
Uses in dentistry:
• nanoshells can be employed for various
therapeutic purposes. When stimulated
with infrared light, the metal coverings of
nanoshells can be used to destroy oral
cancer cells by causing a tremendous
amount of heat to build up around the
nanoshells and eventually kill the cells.
 4. Quaternary ammonium methacrylate (QAM)
1-The antibacterial properties of quaternary ammonium methacrylate
nanoparticles make them suitable for usage in restorative dental
materials.
2-This antibacterial chemical destroys the target cells by causing
cytoplasmic leakage in microorganism cell walls.
3- There are positively and negatively charged surfaces on QAM resins
and bacteria, favoring ionic attachment and increasing osmotic pressure
in the cell membrane, ultimately leading to cell death
4-The capacity of QAM resins to block 3D biofilms is an exciting feature.
When bacteria are exposed to QAM’s antimicrobial properties, they
become more sensitive to apoptosis.
5-The bond strength and antibacterial properties of QAM resins may also
be relevant in the development of more advanced dental adhesive
restorative solutions with QAM resins
 5. Quaternary ammonium
polyethyleneimine (QPEI)
• Nanoparticles It is possible to prevent root canal infections by using
antibacterial sealers.
• The antibacterial properties of QPEI NPs have led to their use in
commercially available endodontic sealers such as Gutta-flow, Epiphany,
and AH plus.
• There were no significant unfavorable effects on mechanical
characteristics when QPEI NPs were used in resin composites.
• QPEI NPs have also shown stability and great antibacterial potency without
generating any byproducts.
 6. Amorphous calcium phosphate
nanoparticles (ACP NPs)
• Dentin or enamel remineralization can have a good effect on oral health.
• Generally, minimally invasive techniques are utilized to remove deep carious
lesions for protecting the pulp along with retain the tooth structure.
• In restorative dental materials, the antimicrobial effects of nanoparticles can
be combined with the remineralization of the decayed tooth by their inclusion
in these materials.
• Nanoparticles of amorphous calcium phosphate in dental composites
release calcium and phosphate ions to maintain pH levels in acidic
conditions
 7-Hydroxyapatite(HAp).
(HAp) Reduces dental hypersensitivity, also acts as a cavity filler,
delays secondary demineralization, and repairs enamel surfaces.
advantages disadvantages
1. HAp nanoparticles are easily 1-They have the ability to interact with
incorporated into tooth tubules. proteins and form protein–particle
Comparable to tooth and bone in complexes that are subsequently
composition, destroyed by macrophages in tissues.
2. biocompatible, 2-Blood carries these particles to and
3. adheres to the tooth enamel distributes them throughout the lungs,
4. protects the tooth by forming a spleen, and liver.
coating of fake enamel around it, 3-Nanoparticle toxicity can have an
and corrects periodontal effect on the inflammatory response,
deficiencies. signaling system, and oxidative stress
 Nanotube-based nanomaterials
1. Carbon nanotubes (CNTs)
• SWCNTs (single-walled carbon nanotubes)
are graphene-coated cylinders that have
attracted the research community.
 Uses:
1. Dental resins including SWCNTs as a filler
have shown great flexural strength and
satisfactory outcomes.
2. CNTs can be used to cover titanium dental
implants.
 1. Carbon nanotubes (CNTs)
advantages
Increased surface area, bringing
active substances to living cells,
quickly attaching to the tooth and
dentin/cementum surface.
disadvantages
• The reactivity of carbon
nanotubes (CNTs) is strongly
influenced by their structure, size,
surface, and purity.
• Crossing membrane barriers
using nanotubes can cause
inflammatory and fibrotic
reactions in rare cases.
 2. Halloysite nanotubes (HNTs)
Uses:
1. HNTs can be used as dental fillers
2. nanodrug delivery agents, making them acceptable
alternatives.
3. HNTs have a nanotubular structure with a typical
nanometer size. Because of their natural milky white
color, elastic modulus, and high strength, they are
suitable fillers in dental composite manufacturing.
4. A nanofiller that can prevent the production of oral
biofilm and hence prevent the growth of secondary
dental caries can be created by loading HNTs with
antibacterial drugs
 3. Nanoplatelet-based nanomaterials
Materials made from nanoplatelets such as nanosheets or flakes are
called nanomaterials. Nanoplatelet-based nanomaterials can use
graphene. The unique features of graphene oxide nanoplatelets make
them ideal for dental applications
 4. Graphene oxide nanoplatelets
 Carbon atoms organized in a hexagonal
honeycomb lattice make up graphene.
Uses:
1. Incorporating graphene into dental materials can
serve as both filer as well as an antibacterial
agent
2. Bioactivity, increased bone production, and
decreased inflammatory reactions have been
attributed to graphene oxide (GO)-coated Ti (GO-
Ti) membranes.
3. They can be used to increase the performance of
dental implants, and they can be employed as
 4. Graphene oxide nanoplatelets
advantages
Economical, fracture-
resistant, low-density, forms
a homogeneous crystal
lattice, and effectively treats
bacterial biofilms.
disadvantages
The toxicity of graphene is
dependent on its structure,
size, and oxidative state.
Metallic impurities may be
introduced during
postsynthesis processing,
eliciting a range of
toxicological reactions.
Toxicity of nanomaterials:

Routes of entry of nanomaterials:

1-ingestion
2-inhalation
3-absorbtion through the skin

After entry, they can induce :

1-The formation of reactive oxygen species (ROS)
including free radicals
2-ROS produces oxidative stress, inflammation
3-Consequent damage to various biological materials
such as protein, DNA.
4- They can cross tissue junctions and even cellular
membranes where they induce structural damage to
the mitochondria or invade the nucleus where they
cause serious DNA mutations leading to cell death
Cytotoxicity is induced by nanomaterials results from the interaction between
the nanomaterial surface and cellular components.

The cytotoxicity of nanoparticles is induced by several factors:

1-Size
2- Surface (surface area, electrostatic statue of surface (surface charge )).
3-morphology.
4-Agglomeration Status.
5-The distribution of particles within the body and the accumulation of a specific type of particle
in a particular part of the body, which is dependent on the p’s size and surface characteristic
7-Mass quantity
8-Their lifespan is based on biological cellular interactions. Some of them are unstable at the
surface, showing unusual communication with their biological neighbors.
 1. Size:
1-As the diameter decreases the surface area of the particle increases
exponentially. even when particles have the same composition
2-They can have significantly different levels of cytotoxicity
depending on both

particle size and surface reactivity. So, not only are chemical properties
induces and size-dependent cytotoxicity
important in assessing a
and
significant nanomaterial’s cytotoxicity, but also
distribution is the amount of size-dependent
differences in
in vivo. cytotoxicity
the cellular
delivery
mechanism
 1.1. Size-Dependent Absorption
• To generate cytotoxicity and inflammatory response in animal models, it is essential
that the nanoparticles should migrate across the epithelial barrier.
• In this respect, the size of the nanoparticles plays a key role in cytotoxicity .
• In the case of nanoparticle inhalation, nanoparticles penetrate deeply into the lung
parenchyma.
• Different sized nanoparticles show specific distribution patterns in the respiratory tract.
• Nanoparticle distribution is also affected by the Stokes number( Sno. Ligther
particle )and Reynolds number.
• Initially, particles are well distributed in the gas phase, but after inhalation they
translocate into the liquid phase in respiratory fluids
1.2. Size-Dependent in Vivo Pharmacokinetics and
Clearance :
• The distribution of a drug or nanoparticles in vivo, or pharmacokinetics, is
also an important consideration in assessing cytotoxicity.
• This pharmacokinetic characteristic of NPs is dependent on particle size
and surface chemistry
• NPs with a diameter greater than 6 nm cannot be excreted by the kidneys
and accumulate in specific organs, such as the liver and spleen, until
clearance by the mononuclear phagocyte system ensues .
• For instance, cadmium selenide (CdSe) quantum dots remain in the tissue
for up to eight months and cause hepatotoxicity .
1.3. Size-Dependent Cellular Uptake and Cytotoxicity:

• Nanoparticle uptake mechanism and efficiency are key factors influencing

cytotoxicity.
• One of the major factors determining cellular uptake efficiency and
mechanism is nanoparticle size. With respect to particle size and surface
features, nanoparticles are internalized into the cell through various
pathways, such as phagocytosis and pinocytosis..
• Sizes suitable for uptake range from 10 to 500 nm with an upper limit of 5
mm. Large particles are most likely to be engulfed via macropinocytosis.
• Extremely small NPs have a surface curvature too great to provide necessary
conformational rigidity to allow for multivalent binding with receptors. As
such, nanoparticles that are 40–50 nm in diameter seem to be the optimal size
for both multivalent receptor interaction and binding rigidity.

• Differences in endocytosis efficiency naturally affect cellular cytotoxicity.

• The internalized NPs generally translocate to endosomal or lysosomal
vesicles for further elimination .During this process, endosomal escape of
internalized NPs occurs, resulting in specific cytotoxicity through the
production of ROS and direct mitochondrial damage.
Clathrin
• It is a protein that plays a major
role in the formation of coated
vesicles.
• Coat-proteins, like clathrin, are
used to build small vesicles in
order to transport molecules
within cells.
• The endocytosis and exocytosis
of vesicles allows cells to
communicate, to transfer
nutrients, to import signaling
receptors, to mediate an immune
response after sampling the
extracellular world, and to clean
up the cell debris left by tissue
inflammation.
 2. Surface:
2.1. Surface Area
• Band gap alterations, decreased melting point, and higher reactivity induced by a large
surface area were investigated and it was found that these features had serious effects
including lung inflammation, cytotoxicity and toxicity in vivo.
• A larger surface area may cause higher reactivity with nearby particles, resulting in
possibly harmful effects when used in fillers, cosmetics, and as drug carriers .
• Decreasing the particle size, its biological activity increases substantially.
• Smaller particles occupy

less volume, such that a larger number of particles can occupy a unit area,
resulting in

increased pathophysiological toxicity mechanisms, for instance oxidative stress, ROS

generation, mitochondrial perturbation.
• Particle surface reactivity, characterized by how easily single particles aggregate, may

also play a significant role in cytotoxicity It has also been suggested that

dosing should be based on nanoparticle surface area.

 2.2. Surface Electrostatic Status:

 External properties of surface electronic status are critical to cellular uptake and may
also be involved in cytotoxicity.
 Higher uptake efficiency in a cell is achieved by replacing the surface functional moiety,
inducing sudden changes in particles’ surface charge .
 Some authors have attempted to envelope nanoparticles in a lipid vesicle changes in
surface charge result in considerable differences in the in vivo biodistribution of NPs
 Particles showed different degrees of toxicity depending on their surface charges

(NPs with a positively(+e) charged surface tended to have much higher

toxicity.
3. Morphology
 It is also a big issue in nanotoxicology. Like other well-established
inhalable fibers (e.g., asbestos), nanoscaled fibers (e.g., carbon
nanotubes) are reported to have a serious risk of lung inflammation and
prolonged exposure may cause several cancers .

4. Agglomeration Status
 Agglomeration could be a potent inducer of inflammatory lung injury in
humans .
 For certain types of chemicals, exposure at higher levels has been shown

to lead to serious chronic diseases such as fibrosis and cancer

Biocompatibility Of Nanobiomaterials
Biocompatibility is defined as “the ability of a material to function in a
specific application in the presence of a suitable host response”.
There are a vast number of cytotoxicity screening techniques
available for measuring the biocompatibility of a dental restorative
material..
Biocompatibility Testing Standards:
1. International standard ISO 7405: is entitled the Preclinical
evaluation of biocompatibility of medical devices used in dentistry. This
ISO document was prepared in combination with the World Dental
Federation. It includes the preclinical testing of materials used in
dentistry and supplements ISO 10993.

2. International standard ISO 10993: entitled the biological evaluation

of medical devices is a combination of international and national standards
and guidelines. The primary goal of it is protection of humans.
Guidelines ISO 7405 and ISO 1099 have mentioned certain standard
practices for the biological evaluation of dental materials. They include:
1. It is incumbent upon the dental material manufacturer to select the suitable tests,
based on the proposed use of the material, and known toxicity profile of the material.
2. A manufacturer may select one of the three cytotoxicity tests in preference to
another due to cost, experience or other reasons.
3. Overall, there are four levels of analysis. New materials should be assessed using
initial cytotoxicity and secondary tissue screening tests before extensive animal
testing and clinical trials.
4. The test result should always be assessed and interpreted with respect to the
manufacturers’ stated use for the particular material
Test Program for the Biological Testing of Dental Material:
The selection and assessment of any material or device intended for use in
humans necessitates a structured evaluation. The test program for the biological
testing of dental materials is divided into four stages.

Phases I and II include initial tests, which are of a short duration, cost effective
and simple.
Only after completing these tests adequately does a material progress through
the testing hierarchy to become assessed in preclinical animal usage studies
(Phase III) prior to clinical testing with a limited number of patients (Phase IV).
Cytotoxicity Screening Methods: General regulation for in vitro
cytotoxicity testing is presented in ISO 10993-5. For in vitro
cytotoxicity screening, the suggested testing methods include;
1. Direct cell culture and culture extract testing or barrier screening
assays
2. Agar diffusion testing
3. Filter diffusion testing
4. Dentin barrier testing
BAuA/VCI-Recommendations for workers’ protection in the handling and
use of nanomaterials
1. Substitution options:
Bind powder nanomaterials in liquid or solid media. Use dispersions, pastes or
compounds instead of powder substances, wherever this is technically feasible and
economically acceptable.

2) Technical protection measures:

A) Perform activities in contained installations, wherever this is possible.
B) If this cannot be done, avoid the formation of dusts or aerosols. To this end, extract
possibly forming dusts or aerosols directly at their source (e.g., in filling and emptying
processes), depending on the materials produced and production conditions. Ensure
regular maintenance and function testing of extraction facilities.
C) Extracted air must not be recirculated without exhaust air purification, for example,
by a laminar air flow box.
a laminar air flow box.
3) Organizational protection measures:
A) Instruct the workers involved, in a targeted manner, about the specific physical
properties of the products free nanoparticles, the need for special measures, and
potential long-term effects of dusts. Include relevant information in the operating
instructions.
B) Keep the number of potentially exposed workers as small as possible. Furthermore,
deny unauthorized persons access to the relevant work areas.
C) Ensure clean work wear.
 Work wear must be cleaned by the employer.
 Work wear and private clothing must be stored separately.
 Ensure the regular cleaning of workplaces.
 The only way to remove deposits or spilled substances is with a suction device or to
wipe them up with a moist cloth; do not remove them by blowing.
4) Personal protection measures:
A)Where technical protection measures are not sufficient or cannot be put
into place, personal protection measures – such a respiratory protection
(e.g., filters of protection levels P2, FFP2, P3 or FFP3, to be selected in the
hazard assessment) – are a suitable step.
B) Depending on substance properties, it might be necessary to wear
protective gloves, protection goggles with side protection, and protective
clothing.
c) With particles in the size range between 2 and 100 nm the efficiency
of filters increases with decreasing particle size. This is because below
100 nm the diffusion of particles gets much stronger; when flowing
through the filter medium, the particles are thus more likely to collide
with the fibers of the filter medium where they are bound.
D) In the selection of protective gloves, it must be ensured that the
glove material is suitable.
The glove material must fulfill requirements for maximum wearing time
under practical conditions. An important relevant criterion is the
permeation time (break-through time depending on glove material and
material strength)
F)In addition to hand protection, it can be necessary to protect further
parts of the skin with protective equipment. This includes in particular
protective suits, aprons, and boots
E) In addition to the dust protection measures mentioned here, it is also necessary to
observe further measures ensuing from special substance properties, for example,
extra antiexplosion measures in the handling of oxidizable nanomaterials or specific
protection measures in the handling of reactive or catalytic nanomaterials.
G)Besides measures designed specifically for nanomaterials, all measures resulting
from the hazard assessment must also be complied with, so that the occupational
exposure levels at the workplace for further working substances – for example, for
solvents – are observed.
H) The effectiveness of applied protection measures (e.g., personal protective
equipment) must be reviewed
 References list:
1-Khatami, M., Nejad, M.S., Salari, S., Almani, P.G.,Plant-mediated green synthesis of silver nanoparticles using Trifolium resupinatum
seed exudate and their antifungal efficacy on Neofusicoccum parvum and Rhizoctonia solani. IET Nanobiotechnol. 2016: 10; 237–43.
2-Umapathy VR , Natarajan PM, SumathiJones C , Swamikannu B, Johnson W.M.S., Alagarsamy V, Rahman Milon A. Current trends and
future perspectives on dental nanomaterials – An overview of nanotechnology strategies in dentistry. King Saud Univ
Sci.2022:34;102231.
3-Katsumiti, A., Gilliland, D., Arostegui, I., Cajaraville, M.P.,. Mechanisms of toxicity of ag nanoparticles in comparison to bulk and ionic
ag on mussel hemocytes and gill cells. PloS One. 2015 10;e0129039.
4-Pourjavadi A, Bagherifard M, Doroudian M. Synthesis of micelles based on chitosan functionalized with gold nanorods as a light
sensitive drug delivery vehicle. Int J Biol Macromol. 2020 : 15;149:809-18.
5-Heo DN, Ko WK, Lee HR, Lee SJ, Lee D, Um SH, Lee JH, Woo YH, Zhang LG, Lee DW, Kwon IK. Titanium dental implants surface-
immobilized with gold nanoparticles as osteoinductive agents for rapid osseointegration. J Colloid Interface Sci. 2016 : 1;129-137.
6-Bapat RA, Chaubal TV, Dharmadhikari S, Abdulla AM, Bapat P, Alexander A, Dubey SK, Kesharwani P. Recent advances of gold
nanoparticles as biomaterial in dentistry. Int J Pharm. 2020 :30;586:119596.
7-Ruparelia JP, Chatterjee AK, Duttagupta SP, Mukherji S. Strain specificity in antimicrobial activity of silver and copper nanoparticles.
Acta Biomater. 2008 ;4:707-16.
8-Kishen A, Shi Z, Shrestha A, Neoh KG. An investigation on the antibacterial and antibiofilm efficacy of cationic nanoparticulates for root

canal disinfection. J Endod. 2008 ;34:1515-20 .

9-Gutiérrez MF, Malaquias P, Hass V, Matos TP, Lourenço L, Reis A, Loguercio AD, Farago PV. The role of copper nanoparticles in an etch-
and-rinse adhesive on antimicrobial activity, mechanical properties and the durability of resin-dentine interfaces. J Dent. 2017 ;61:12-20.
10-Yuan JH, Chen Y, Zha HX, Song LJ, Li CY, Li JQ, Xia XH. Determination, characterization and cytotoxicity on HELF cells of ZnO

nanoparticles. Colloids Surf B Biointerfaces. 2010 1;76:145-50 .

11-Kasraei S, Sami L, Hendi S, Alikhani MY, Rezaei-Soufi L, Khamverdi Z. Antibacterial properties of composite resins incorporating silver
and zinc oxide nanoparticles on Streptococcus mutans and Lactobacillus. Restor Dent Endod. 2014 ;39:109-14.
12-Wang Y, Hua H, Li W, Wang R, Jiang X, Zhu M. Strong antibacterial dental resin composites containing cellulose nanocrystal/zinc oxide
nanohybrids. J Dent. 2019 Jan;80:23-9.
13-Özcan, M., Hämmerle, C.,. Titanium as a reconstruction and implant material in dentistry: Advantages and pitfalls. Materials.2012 ;5:
1528–45.
14-Garcia-Contreras R, Sugimoto M, Umemura N, Kaneko M, Hatakeyama Y, Soga T, Tomita M, Scougall-Vilchis RJ, Contreras-Bulnes R,
Nakajima H, Sakagami H. Alteration of metabolomic profiles by titanium dioxide nanoparticles in human gingivitis model. Biomaterials.
2015 ;57:33-40.
15-Sodagar A, Akhoundi MSA, Bahador A, Jalali YF, Behzadi Z, Elhaminejad F, Mirhashemi AH. Effect of TiO2 nanoparticles incorporation on
antibacterial properties and shear bond strength of dental composite used in Orthodontics. Dental Press J Orthod. 2017 ;22:67-74.
16-Shi H, Magaye R, Castranova V, Zhao J. Titanium dioxide nanoparticles: a review of current toxicological data. Part Fibre Toxicol.
2013 ;10:15.
17-Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Front Cell Neurosci. 2013 ;7:45.
18-Lawson LJ, Perry VH, Gordon S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience. 1992;:405-15.
19-Filiano AJ, Gadani SP, Kipnis J. Interactions of innate and adaptive immunity in brain development and function. Brain Res.
2015 ;1617:18-27.
20-Kreutzberg GW. Microglia, the first line of defence in brain pathologies. Arzneimittelforschung. 1995 ;45:357-60.
21-Bushong EA, Martone ME, Jones YZ, Ellisman MH. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical

domains. J Neurosci. 2002 ;22:183-92.

22-Gehrmann J, Matsumoto Y, Kreutzberg GW. Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev. 1995 ;20:269-
87.
23-Gehrmann J, Matsumoto Y, Kreutzberg GW. Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev. 1995;20:269-
87.
24-Dissing-Olesen L, Ladeby R, Nielsen HH, Toft-Hansen H, Dalmau I, Finsen B. Axonal lesion-induced microglial proliferation and
microglial cluster formation in the mouse. Neuroscience. 2007 ;149:112-22.
25-Asadpour, E., Sadeghnia, H.R., Ghorbani, A., Sedaghat, M., Boroushaki, M.T.,.Oxidative stress-mediated cytotoxicity of zirconia
nanoparticles on PC12 and N2a cells. J. Nanoparticle. 2016 ; 18:14.
26-Gad MM, Rahoma A, Al-Thobity AM, ArRejaie AS. Influence of incorporation of ZrO 2 nanoparticles on the repair strength of polymethyl
methacrylate denture bases. Int J Nanomedicine. 2016 Oct 27;11:5633-5643.
27-Arena A, Prete F, Rambaldi E, Bignozzi MC, Monaco C, Di Fiore A, Chevalier J. Nanostructured Zirconia-Based Ceramics and Composites in
Dentistry: A State-of-the-Art Review. Nanomaterials (Basel). 2019 ;9:1393.
28-Llorente, A., Serrano, B.J., Baselga, G., Gedler, O.R.,. Nanoindentation and wear behavior of thermally stable biocompatible polysulfone–alumina
nanocomposites. RSC. Adv. 2016;102:100239–100247.
29-Besinis A, van Noort R, Martin N. Infiltration of demineralized dentin with silica and hydroxyapatite nanoparticles. Dent Mater. 2012 ;28:1012-23.
30- Yoshida K, Tanagawa M, Matsumoto S, Yamada T, Atsuta M. Antibacterial activity of resin composites with silver-containing materials. Eur J Oral
Sci. 1999 ;107:290-6.
31-Lee DK, Kim SV, Limansubroto AN, Yen A, Soundia A, Wang CY, Shi W, Hong C, Tetradis S, Kim Y, Park NH, Kang MK, Ho D. Nanodiamond-Gutta Percha Composite Biomaterials
for Root Canal Therapy. ACS Nano. 2015 ;9:11490-501.
32-Kanaparthy R, Kanaparthy A. The changing face of dentistry: nanotechnology. Int J Nanomedicine. 2011;6:2799-804.
33-El-Sayed IH, Huang X, El-Sayed MA. Selective laser photo-thermal therapy of epithelial carcinoma using anti-EGFR antibody conjugated gold nanoparticles. Cancer Lett.
2006 ;239:129-35.
34-Li F, Weir MD, Chen J, Xu HH. Effect of charge density of bonding agent containing a new quaternary ammonium methacrylate on antibacterial and bonding properties. Dent
Mater. 2014 ;30:433-41.
35-Cheng L, Weir MD, Zhang K, Arola DD, Zhou X, Xu HH. Dental primer and adhesive containing a new antibacterial quaternary ammonium monomer dimethylaminododecyl
methacrylate. J Dent. 2013 ;41:345-55.
36-Beyth N, Houri-Haddad Y, Baraness-Hadar L, Yudovin-Farber I, Domb AJ, Weiss EI. Surface antimicrobial activity and biocompatibility of incorporated polyethylenimine
nanoparticles. Biomaterials. 2008 ;29:4157-63.
37-Xu HH, Moreau JL, Sun L, Chow LC. Nanocomposite containing amorphous calcium phosphate nanoparticles for caries inhibition. Dent Mater. 2011 ;27:762-9.
38-Bhirde AA, Patel V, Gavard J, Zhang G, Sousa AA, Masedunskas A, Leapman RD, Weigert R, Gutkind JS, Rusling JF. Targeted killing of cancer cells in vivo and in vitro with EGF-
directed carbon nanotube-based drug delivery. ACS Nano. 2009 ;3:307-16.
39-Akasaka T, Nakata K, Uo M, Watari F. Modification of the dentin surface by using carbon nanotubes. Biomed Mater Eng. 2009;19:179-85.
40-Avani, F., Damoogh, S., Mottaghitalab, F., Karkhaneh, A., Farokhi, M.. Vancomycin loaded halloysite nanotubes embedded in silk fibroin hydrogel applicable for bone tissue
engineering. Int. J. Polym. Mater . 2020;69: 32–43.
41-Sava, S., Tonea, A., Stanca, B., Alb, C., Sarosi, C., Dudea, D.. The study of new composites with graphene used in dentistry. Studia Universitatis Babes-Bolyai, Chemia, 2015 ;p.
60.
42-Shin SW, Song IH, Um SH. Role of Physicochemical Properties in Nanoparticle Toxicity. Nanomaterials (Basel). 2015 Aug 19;5(3):1351-1365.
43. Li, Z.; Hulderman, T.; Salmen, R.; Chapman, R.; Leonard, S.S.; Young, S.H.; Shvedova, A.; Luster, M.I.; Simeonova, P.P. Cardiovascular effects of pulmonary exposure to single-
wall carbon nanotubes. Environ. Health Perspect. 2007, 115, 377–382.
44. Bantz, C.; Koshkina, O.; Lang, T.; Galla, H.-J.; Kirkpatrick, C.J.; Stauber, R.H.; Maskos, M. The surface properties of nanoparticles determine the agglomeration state and the size
of the particles under physiological conditions. Beilstein J. Nanotechnol. 2014, 5, 1774–1786.
45. Donaldson, K.; Aitken, R.; Tran, L.; Stone, V.; Duffin, R.; Forrest, G.; Alexander, A. Carbon nanotubes: A review of their properties in relation to pulmonary toxicology and
workplace safety. Toxicol. Sci. 2006, 92, 5–22.
46-Heinemann M, Schäfer HG. Guidance for handling and use of nanomaterials at the workplace. Hum Exp Toxicol. 2009 ;28:407-11.
“
Thank you