Nano 101: A Review of the Art and Science of Nanotechnology

Nano 101: A Review of
the Art and Science of
Nanotechnology
Mark Liffers, CIH
Jason Criscione, PhD
JM Criscione
Consulting, LLC

Meet Your Moderator
James Ciccone

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Meet Your Presenters
Mark Liffers, CIH Jason Criscione, PhD

Agenda
What are Nanoparticles?
Types of Nanoparticles
EH&S Issues
Evaluation and Control
Nano Safety Programs
Summary / Q&A

Which best
describes
your facility?

What are They?
• The ASTM Committee on Nanotechnology defines a
nanoparticle as a particle with lengths in two or three
dimensions between 1 and 100 nanometers (nm)
• Nanoparticles might be composed of many different base
materials and may take on different shapes including:
spheres, rods, discs, cubes, tubes, globular or amorphous
• Nano-particles or -materials used in the laboratory are likely
to be in the form of a powder, a suspension, or a solid matrix
• Nanomaterials properties can differ from those of the same
materials with micron- or mm-scale dimensions

Industry Overview
Noninvasive molecular imaging
Therapeutic delivery
http://mritnt.com/education-centre/common-uses/mri-of-the-brain/
Freiberg, S and Zhu, X. Int. J. Pharmaceutics. (2004) 282, 1–18
Industries:
• Biotechnology
• Pharmaceuticals
• Cosmetics
• Diagnostics
• Sensors
• Electronics
• Pigments
• Ceramics
• Textiles
• Water Purification
Fields of Research:
• Chemistry
• Physics
• Biology
• Biomedical Engineering
• Chemical Engineering
• Electrical Engineering
• Mechanical Engineering
• Drug Delivery
• Tissue Engineering
• Medical Imaging
Biomedical Engineering Applications

• Nanopowders are solid powders of nanoparticles, often containing micron-sized
agglomerates
• These agglomerates can be dispersed by mechanical agitation (ultrasonics, milling,
homogenization)
• Resulting nanoparticle dispersions are suspensions of nanoparticles in water or
organic solvents
Nanopowders and Dispersions
Quantum DotsCarbon Nanotubes Gold Nanorods

• High surface-to-volume ratio and surface area
• Aspect ratio
• Surface charge (+, -, or neutral)
• Size of 1<x<100 nm in 2- or 3-D
• Shape (spherical, rod, cubic, tubular, amorphous)
• Porosity (solid, matrix, hydrogel, porous, hollow)
• Biodegradable vs. non-biodegradable
• Surface functionality that gives rise to charge
• Amine, carboxyl, hydroxyl, thiol, acetyl, sulfonyl, PEG
• Coupling of surface ligands and molecules
Properties of
Nanoparticles

Classes of Nanoparticles
http://www.sigmaaldrich.com/

Kolhar P., et al. PNAS (2013) 110 (26), 10753-10758.
Ragheb RRT., et al. Magn Reson Med (2013) 70, 1748-1760.
PLGA NPs
Polystyrene NPs
Biodegradable
Non-biodegradable
-Is it a polymeric nanoparticle?
-If so, is it biodegradable?
-If so, what are the degradation products?
-If so, is it non-biodegradable?
-Are the polymeric components
FDA-approved?
Polymeric
Nanoparticles

http://www.cytodiagnostics.com
http://nanocomposix.com/technology/gold Demortiere A., et al. Nanoscale. (2011) 3, 225-232.
http://www.sigmaaldrich.com/
Gold NPsIron Oxide NPs Silica-coated Au
core-shell NPs
Cd-Se Q-dots
-Is it a metallic nanoparticle or nanocrystal?
-If so, is it comprised of a noble metal?
-If so, is it a metal oxide nanoparticle?
-If so, is it a core-shell nanoparticle?
-If so, what comprises the core and the shell?
-If so, is it a quantum dot?
-If so, what comprises the quantum dot?
Metallic
Nanoparticles

http://www.alibaba.com
Nandiyanto ABD., et al. Microporous and Mesoporous Materials (2009) 120, 447-453.
Trofimova EY., et al. Nanotechnology (2013) 24, 155601-611.
Silica NPsExamples of Ceramic
Nanoparticles or Nanopowders
Type Morphology
Silica Spherical
Silicon carbide Cubic, hexagonal
Silicon nitride (α) Cubic, spherical
Silicon nitride (β) Rod-like
Titanium dioxide Spherical
Aluminum oxide Spherical
Scale bar is 1 𝜇m
Ceramic Nanoparticles

http://www.cabot-corp.com
http://www.nano-lab.com/single-walled-carbon-nanotubes.html
http://www.chemicool.com/elements/carbon.html
-Is it a carbon black?
-Is it a fullerene?
-Is it a carbon nanotube?
-If so, is it single or multi-walled?
-If so, is it surface-modified?
-If so, what is the surface area and
aspect ratio?
Carbon-based
Nanoparticles

Bitounis D., et al. ISRN Pharm (2012) doi:10.5402/2012/738432.
-Is it a vesicular nanoparticle?
-If so, is it a liposomal
nanoparticle?
-If so, is it comprised of
natural or synthetic
lipids?
-If so, is it a polymersomal
nanoparticle?
-If so, what block
copolymer are used?
-Is it a micellar nanoparticle?
-If so, what surfactants or
amphiphilic polymers are
used?
Vesicular/Micellar
Nanoparticles

Macromolecular
Nanoparticles
https://macrocyclics.com
Tomalia DA, et al. Tetrahedron 59 (2003) 3799–3813
Svenson S and Tomalia DA. Adv Drug Deliv Rev 57 (2005) 2106– 2129
Dendritic
Macrocyclic chelator
-Is it a dendritic polymer-based nanoparticle?
-e.g. PAMAM, PEI, PEG, or polyester-
based dendrimers or dendrons
-Is it a macrocyclic or acyclic metal chelator?
-e.g. DTPA, DOTA, NOTA
-If so, what metal is chelated?

Multifunctional
Nanoparticles
Potential biomedical applications
Theranostics
= small molecule, protein, or
oligonucleotides
= MRI or CT
= PET or SPECT
= PEGylation
= Optical
= antibody, peptide, sugar, or
aptamer
Multimodal imagingIntelligent systems

How are the Nanoparticles being Prepared?
-Are the surfaces being functionalized?
-Are the surfaces going to incorporate
poly(ethylene glycol)?
-Are the nanoparticles going to encapsulate
therapeutics?
-Small-molecule drugs
-Genetic materials
-Proteins or peptides
-Are the nanoparticles going to encapsulate
fluorescent dye molecules?
-Via nanoprecipitation?
-Via nano-emulsification?
-Via electro-spinning?
-Via electro-spraying?
-Via extrusion?
-Via self-assembly?
-Via chemical cross-link?
-Via chemical synthetic methods?
-Via chemical vapor deposition (CVD)?
-Via catalytic growth?
-Via incomplete combustion?
-Via mechanical milling or grinding?

Characterization of Nanoparticle Physico-
chemical Properties
What are the nanoparticles size distribution and how is this characterized?
-5nm < x <200 nm?
-Is the size measured by dry powder radius? (e.g. SEM, TEM)
-Is the size measured by hydrodynamic radius? (e.g. DLS, SEC)
What is the geometric shape of
the nanoparticle?
-Amorphous?
-Spherical?
-Rods?
-Cubes?
-Tubular?
What is the aspect ratio
of the nanoparticle?
What is the surface charge and character?
-Is it positive, negative or neutral?
-Is it hydrophilic or hydrophobic?
-Is it lipophilic or lipophobic?
-What is the surface functionality giving
rise to the surface charge?
-amine
-carboxyl
-hydroxyl
-sulfonyl
-acetyl
-PEGylation
What is the surface area of
the nanoparticle?

How are the Nanoparticles Handled?
-Is the material handled as a dry nanopowder?
-Are the balances located in a chemical fume hood or biosafety cabinet?
-Is there any transferring of dry nanopowders?
-Where is this performed?
-Is the material handled as a nano-emulsion, -suspension, or -dispersion?
-Are the solutions transferred? Or aliquotted?
-Where is this performed?
-Are the solutions lyophilized?
-Are appropriate engineering controls available and utilized to enable safe handling?
-biosafety cabinets
-laminar flow hoods
-downdraft tables
-chemical fume hoods
-glove boxes
-ESD mats and devices

Has your
facility ever
conducted a
nano
assessment?

• We know very little about exposures during
common lab and industry processes
• Transferring and weighing NM
• Mixing and pouring NM
• Sonicating dispersions
• Cleaning of equipment and glassware
• Cleaning of surfaces
• The types of functionalized NM are vast
and so little have been studied
Health, Safety and Environmental Issues
Mesotheliomas have been produced in mice with MWCNTs that
are fibers with long aspect ratios (Takagi 2008, Poland 2008)
Multi-walled carbon nanotube penetrating the pleura of the lung.
Courtesy of Robert Mercer, and Diane Schwegler- Berry, NIOSH

• The molecular structure of nanoparticles and the relatively greater
surface area give these particles different chemical reactivities than
for larger structures made from the same elements or molecules
• Nanoparticles present a unique challenge from an occupational
health perspective as there is a limited amount of toxicological
data currently available for review
• What does “FDA approved materials” mean?
• Currently, agencies charged with providing safety guidelines,
including NIOSH, the NIH and the EPA, advocate caution in
research, with a view toward minimizing or eliminating
exposures to nanoparticles
Health, Safety and
Environmental Issues

Occupational Standards are Emerging
NIOSH recommended exposure limit (REL)
• 2.4 mg/m3 for pigmentary titanium dioxide (TiO2)
• 0.3 mg/m3 for ultrafine TiO2.
• (NIOSH has also concluded that ultrafine TiO2 is a potential
occupational carcinogen)
• 1 ug/m3 for carbon nanotubes or carbon nanofibers
• Based on limit of detection
• Draft CIB 10 μg/m3 (8-hour TWA) for silver nanomaterials
OTHER
• Manufacturer OEL’s and Control Banding

NIOSH chose mass-based REL over
counting with electron microscopy
Animal toxicology studies are
mass-based
Counting protocols haven’t
been developed, although
ASTM has a committee
working on it

• Harvesting (Scraping material out of reactor)
– Small -inside fume hood
– Large - reactor in housing
• Bagging
• Packaging
• Mixing
• Weighing
• Nanocomposite machining
• Maintenance, filter change-outs
Common Processes

Laboratory research
• Limited data exists for research work
• At research scale, Tsai et al. (2008)
found that the handling of dry powders
consisting of nano-sized particles inside
laboratory fume hoods can result in a
significant release of airborne
nanoparticles from the fume hood into
the laboratory environment and the
researcher’s breathing zone
Common Processes

Examples of Potential Exposures
Photos courtesy of M. Methner, NIOSH

Exposure Pathways
• Inhalation. Respiratory absorption of airborne nanoparticles may occur through
the mucosal lining of the trachea or bronchioles, or the alveolus of the lungs.
Certain nanoparticles appear to penetrate deep into the lungs and may
translocate to other organs or pass through the blood-brain barrier Thus,
whenever possible, nanoparticles are to be handled in a form that is not easily
made airborne, such as in solution or on a substrate.
• Dermal absorption. In some cases nanoparticles have been shown to migrate
through skin and be circulated in the body. If the particle is carcinogenic or
allergenic, even tiny quantities may be biologically significant. Skin contact can
occur during the handling of liquid suspensions of nanoparticles or dry powders.
Skin absorption is much less likely for solid bound or matrixed nanomaterials.
• Ingestion. As with any material, ingestion can occur if good hygiene practices
are not followed. Once ingested, some types of nanoparticles might be absorbed
and transported within the body by the circulatory system.
• Injection. Exposure by accidental injection (skin puncture) is also a potential
route of exposure, especially when working with animals or needles.

Environmental Sampling and
Exposure Assessments
Photo courtesy of NIOSH
TSI Scanning Mobility Particle Sizer
Spectrometer

Worker Exposure
• One important point to consider in workplaces exposure
is that most exposures to nanomaterials are in the form
of aggregates and agglomerates.
• In those cases size measured by e.g. impactors or
mobility analyzers can not reveal the agglomeration state
and thus to which degree an agglomerate can break up
into many smaller units in the lung fluid.
• Thus results of such measurements cannot be directly
related to risk if particle number is a relevant measure of
this risk

Agglomeration of
Carbon nanotubes

Evaluation
• Strategies are being developed by a number of researchers
• Non-mass based metrics such as particle surface area or
particle number may be a reasonable approach.
• Evaluation should consider:
- ID emission sources
- Background and area monitoring
- Air concentration by direct reading instruments
- Measurement of air velocity patterns

Occupational Exposure
Assessments
• Aerosol mass concentration is a standard measure
• Use a filter-based personal sampler comprising
some form of inertial particle pre-selector.
• However, conventional pump-based filter sampling
is NOT the best solution for exposure assessment
for an aerosol of nanostructured particles.
Background Levels
• To assess occupational exposure to nanomaterials, it is
important to know background particles that include those
particles that penetrate from outdoors to indoors and those
that are suspended by background activities in the production
facility like combustion engines, heating units or cleaners.
• The particle number size distribution and the particle number
concentration are useful parameters for identifying sources of
particles

Occupational Exposure
Measurements
• Mass concentration, which is the parameter considered in
this form of sampling, is not well-suited to the toxicity
assessment of inhaled nanoparticles.
• Toxicity studies show that particle toxicity increases as
they become smaller
• None of the existing instruments used for monitoring
give specific information about particle concentration
below 1 μm aerodynamic diameter

Cascade impactor
• The cascade impactor is an example of a
traditional aerosol sampling method, which
provides the aerosol mass distribution for the
aerosol with respect to the aerodynamic
diameter of the collected particles.
• The last, smallest diameter stage only allows
nanoaerosols to be collected on a filter.
• The cut-off diameter of their last stage is more
than 250 nanometers
What’s an IH to Do?
Available Monitoring tools and Limitations

Tapered Element Oscillating Microbalance (TEOM)
Available IH Tools and Limitations
• Performs the measurement of the mass of a sampled
aerosol in a single operation
• The TEOM enables the measurement of aerosol
mass concentration ranging from μg/m3 to g/m3.
• Particles are collected on a glass tube-mounted filter,
the system being oscillated at a vibration frequency f.
• The variation in oscillation frequency is observed
when the aerosol is collected. This variation is
directly proportional to the mass of particles
deposited on the filter.
• Used for EPA air quality work
Model 1405-F Single Flow TEOM

Scanning Mobility Particle Sizer (SMPS)
TSI Scanning Mobility Particle
Sizer Spectrometer
• This instrument measures the particle number size
distribution. It is composed of a Differential Mobility
Analyser (DMA) which is coupled in series with a
Condensation Particle Counter (CPC).
• Size range of 2 nm to 1 micron
• An electric field is created and the airborne particles
drift according to their electrical mobility. Particle
size is then calculated from the mobility distribution.
• Particles must be neutralized at the DMA inlet using
radioactive sources (Kr85, Am241) to reach a state
of charge equilibrium. Transport could be an issue.

Electrical Low Pressure Impactor (ELPI)
Dekati® ELPI™
Electrical Low Pressure Impactor (77 lbs)
• Sampled particles are charged
electrically by corona effect at the
instrument inlet and neutralize their
charge by depositing themselves at the
collection stage corresponding to their
aerodynamic diameter.
• The current measured at each stage
enables the determination of the
particle number concentration
• Particle size to 10 microns

Condensation Particle Counter (CPC) or
Condensation Nuclei Counter (CNC)
TSI Nano Water-based
Condensation Particle Counter
3788 (18 lbs)
• This instrument measures the particles’ numerical
concentration in air sampled by laser optical detection.
• Optical reading restricted to particles with diameters
less than 100 nm requires their artificial growth for
detection purposes.
• To achieve this, sampled particles are used as alcohol
or water vapour condensation nuclei.
• This particle growth operation then enables the
detection of nanoparticles as small as three nm in
diameter in the case of the most sensitive instruments.

Nanoparticle Surface Aerosol Monitor (NSAM)
TSI AeroTrak Nanoparticle
Aerosol Monitor 9000 (16 lbs)
• This instrument measures the surface
concentration of an aerosol that would be
deposited either in the tracheobronchial or
alveolar section of the airway.
• Sampled aerosol particles are charged by a
corona effect-induced ion diffusion at their
surface. The number of charges carried by a
particle is related to its surface area. Particles
charged in this way are then collected on a filter,
which current conduction, measured against time,
allows to determine the surface concentration.
• This is a full measurement, but it does not
provide the particle size distribution of the
collected particles.

Agenda
What are Nanoparticles?
Types of Nanoparticles
EH&S Issues
Assessment and Control
Nano Safety Programs
Summary / Q&A

Basic Safety Guidelines for Handling
Engineered Nanoparticles
The current practices for
working with engineered
nanoparticles safely are
essentially the same as
one would use when
working with any
research chemical of
unknown toxicity…

If handling materials outside of a fume hood, biosafety cabinet or glovebox,
workers should wear protective equipment, including:
• Latex or nitrile gloves when handling nanoparticle powders and
nanoparticles in suspension (glove changes should be performed
frequently); Outer gloves should always be removed inside the hood or
under the influence of local exhaust ventilation and placed into a sealed
bag. This will prevent the particles from becoming airborne.
• Chemical splash goggles when working with nanomaterials in
suspension or dry powdered form.
• Lab coats should be laundered on a periodic basis. Do not take lab coats
home for laundering.
• Respirators (N95, N100, P100, half-face or full-face with P100 cartridges)
Basic Safety Guidelines

• When purchasing commercially available nanoscale materials, be sure to obtain
the Safety Data Sheet (SDS) and to review the information in the SDS with all
persons who will be working with the material. Note, however, that given the lack of
extensive data on nanoparticles, the information on an SDS may be more
descriptive of the properties of the bulk material.
• Nanoparticle solutions may be handled on the lab bench once placed in
solution.
• Transport of nanomaterials should employ a sealed secondary containment device.
• Work surfaces should be wet-wiped regularly – daily is recommended. Because
many engineered nanoparticles are not visible to the naked eye, surface
contamination may not be obvious. The cleaning solution should be compatible
with the vehicle in which the nanoparticles are suspended.
Basic Safety Guidelines for
Handling Engineered Nanoparticles

Managing Spills and Wastes
• All spills involving nanoparticles should be treated like a hazardous material spill
and cleaned up immediately.
• Wastes are classified and managed as the parent material(s).
• Solid wastes, where possible, should be converted to liquid wastes and
managed appropriately.
• The person cleaning up should wear double nitrile gloves and either vacuum up
the area with a HEPA filtered vacuum or wet wipe the area with towels, or
combination of the two.
• For spills that might result in airborne nanoparticles, proper respiratory protection
should be worn, such as a respirator with NIOSH-approved filters that are rated
as P-100 (HEPA).
• Do not brush or sweep spilled/dried nanoparticles.

Research Nano Safety Programs Vary Greatly
From one page handouts…
University Nanoparticle Safety
…to detailed SOPs
NIOSH Nanoparticle Safety

Common Plan Elements
Identification and Registration of EHS
Engineering Controls
• Chemical fume hood or biosafety cabinet w/ HEPA
filtration
• Glove boxes
• Laminar flow hoods
• ESD controls
Administrative/Work Practice Controls
• SOPs based on risk assessment
• ALARA principle
PPE
• Eyes, Hands, Body
• Respirators (N-95, P100)
Emergency and Waste Management procedures
• Eye wash/Shower
• Routine and Upset
Boron nanotube harvest

Hierarchy of Controls
Source: osha.gov
Hierarchy of Controls
• Select the highest
level that is feasible.
• If elimination or
substitution can’t be
used, a combination
of controls and PPE is
typically the most
effective control
measure.

Control Banding
CB Nanotool 2.0 LLNL

Thank You For Attending!
Call Us!
1-888-834-9697
www.triumvirate.com
Contact:
Mark Liffers:
mliffers@triumvirate.com
Practice Director, EHS Consulting
Triumvirate Environmental
Jason Criscione:
jason@jmcriscioneconsulting.com
Owner & Managing Director
JM Criscione Consulting LLC
Request a Free Consultation:
http://info.triumvirate.com/nano-safety-program-consultation

NIOSH References
Current Strategies for Engineering Controls in Nanomaterial
Production and Downstream Handling Processes, DHHS
(NIOSH) Publication No. 2014-102
Occupational Exposure to Carbon Nanotubes and
Nanofibers, DHHS (NIOSH) Publication No. 2013-145
Filling the Knowledge Gaps for Safe Nanotechnology in the
Workplace, DHHS (NIOSH) Publication No. 2013-101

Nano 101: A Review of the Art and Science of Nanotechnology

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Nano 101: A Review of the Art and Science of Nanotechnology