Fahlman B.D. Materials Chemistry

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– National Cancer Institute Alliance for Nanotechnology in Cancer (Bethesda, MD),

http://nano.cancer.gov/

– ASME Nanotechnology Institute (New York, NY), http://nano.asme.org

– Nanotechnology Institute (Philadelphia, PA), http://nanotechinstitute.org

– Center for Nanoscale Chemical–Electrical–Mechanical Manufacturing Systems

(Urbana, IL), http://www.nano-cemms.uiuc.edu/

– Nano/Bio Interface Center (University of Pennsylvania), http://www.nanotech.

upenn.edu/

– Center for Nanotechnology in Society (University of California, Santa Barbara),

http://www.cns.ucsb.edu/

– Center for Nanote chnolo gy in Society (Arizona State University), http://cns.asu.

edu

– The NanoTechnology Group, Inc. (Nanoscience educational outreach, Wells,

TX), http://www.tntg.org/

– Nanotechnology Law Report (Washington, D.C.), http://www.nanolawreport.com/

– The Foresight Institute (Palo Alto, CA), http://www.foresight.org

– The Institute for Soldier Nanotechnologies (Massachusetts Institute of Technology),

http://web.mit.edu/isn/aboutisn/index.html

The ﬁrst nationa l network focused on the design/fabrication/testing of nanoma-

terials was instituted in 2004 through funding from the National Science Foundation.

The National Nanotechnology Infrastructure Network (NNIN) consist s of a con-

glomerate of 14 sites across the country (Figure 6.1) that are focused on all aspects

of nanomaterials. Since “nanotechnology” is such an interdisciplinary ﬁeld, many

more nano-related research centers will likely be instituted in the near future.

However, as with all scientiﬁc disciplines, a major roadb lock toward research

progress in the U.S. is domestic student recruitment. There are a declining number

of degrees awarded in the sciences within recent years (from B.S. to Ph.D. levels) in

the U.S., relative to other foreign countries (e.g., China, India). This represents

an ominous forecast that our advanced technology and warfare capabilities will

greatly lag behind other countries, threatening our everyday way of life and the

“superpower” status long enjoyed by the U.S.

The introduction of a new architecture such as nanomaterials necessitates the need

for new terminology and methods of classiﬁcation and characterization. We must also

understand the mechanisms by which individual nanostructures may assemble into

larger materials, as this will greatly affect the properties of the bulk device for a

particular application. This chapter will focus on all of these important issues, with an

introduction to the various types of nanomaterials, laboratory techniques used for their

synthesis, and (perhaps most importantly) their role in current/future applications.

6.1. NANOTOXICITY

As exciting as the futuristic applications may sound, is it possible that such techno-

logical growth may be associated with dire societal consequences? In Eric Drexler’s

book “Engines of Creation,”

[3]

it was forecasted that self-replicating nanomachines

would take over all life on Earth! Although that notion is far from reality, there may

458 6 Nanomaterials

be more serious issues that arise through introduction of nanomaterials into the

biosphere. Since we haven’t yet determined the extent of long-term effects that may

arise from the widescale introduction of nanoscale materials, are we on the verge of

upsetting the natural balance in ways that cannot be overturned?

History has revealed that chemistry is a two-edged swo rd, with beneﬁts that

greatly imp rove our lives but also negative consequences for human health and

our environment. For example, think of the chloroﬂuor ocarbons (CFCs) that were

once used for refrigerants. Their discovery was heralded as one of the greatest

triumphs of modern science. Alas, many years after their worldwide adoption,

it was realized that they contributed to the ozone hole and likely increase in the

incidences of skin cancer. Likewise, emissions from factories and automob iles were

not considered as problematic many years ago, but we are now aware of the

destructive consequences of these sources (e.g., acid rain and global warming –

the leading cause of catastrophic changes in our climate/weather patterns).

The number of engineered nanostructures is expanding at an astounding pace.

Nanomaterials are already used in a diverse range of products such as cosmetics,

electronics, sporting equipment, fuel catalysts, food additives, paints, drug-delivery/

biomedicine, ultraﬁltration, stain-/wrinkle-free textiles, scratch-resistant coatings, and

many more. With so many stakeholders in the nanotechnology arena who stand to

make a lot of money from commercial products,

[4]

it is no wonder why the technologi-

cal innovation has far surpassed nanotoxicity studies. In fact, it is estimated that only 3–

5% of nanotechnology research funding is currently being spent on determining the

potential health and environmental impacts of nanomaterials. Most of the early work

Figure 6.1. The 14 sites of the National Nanotechnology Infrastructure Network. Reproduced from

http://www.nnin.org.

6.1. Nanotoxicity 459

has taken place in the European Union,

[5]

with the assessment of toxicological/

environmental consequences of nanoscale materials via comparisons to known

contaminants such as colloids, aerosols/smoke/soot particulates, and asbestos.

As we will see later in this chapter, not only is one able to alter a nanostructure

by the types of atoms and their stoichiometries, but also their 3-D arrangement.

With such profound nanostructural variety, it is no wonder that standardized

toxicokinetics studies (i.e., absorption, distribution, metabolism, and excretion

characteristics) are still greatly lacking. For this to occur, there is a need for reference

nanomaterials that would allow a systematic ‘structure vs. toxicity’ assessment for

various classes of nanostru ctures. To date, the only commercially-available reference

materials are spherical nanoparticles that are used to calibrate particle-size analyzers.

Such reference materials will only be possible once we have standardized protocols

for the synthesis and characterization of various types of nanomaterials, an active

area of investigation at the National Institute of Standards and Technology (NIST).

The toxicity and fate of a nanostructure (Figure 6.2) is governed by physical

properties such as its size distribution, morphology, degree of agglomeration,

speciﬁc surface area, crystallinity, and aspect ratio. The size reduction of a bulk

material to the nanoregime results in an exponential increase in its surface:volume

Figure 6.2. Some possible exposure routes for nanostructures based on current/potential applications.

Reproduced with permission from “Nanoscience and Nanotechnologies: Opportunities and Uncertainties”,

Nanoscience and Nanotechnologies, July 2004. Copyright the Royal Society 2004.

460 6 Nanomaterials

ratio. Hence, nanoparticles are generally more toxic than larger particulates of the

same insoluble material (on a mass dose basis), since relatively more molecules of

the material are available on its surface thus enhancing its intrinsic toxicity.

[6]

In addition, chemic al properties that govern overall reactivity and solubility also

contribute to nanotoxicity such as purity, atomic composition/structure, and surface

chemistry (e.g., charge, reactive/defect sites, functionalization, protective coating).

[7]

The most common exposure routes for nanostructures are inhalation, ingestion,

and uptake through the skin; intravenous injection may also be used for medical

purposes (e.g., drug-delivery). The following represent some important questions

that are currently being investigated, along with recent data

[8]

(i) What is the danger of exposure to nanomaterials via skin absorption, ingestion,

or inhalation routes?

The ﬁrst news report on the potential damaging effects of nanoscale materials

surfaced about a decade ago, when TiO

/ZnO nanoparticles from sunscreen

were found to cause free radicals in skin cells, damaging DNA.

[9]

Since then,

there have been an increasing numb er of such reports suggesting that nanos-

tructures are able to traverse across membranes in the body, with an increasing

toxicity with decreasing nanoparticulate dimensions. Perhaps the most widely

reported study surfaced in mid-2004, where it was shown that fullerenes, a

nanoscale allotrope of carbon, cause brain damage in aquatic species.

[10]

Skin Absorption

Skin represents the largest organ in our bodies, and serves as the ﬁrst stage

of protection against the uptake of airborne and/or solubilized contami-

nants from our surroundin gs. There are three layers that comprise skin: the

epidermis, dermis, and hypodermis; the outermost layer of the epidermis

is referred to as the stratum corneum (Figure 6.3), and consists of dead

cells that are strongly keratinized. However, o nce particulates are able to

diffuse across this barrier (known as percutaneous penetration), absorption

through underlying skin layers may take place. If resorption takes place, the

compound is taken into the vascular system (lymph and/or blood vessels) and

is delivered to organs system-wide. It has been shown that nanomaterials have

a greater risk of being absorbed through the skin than larger particulates.

[11]

Though the therapeutic absorption of nanoparticles through skin would

be desired for drug-delivery applications, we need to identify the health

risks posed by unintentional absorption of nanostructures through the

skin; for instance, involving personnel active in nanomaterials synthesis/

characterization.

The structural diversity of nanostructures equates to amazingly complex uptake/

absorption proﬁles through skin – much more so than bulk chemical agents

(e.g., organic/inorganic liquids, solutions, gases, etc.), of which have pre-

dictable diffusion/absorption proﬁles. Nanostructures may move between

individual cells of the stratum corneum (intercellular), through cells (trans-

cellular), or through the hair follicle or sweat ducts (transappendageal).

[12]

6.1. Nanotoxicity 461

Thus far, in vivo (living organism) diffusion-based studies have been per-

formed on pig skin, since it represents the closest match to humans.

In contrast, in vitro (tissue/cell) testing is used to determine the starting

dose for in vivo toxicity assays.

To date, the greatest skin exposure to nanostructures is from prolonged contact

with over-the-counter pharmaceutical and cosmetic formulations (Table 6.1).

Fullerenes (carbon clusters such as C

, etc. – discussed later) are present

in a n umber of these products, as well as other therapeutic agents that exploit

their inherent phototoxic properties.

[13]

Water-soluble aggregates of C

may exhibit signiﬁcant cytotoxicity even at concentrations as low as

20 ppb; however, fullerenes with different surface functionalization (e.g.,

2–3

7–9

(OH)

12–15

]

(2–3)

and C

(OH)

) are signiﬁcantly less cyto-

toxic.

[14]

The toxicity of C

-based nanostructures is thought to arise from the

degree of oxygen radicals generated, which is less pronounced for more

heavily derivatized (and water-soluble) fullerenes. Amino acid functionalized

fullerenes have also been shown to penetrate the outer layers of ﬂexed or

imperfect skin (not intact skin).

[15]

In fact, the relationship between nanopar-

ticulate absorption and mechanical ﬂexing is likely responsible for the high

onset of podoconiosis in u nprotected feet that come into contact with certain

soils that have high concentrations of Be and Zr.

[16]

Figure 6.3. Cross-section illustration of skin. Reproduced with permission from Monteiro-Riviere, N. A.

Comparative Anatomy, Physiology and Biochemistry of Mammalian Skin” in Dermal and Ocular

Toxicology, Hobson D. W., ed. Boca Raton: CRC Press, 1991.

462 6 Nanomaterials

Inorganic-based nanocrystals such as quantum dots (QDs)

[18]

and TiO

[19]

have

also been shown to penetrate the human stratum corneum and hair follicles,

which may further interact with the immune system.

[20]

Most importantly, it

has been demonstrated that QDs are able to penetrate intact skin, without the

assistance of any mechanical stressors.

[21]

The lipid layers within the cells of

the stratum corneum are thought to form a pathway for the migration of

nanoparticles into the skin, which may then be sequestered (phagocytized) by

the Langerhans cells.

[22]

However, surface-functionalized QDs have also

been noted to exhibit signiﬁcant penetration to the highly vascularized der-

mis, offe ring a route for systemic absorption.

[21]

In fact, it is believed that the

dermal translocation of nanoparticulates may follow the same pathway(s) as

viruses such as Herpes, which closely interact with the peripheral and central

nervous systems. However, there are other contradictory studies that have

shown that metallic nanoparticles read ily penetrate the stratum corneum and

hair follicles, but not beyond the epidermis in full-thickness human skin

studies.

[23]

It should be noted that high aspect ratio nanostructures such as

carbon nanotubes have also been shown to be absorbed within human epider-

mal kera tinocytes, giving rise to an irritation response.

[24]

However, there are

currently no reports of pronounced dermal migration of these nanostructures.

Inhalation or Ingestion

The danger of unintentional inhalation of nanostructures is not limited to work-

ers and researchers speciﬁcally involved in nanotechnology-related ﬁelds.

In fact, there are a surprisingly large number of nanoparticles in our ambient

atmosphere, reaching as high as 10

–10

nanoparticles/L of air in both urban

Table 6.1. List of Nanostructures Commonly Present in Cosmetics Formulations

[17]

Fullerenes

Anti-aging cream, around-eye cream

Vitamin Nanocapsules or Nanosized Vitamins

After-sun products, bronzer/highlighter, sunscreen/tanning oil

Nanosized ZnO and/or TiO

(coated or uncoated with dimethicone)

Anti-aging cream, blush, bronzer/highlighter, concealer (also may contain Al nanoparticles), anti-itch

cream, diaper cream, eye shadow, foundation, lip balm, sunscreen/tanning oil

Nanosomes (e.g., sodium lactate, calendula, witch hazel, ginseng, urea, vitamins (A, E, B5),

a-bisabolol, germal (II))

Anti-aging cream, body-ﬁrming lotion, concealer, body wash/cleanser

Nanosized Liposomes

Anti-aging cream, around-eye cream, facial moisturizer

Nano-delivery system

Facial moisturizer, body-ﬁrming lotion

Lyphazome nanospheres

Around-eye cream, moisturizer, nail treatment

Nanosized Minerals (e.g., rose quartz, talc, topaz)

Concealer, exfoliant/scrub, facial cleanser, facial moisturizer, foundation, glitter, lip gloss, lipstick, mask,

sunscreen/tanning oil

6.1. Nanotoxicity 463

(e.g., automobile exhaust, building-material particles) and rural (e.g., dust,

diesel exhaust, combustion of wood, waste, etc.) areas.

[25]

Diesel exhaust

emissions are comprised of a wide distribution of particle sizes, with the bulk

of the particulates with dimensions <50 nm – well within the nano range.

However, even gasoline exhaust gases contain nanopart iculates, ranging from

1.9  10

to 9.9  10

particles.km

1

and 2.2  10

to 1.1  10

particles.

1

fuel, with the greatest concentrations and smallest sizes associated with

high-speed road trafﬁc.

[26]

Table 6.2 compares the number and size of

nanoparticles in a typical amb ient environment of a variety of workplaces.

It has been reported that nanoparticles may enter the circulation system of

rodents via the respiratory or gastro-intestinal tracts, which may then reach

other target sites such as the liver, spleen, heart or brain (Figure 6.4).

[28]

Regarding ingestion, smaller sizes of nanoparticulates resulted in higher

organ uptake, whereas larger agglomerates were found almost exclusively

within the GI tract.

[29]

Based on the limited data available thus far, it is likely

that size is the predominant factor that governs overall translocation of

ingested nanostructures, which must cross the GI tract barrier in order to

be distributed into the circulat ion system.

As one would expect, the extent of circulation through the body increases when

the nanostructures are functionalized with a hydrophilic and/or positively-

charged surface. In contrast, inhaled insoluble nanoparticulates mostly

remain in the lungs, which are then transported via mucociliary action to

the GI tract where they leave the body as fecal excr etion. Thus far, reports

indicate that only about 1% of inhaled nanoparticles are translocated from the

lungs across the air-blood barrier, being accumulated in secondary target

organs (liver, spleen, kidneys, heart, and brain) as well as in soft tissue and

bone. However, there are precedents of more extensive organ uptake (as

much as 10% of the administered dose) for small-diameter nanostructures,

with dimensions <10 nm.

[30]

A recent study has also shown that rat-inhaled

magnetic nanoparticles with relatively larg e diameters of 50 nm are still able

to penetrate the blood-testes and blood-brain barriers.

[31]

Other direct evi-

dence for translocation of metallic nanoparticles into the olfactory bulb from

nasal exposure in rats has also been demonstrated;

[32]

in one case, observed in

the brain up to 6 months after the inhalation exposure was administered.

[33]

Table 6.2. Comparison of Environmental Nanoparticles in a Variety of Workplaces

[27]

Workplace Nanoparticle concentration

(particles.cm

3

)

Average size (nm)

Silicon processing up to 100,000 280–520

Metal grinding up to 130,000 17–170

Soldering up to 400,000 36–64

Plasma cutting up to 500,000 120–180

Bakery up to 640,000 32–109

Airport ﬁeld up to 700,000 <45

Welding 100,000–40,000,000 40–600

Particles within the 14–673 nm size range only.

464 6 Nanomaterials

Perhaps most interestingly, the human inhalation of diesel exhaust is reported

to give rise to changes in brain activity, as demonstrated by changes in EEG

signals.

[34]

More studies are needed to determine whether nanoparticle expo-

sure is a contributing factor in the relatively high onset of brain diseases

occurring throughout the world.

Everyone is familiar with the toxicological effects generated from the inhalation

of long ﬁbrous materials such as asbestos. The form of cancer caused

by asbestos exposure is known as mesothelioma – responsible for ca. 3,000

deaths per year in the U.S. and signiﬁcantly more in other countries such as

Britain, Australia and Belgium . Two recent reports have investigated the

toxicity of analogous high aspect ratio (i.e., length:diameter ratio) nanostruc-

tures known as carbon nanotubes (CNTs). Their studies showed that nano-

tubes induced mesothelioma in mice, with the greatest toxicity occurring as

the aspect ratio increased.

[35]

Another recent study by Pacurari et al. used

cultured mesothelial cells to show that CNTs induced the activation of

molecular-signaling pathways associated with oxidative stress, similarly to

asbestos.

[36]

In addition, surf ace functionalization of carbon nanotubes with

hydroxyl (—OH), carbonyl (C═O), and carboxyl (COOH) groups, as formed

during acid puriﬁcation steps, has been shown to generate a greater cytotox-

icity than pristine analogues.

[37]

Figure 6.4. Scheme illustrating the absorption, translocation, and excretory pathways of nanostructures

within the body. The solid arrows indicate conﬁrmed routes, whereas dashed arrows indicate potential

routes. BBB refers to the blood-brain barrier and CSBB is the cerebrospinal-brain barrier. Adapted from

Oberdorster, G. Nanoparticles (NP) and the Brain: Pathways of Translocations and Effects, International

conference on Nanotechnology, Cincinnati, Ohio, Dec. 7, 2006. May be accessed online at: http://

www.uc.edu/NOEHS/pdf/Thursday/Copy%20of%20Cincinnati%20NIOSoberdorsterH.pdf.

6.1. Nanotoxicity 465

In addition to size and surface-functionalization effects, there is also a com-

positional effect of nanoparticulates on their resultant toxicity. For instance,

the cytotoxicity of carbon black has been shown to be more severe than

that of titanium dioxide for identical particle sizes.

[38]

In addition, DuPont

researchers have recently found that TiO

nanoparticles were not increasingly

more toxic in rats than larger (micron-sized) particulates. Whereas both sizes

of TiO

gave rise to an inﬂammatory response that lasted only a week, quartz

nanoparticles were found to trigger a longer inﬂammatory response lasting for

months – again, not unlike micron-sized quartz particles.

[39]

What generates even more complexity is that nanoparticles may react with one

another in the atmosphere, generating complex aggregates that may exhibit

very different toxicity proﬁles than their original native compositions.

[40]

No wonder we are having trouble identifying a standard toxicity proﬁle for

particular nanoparticles – we must consider their exact compositions, aggre-

gate size, surface structure /charge at the time of ingestion/absorption.

(ii) Do nanomaterials bioaccumulate?

The use of nanomaterials for drug-delivery and cancer-targeting applications

exploits their ability to localize within certain cells within the body. For

instance, coated magnetite nanoparticles were found within human

mammary carcinoma cells,

[41]

and we have already seen that functionalized

carbonaceous nanostructures (fullerenes, carbon nanotubes) may become

localized within human epidermal keratinocytes (HEKs).

[42]

Nanocrystals

known as quantum dots (QDs) feature a tunab le coating to improve their

aqueous solubility and facilitate the attachment of antibodies or other thera-

peutic/diagnostic moieties for cell imaging, immunohis tochemistry, and

cancer-targeting applications.

[43]

Depending on the type of coating present,

QDs have been shown to accumulate within a variety of human cells.

[44]

A recent report by Zh ang and Monteiro-Riviere provides the ﬁrst mechanis-

tic insights for the uptake of quantum dots by cells, which is governed by

their size, surface coating and charge.

[45]

It is now recognized by the breadth of research studies that materials with low

solubility or degradation proﬁles may accumulate within biological systems

and persist there for long durations. Studies have shown that bacteria and

living cells are capable of taking up nanosized particulates,

[46]

which has

been recently acknowledged by the U.S. Environmental Protection Agency

(EPA) as ‘providing the basis for potential bioaccumulation in the food

chain’.

[47]

Further, the presence of nanoparticles has been shown to

enhance the bioaccumulation of other toxic materials such as Cd in aquatic

species.

[48]

A recent study has also demonstrated that nanostructures may

also be transferred to offspring, which may even affect future generations of

species.

[49]

There is also evidence that exposure to various nanostructures will result in

either direct (oxidative cellular stress) or indirect (inﬂam mation-mediated)

genotoxicity.

[50]

Their small size allows nanoparticulates to penetrate into

466 6 Nanomaterials

regions such as the mitochondria and nucleus of the cell, the latter of which

would yield direct intera ction with DNA. Recent studies have shown that

unmetabolized nanomaterials may resu lt in granulomas,

[51]

lesions (areas of

damaged cells or tissue),

[52]

and cancer.

[53]

There is also evidence from

animal studies that some nanoparticles can cross the placenta, posing

particularly signiﬁcant risks to developing embryos.

[54]

However, even if

the nanoparticles are not able to cross blood-brain or placental barriers, there

still may be cellular damage. A new mechanism elucidated by Bhabra et al.

has shown that Co-Cr nanoparticles of ca. 30 nm diameter are able to cause

damage to human ﬁbroblast cells, even across an intact cellular barrier.

[55]

(iii) What is the fate, transport, and transformation of nanosized materials after

they enter the environment?

Unfortunately, the majority of nanostructures currently in production for appli-

cations consist of non-biodegradable sub-units. Further, nanostructures

often exhibit a low solubility, may be transported long distances by wind,

water, and wildlife, and have a strong propensity to form aggregates. All of

these factors suggest that nanomaterials will have a lasting presence within

the environment. In general, the fate of a nanomaterial within an environ-

mental medium such as soil and water will be governed by the inherent

properties of the nanostructure discussed above, as well as its reactivity

with the particular medium that might affect its degree of agglomeration

transformation into a more or less stable material (Figure 6.5).

Figure 6.5. Possible nanoparticle modiﬁcations within the environment. Reproduced with permission

Chemical Society.

6.1. Nanotoxicity 467