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Halloysite Clay Nanotubes for Loading and Sustained

REVIEW
Release of Functional Compounds
Yuri Lvov,* Wencai Wang, Liqun Zhang, and Rawil Fakhrullin

Clay minerals have a layered structure

Halloysite is an alumosilicate tubular clay with a diameter of 50 nm, an inner of tetrahedral silica oxide and octahedral
lumen of 15 nm and a length of 600–900 nm. It is a natural biocompatible Al, Fe, or Mg oxide. Kaolin clays are 1:1
nanomaterial available in thousands of tons at low price, which makes it a phyllosilicates and montmorillonite and
ilite clays are 2:1 phyllosilicates. Most of
good candidate for nanoarchitectural composites. The inner lumen of hal-
the research concerning clay materials is
loysite may be adjusted by etching to 20–30% of the tube volume and loading devoted to smectite clay groups (such as
with functional agents (antioxidants, anticorrosion agents, flame-retardant montmorillonite, bentonite, and hectorite)
agents, drugs, or proteins) allowing for formulations with sustained release or kaolin where ca. 1 nm-thick clay alumo-
tuned by the tube end-stoppers for hours and days. Clogging the tube ends silicate sheets are stacked in bulky plate-
in polymeric composites allows further extension of the release time. Thus, lets or processed with exfoliation to bilayer
sheets. However, alumosilicate clays may
antioxidant-loaded halloysite doped into rubber enhances anti-aging proper- have other morphologies, such as nanotu-
ties for at least 12 months. The addition of 3–5 wt% of halloysite increases bule halloysite and imogolate. The tubular
the strength of polymeric materials, and the possibility of the tube’s orienta- mineral halloysite was discovered more
tion promises a gradient of properties. Halloysite nanotubes are a promising than 100 years ago, but was utilized for
mesoporous media for catalytic nanoparticles that may be seeded on the tube applications only in the last 10–20 years
when it became available in pure form.[4–8]
surface or synthesized exclusively in the lumens, providing enhanced cata-
Almost every natural kaolin deposit has
lytic properties, especially at high temperatures. In vitro and in vivo studies a fraction of halloysite, which is often
on biological cells and worms indicate the safety of halloysite, and tests for referred to as rolled kaolin, but there are
efficient adsorption of mycotoxins in animals’ stomachs are also carried out. only a few deposits where halloysite is pre-
sented in almost pure form and contains
90–95 wt% of tubes (Figure 1). Very pure
1. Introduction halloysite nanotubes may be purchased from Sigma–Aldrich,
as well as directly from companies in the USA, New Zealand,
Clays are natural materials with proven biocompatibility and are China, Canada, and Turkey in tons. Annually, the ceramic
available in large amounts at low prices. They have nanoscale industry uses tens of thousands of tons of halloysite.[4] This is
organization and show many promising properties for various a minor fraction of the clays used in industry especially con-
applications.[1–3] Designing organized clay–polymeric compos- sidering typical consumption is in the millions tons; however,
ites demands well-defined clay nanoparticles. This means that halloysite has the advantage of utilizing existing processing
not only must we consider the chemical composition of the clay techniques, similar to other clays, but it has a unique elon-
but also the morphology of the clay, including the size, aspect gated rod-like shape with axis ratio of 20:1 and an inner lumen
ratio, and tertiary structure. which may contain different functional chemicals for sustained
(hours, days and months) release. Besides, halloysite dispersion
to single particles is much easier because these clay nanotubes
are not stacked together as platy kaolin, montmorillonite, or
Prof. Y. Lvov
Institute for Micromanufacturing bentonite particles.[5,7]
Louisiana Tech University
911 Hergot Ave, Ruston, LA 71272, USA
E-mail: [email protected]
Prof. Y. Lvov, Dr. R. Fakhrullin
2. Halloysite Structure
Bionanotechnology Lab
Kazan Federal University
2.1. Tubular Morphology
Kreml uramı 18, Kazan, Republic of Tatarstan
Russian Federation, 420008 The general stoichiometry of halloysite is Al2Si2O5(OH)4·nH2O,
Prof. W. Wang, Prof. L. Zhang where n = 4 for 1.0 nm wall-packing spacing (row halloysite)
State Key Laboratory of Organic-Inorganic Composites and 2 for 0.72 nm (dried sample). The interlayer water in 1 nm
Beijing University of Chemical Technology halloysite evaporates under heating and causes wall compres-
15 Chaoyang North Third Ring Rd. Beijing 100029, China
sion and smaller packing spacing. The tube wall is a crystalline
DOI: 10.1002/adma.201502341 multilayer belonging to the monoclinic system. The layer unit

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consists of a corner-shared tetrahedral SiO4 sheet stacked with

an edge-shared octahedral AlO6 sheet with an internal alu- Yuri M. Lvov is Professor of
minol group Al–OH. A water layer exists between the adjacent Chemistry, T. Pipes Eminent
two layers. Typically, 10–15 alumosilicate bilayers roll into the Endowed Chair on Micro and
cylinder and its wall packing may be examined with (00l) X-ray Nanosystems at Louisiana
Bragg reflection of 0.72 nm for dry halloysite (Scheme 1). Hal- Tech University. He was
loysite clay tubes have external diameter of 40–60 nm, internal among the pioneers of
diameter of 10–15 nm and length of 700–1000 nm (commer- polyelectrolyte layer-by-layer
cially available from Sigma–Aldrich, Applied Minerals Inc., nanoassembly, and he also
Imerys, and Henan Province, China). In some deposits, we developed tubule halloysite
observed halloysite tubes with length up to 3–5 µm (Aus- clay as nanocontainers
tralian and Canadian deposits) but in the size distribution for delivery and controlled
curve they have a minor fraction. Besides, clay tubes 1 µm release of drugs, proteins,
in length may have an advantage because it is a safe dimen- and functional chemicals (anticorrosion, antioxidant,
sion for macrophage removal of the nanoparticles from living flame-retardant).
organisms.[7] There are also larger diameter halloysite tubes
Liqun Zhang received his
(usually loosely rolled). The smaller clay nanotubes are most
Ph.D. from Beijing University
interesting for composites with sustained delivery chemicals
of Chemical Technology and
and drug formulations. In many cases, commercially available
was carried out postdoctoral
halloysite tubes are shorter (of 400–500 nm length) because
research at the Polymer
of harsh milling during industrial processing. For research
Science and Engineering
purposes, one can use gentler processing: crushing halloysite
Department of the University
mineral with a pestle, dispersing in water with sonication
of Akron and at Case
and removal by the larger particles, such as admixed quartz
Western Reserve University.
or kaolin, by sedimentation. Halloysite is stable up to 460 °C
His research focuses on
when de-hydroxylation occurs with a disruption of the tube-
elastomer science and
wall multilayer packing (the X-ray peak at 0.72 nm disappears)
technology, polymer nano-
and ca. 12 wt% mass decrease is detected by thermogravi-
composites, and biocompatible materials.
metric studies; however, the tubular shape of the clay is pre-
served up to 900 °C.[7]
Rawil F. Fakhrullin is
The outermost layer of the halloysite tubes is silica, so its sur-
Associate Professor at the
face electrical ξ-potential is ca. –30 mV at pH 4–8. This nano-
Department of Microbiology,
tube surface charge allows for their moderate 2–3 h colloidal
Institute of Fundamental
stability in water. This ξ-potential is less than the typical poten-
Medicine and Biology,
tial for pure silica particles (–50 mV) and may be explained by
Kazan Federal University. He
superposition of the tube’s negative outermost surface charges
received his Ph.D. from Kazan
with positive (alumina) inner lumen charge. Neutralization
State University in 2006, then
of the tube’s innermost positive charges with anionic species,
worked at the University of
such as polyanions or anionic amphiphiles, typically increases
Hull, UK, Yeditepe University,
the tube negativity to ξ-potential of –60 to –70 mV which pro-
Turkey, and Louisiana Tech
vides for very stable aqueous colloids of halloysite tubes.[9–12]
University, USA. His research
Halloysite with a positively charged Al(OH)3 inner lumen and
is focused on cell-surface engineering, drug delivery, tissue
a negatively charged SiO2 outer surface is among the rare nano-
engineering, and nanotoxicity.
tubes with a different composition of inner and outer surfaces.
Most of the reported non-clay nanotubes, such as carbon nano-
tubes, have the same inner and outer chemistry, which makes deposits at Dragon Mine in Utah, USA are located within a few
their selective lumen modification difficult. miles of a volcano.
Mineralogists disagree on the origin of halloysite tube for- Halloysite nanotubes have a density, porosity, and cati-
mation, and there are two points of view. The first idea advo- onic exchange capacity of 2.53 g cm–3, 50–60 cm2 g–1, and
cates the direct rolling of pre-formed kaolin sheets. It has been 30–50 × 10–2 mol kg–1, respectively.[7] This porosity reflects the
shown that halloysite tubes can be produced by sonication of availability of the inner and outer tube surfaces for adsorption,
kaolin in water with the addition of detergents for extended but does not include a possibility of guest molecules replacing
periods of times, which lends credibility to the first explana- intercalated water. Displacement of intercalated water mol-
tion of the origin of halloysite.[13–17] The second group believes ecules is possible with salt ions or small organic molecules,
that dissolution and co-precipitation of silicone and aluminum such as urea,[4,20] and may be controlled via increasing the wall
oxides from amorphous allophane and feldspar is responsible multilayer spacing up to 1.1–1.2 nm. Theoretically, this means
for halloysite formation. Natural halloysite is formed through that the interlayer surface could be available for gas adsorp-
weathering of volcanic making structures with curved concen- tion and could increase halloysite porosity to 700–800 cm2 g–1.
tric bands of kaolin layers;[18,19] for example, the rich halloysite However, our attempts to modify the spacing of the multilayers

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Figure 1. SEM, AFM, and TEM images of halloysite. Halloysite supplied by Applied Minerals Inc. USA (images c,e,f), and Henan province, China
(images a,b,d). Panel (c) was provided by and is used with permission from A. Zeitoun, Applied Minerals Inc.

have shown that the process is reversible. For example, urea (Figure 2).[21] This could triple the tube lumen volume from
intercalated between the walls increased the distance between 10 to 30 vol% making this container comparable with poly-
the walls from 0.72 nm to 1.1 nm, but after drying the modi- meric micro-/nanocapsule loading capacities. The etching pro-
fied sample and X-ray measurement, it was found that the layer cess starts at the tube openings, so that the lumen diameter is
spacing had collapsed back to 0.72 nm, an indication of the slightly smaller in the center. The authors explained the selec-
removal of the urea from the interlayer space. tive etching by dissolution of aluminum oxide in the acidic
environment.
This explanation is not completely clear, because acid
2.2. Selective Lumen Etching sequentially decomposes the inner alumina layer followed by
the silica layer. Probably, crystalline defects in the tube multi-
Two-component chemistry of halloysite tubes allows for a sepa- layer wall play a role in the further penetration of acid. During
rate and controlled acid etching of alumina or base decomposi- longer 15–20 h acid processing one can see the accumulation
tion of silica (Scheme 2).[21–24] Processing halloysite with 0.1 M of 3–4 nm diameter silica nanoparticles in the tubes’ lumen,
H2SO4 or HCl at a temperature 60 °C over 8 h allowed the accomplished by increasing perforation of the tube wall, and
lumens’ diameter to be increased from 12 ± 2 nm to 21 ± 4 nm finally converting the tubes into nanorods decorated with
while preserving the outermost tubes’ diameter at 50 ± 5 nm silica nanoparticles. During this process, the porosity of the

Scheme 1. a) Halloysite nanotubes are formed by rolling alumosilicate sheets so that alumina forms on the inside surface (green) and silica on the
outside surface (red). b-d) TEM and AFM images of the tube end.

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A simple and the most common method for increasing the

external hydrophobicity of halloysite is by treating its SiO2
surface with silanized agents (e.g., octadecyltrimethoxysilane,
tetraethoxysilane, or methacryloyl oxypropyltrimethoxysilane).
This is widely used for making clay nanotubes mixable with
nonpolar plastics, such as styrene–butadiene rubber or for
binding different agents to these nanotube surfaces[28,29] With
this, one can adjust the water surface contact angle of halloysite
between 12 and 100° (most commonly 40–60°).
The tube’s surface modification we described above is based
on covalent binding, and it may be advantageous in the stability
in chemically active media, such as salty sea water. However,
selective halloysite modification may be reached with simple
electrostatic adsorption of a negative component inside a posi-
tive tube lumen, and, vice versa, positive components onto
Scheme 2. Etching of halloysite nanotubes with acid or alkali (pH 2 or negative outermost silica (Scheme 4).[9–11,30] This modification
12) allows alumina or silica to be selectively removed, producing porous is much simpler and may be reached by stirring of halloysite
nanotubes with a larger lumen. with charged amphiphile molecules (e.g., sodium decanoic
acid and decyltrimethyl ammonium) or polyanions and polyca-
halloysite including the lumen increased from an initial 60 tions. Deposition of anionic compounds inside the tubes neu-
to 400–450 cm2 g–1.[23,24] Preliminary halloysite calcination at tralized internal positive charges and drastically increased the
800 °C makes the etching process more efficient. overall nanotube negativity, making the ξ-potential equals to
–70 mV. Loading sodium alkanoates in the tube lumen (NaC10,
NaC12, and NaC14) proved stable aqueous colloids of inorganic
2.3. Inorganic Tubule Micelles tubular micelles having hydrophobic core coated with aliphatic
chains[10,30] This nanoformulation is very promising for selec-
The different inside/outside chemistries of the clay nano- tive adsorption of spilled oil or other hydrophobic impurities
tubes also allows for their selective modification. A number from water.
of compounds having different reactivities toward silica and
alumina were found; in particular, selective hydrophobiza-
tion of the halloysite lumen through reaction with dopamine 2.4. Nematic Liquid-Crystalline Ordering and Tube Orientation
or phosphonic acid.[25–27] Aqueous phosphonic acid binds
to alumina sites at the tube lumen and does not bind the The enhanced surface charge and high colloidal stability of
tube outer siloxane surface (Scheme 3). With this, produc- halloysite internally modified with anionic macromolecules
tion of inorganic tubular micelles was demonstrated.[25] Such allows for elaboration of electrically driven orientation of
treated halloysite preserves its external water contact angle of these tubes.[12] Even pristine halloysite nanotubes possessing
ca. 12°, which is typical for pristine clay nanotubes, while it a relatively low ξ-potential of –30 mV demonstrate features of
possesses a hydrophobic core covered with aliphatic chains. nematic liquid-crystalline ordering in mixtures with water. Ori-
Such a structure allows for selective adsorption of hydro- entation domains with a size of a few hundred micrometers
phobic molecules, such as oil or phenol, and provides better may be visualized by polarized light microscopy.[31,32] At higher
loading/release characteristics for non-water soluble mate- concentrations, when the water volume per one halloysite
rials. As an example, one can analyze loading flame-retardant tube becomes close to 1 µm3, these tubes have a tendency to
bisphenol-bis(diphenyl phosphate) (BDP) into such a modi- align. This ordering is drastically enhanced with increased
fied halloysite.[25] The lumen hydrophobization allowed tube surface charge due to their electrostatic repulsion. The
for 5-times larger BDP loading from its saturated ethanol simplest experimental approach is orientation of modified
solution (as compared with non-modified halloysite), and clay nanotubes in the meniscus of a drying halloysite droplet
then the flame-retardant demonstrated linear 70 h release (Scheme 5 and Figure 3).[12] During drying, an aqueous suspen-
(Scheme 3b). sion of strongly charged halloysite nanotubes concentrates at
The catecholic anchor Dopa: 2-bromo-N-[2-(3,4-dihydroxy- the edge of the droplet (similar to the “coffee-ring” effect), which
phenyl)ethyl]-isobutyryl amide was also used for selective modi- provides alignment of the tubes along the liquid–solid contact
fication of the inner surface of halloysite clay nanotubes.[26] line. This phenomenon’s mechanism was clarified both experi-
Aqueous Dopa binds to alumina at the tube lumen and does mentally and theoretically: First, the surface charge of the nano-
not bind the silica surface under the same conditions. The tubes was enhanced by anionic polystyrene sulfonate adsorption
selectivity of a Dopa coating for the halloysite lumen may be inside the lumen to compensate for the internal positive charge.
ascribed to the high affinity of the catechol group for metal This increased the magnitude of the tube’s ξ-potential from
oxides located at the tube inner surface and the weaker cat- –30 to –72 mV and stabilized the colloids. Then, colloidal hal-
echol–silica bond (the tube’s outer surface). A similar selectivity loysite was dropped onto the hot solid substrate, dried at 70 °C,
is expected for other silica–metal oxide systems, such as silica– and, after concentration 0.1 mg mL–1 was reached, the align-
titania and silica–zirconia. ment of the nanotubes occurred starting from the droplet edges.

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Figure 2. a–f) TEM images of pristine halloysite before acid treatment (a,b), after the removal of 20% (c,d), and 75% (e,f) of alumina by treatment
with H2SO4 at 50 °C. The external diameters of the tubes are ca. 60 nm. The lumen diameters are 10, 21, and 35 ± 2 nm for the original, 20% alumina-
etched, and 75% alumina-etched halloysite Reproduced with permission.[21] Copyright 2012, American Chemical Society.

Al

O
O P

O O

O P O O P O

O O

flame retardant (BDP)

a b
Scheme 3. a) Selective lumen modification for more-efficient loading of hydrophobic compounds; in the second stage, an external hydrophobization
is also possible through silanization. Reproduced with permission.[25] Copyright 2012, American Chemical Society. b) Flame-retardant loading into
hydrophobized halloysite.

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the oil component is separated from the water by a nanopar-

ticle interface layer (Scheme 6). An addition of 0.5–1 wt% of
halloysite in 20 wt% decane (oil model) in water allows for
the formation of 40–50 µm diameter colloids that are stable
for weeks. In ref.,[34] this approach was suggested for oil-spill
remediation. Interesting that loading into halloysite of the
standard surfactants used in the petroleum industry for spill
cleaning (DOSS, Tween, Span) along with their further sus-
tained release allows for synergetic combination for oil-spill
cleaning with the formation of emulsions stabilized with these
Scheme 4. Scheme of selective anionic and cationic amphiphile mol-
ecules adsorbed inside and outside halloysite nanotubes. two components. Another interesting feature is that the hal-
loysite-coated surface has a nanoscale relief, which is favorable
for anchoring and proliferation of biological cells.[35,36] This
The process was described with Onsager’s theory, in which could promote faster bacterial decomposition of emulsified oil
longer nanorods, which have higher surface charge, give better spills.
ordering after the critical concentration is reached.[33] This study In a complementary approach, water may be dropped on an
indicates a new application of halloysite clay nanotubes in poly- alkylsilane-hydrophobized halloysite powder, forming stable
meric composites with anisotropic properties, microchannel ori- marbles with a diameter of ca. 1 mm, evenly coated with a
entation, and production of coatings with aligned nanotubes.[12] clay-nanotube multilayer. Such water marbles prepared with
octadecyl-trimethoxysilane halloysites could even bounce on a
wafer with a height of 2.5 cm, which is comparable to that pre-
2.5. Oil Emulsification with Clay Nanotubes pared with polytetrafluoroethylene microparticles.[37] For pos-
sible bioreactor design, one could include functional enzymes
Nano and microparticles may be used for emulsification of oil or microbes in such water marbles stabilized with a permeable
compounds forming so called Pickering emulations, where ceramic shell.

Scheme 5. a) Orientation of nanotubes in the meniscus of drying halloysite droplet. b) SEM images of PSS/l-HNTs films oriented in 5 µm channel,
concentration 10 mg mL−1. Reproduced with permission.[12] Copyright 2014, Elsevier.

Figure 3. a) Images of pristine and PSS-modified halloysite dispersion after 0 and 24 h, s-HNT- short 500 nm length halloysite tubes and l-HNT- long
800 nm length halloysite. b) SEM images of PSS/l-HNTs coating after water evaporation at the edge of the droplet on a silicon substrate. PSS: sodium
polystyrene sulfonate. Reproduced with permission.[12] Copyright 2014, Elsevier.

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Halloysite nanotube (HNT)

Surfactant-loaded HNT

Oil Droplet

Aqueous
Phase
Scheme 7. a) Loading clay nanotubes with drug from saturation solu-
tion. b,c) Mixing with drug solution, pumping out air, and pulling in drug
Surfactant molecules released from HNTs molecules, washing, and loaded tubes.
Scheme 6. Halloysite nanotube stabilization of an emulsion droplet and
the release of surfactant cargo (above). Cryo-SEM showing an oil droplet 12 h (40% release in 5 h). In all three release curves, an
stabilized with halloysite on the left, and a magnified view on the right initial burst within 20 min was followed by 8–10 h release.
showing the tube network on the oil–water interface (below). Reproduced
The initial burst may be due to release from externally
with permission.[34] Copyright 2014, American Chemical Society.
bound drugs. The release profile from the halloysite fits the
Peppas model[40] (Mt/M∞ = ktn, where Mt is the amount of
3. Clay-Nanotube Loading with Chemicals drug released at time t, M∞ is the amount of drug released at
and Controlled Release infinite time, n is the exponent characteristic of the release
mechanism, and k is a constant). The value of n is 0.5 for all
3.1. Drug Loading and Sustained Release three drugs, indicating that the release mechanism is Fickian
diffusion. In the case of loading using 50% ethanol and
One of the attractive features of halloysite clay is an inner release in water, the value of n is around 0.75, indicating that
lumen with a diameter capable of encasing macromolecules, the release mechanism is approaching zero-order kinetics.
including drugs, DNA, and proteins. In their pioneering This linear release might be due to heavier loading of the
work, Price, Gaber, and Lvov suggested using halloysite for drugs inside the halloysite tubules, giving a nanopore con-
sustained drug delivery.[38] They loaded halloysite nanotubes trolled release. No drug was inserted between the halloysite
from saturated drug solutions (e.g., antibiotics – tetracy- clay layers in the roll, as confirmed by the preserved 0.72 nm
cline, gentamicin) or from a melt for low-water-soluble drugs packing X-ray reflection.
(e.g., khellin). Loading from drug solutions accompanied by
cyclic vacuum pumping in/out enhanced the replacement of
air in the internal cavities with liquid. After the first appli- 3.2. Proteins and DNA Loading
cation of a vacuum, one can see bubbles at the surface of
the dispersion, similar to bubbles at the interface of boiling Loading DNA into clay nanotubes is very interesting and prom-
water, which indicates replacement of the inner air with the ising.[49,50] During this loading performed by the described
aqueous drug. The wettable lumen diameter of 15 nm pro- above method, the electonegativity of the composite tubes
vides a very high capillary force of ca. 200 atm, pushing solu- became –56 mV (our data). Based on the increased negative
tion into the tubes; however, cyclic air pumping was still potential on the tube surface, the authors assumed an external
necessary for the highest loading efficiency. For drug loading, adsorption of DNA on the nanotubes. We, however, think that
water, alcohol, or acetone were often used as solvents. After adsorption of anionic DNA more probably occurs into the cati-
loading, clay tubes were quickly washed with water to remove onic tube lumen, which will also result in an increase of the
the outermost adsorbed drug and dried at 70 °C. Such drug magnitude of the tube’s negative ξ-potential. Such nanotube
nanoformulation may be kept in a dry form for a long time DNA formulations may be used for intracellular delivery. We
(Scheme 7).[39–49] have to mention here discussing clay nanotube drug formula-
Typically, a successful drug loading reached 5–10 wt% of the tion, that we do not expect their intravenous injection because
tube weight. Taking the density of the organic drug as close these alumosilicate tubes are not biodegradable, but are rather
to 1.2 and halloysite 2.53 g cm–3 one could see that this value thinking about external medical applications (creams, wound
almost coincides with the complete filling of the lumen with healing tissue, implants) or work on modification of cell cul-
condensed drug. We assume that drug condensation could tures and bacteria.
occur from saturated solution in the nanoconfined lumen The 10–20 nm inner diameters of halloysite tubes make
volume, though this is not proven yet. them a good container for loading proteins that have globule
If loaded halloysite nanotubes are exposed to water, they diameters of 3–8 nm. Besides, it is possible to utilize electro-
release drug within 4–12 h. In Figure 4, one can see that static interactions to enhance internal loading in the tubes
dissolution of dexamethasone, furosemide, and nifedipine and prevent external protein adsorption. Taking proteins at a
microcrystalline powder in water happens within 0.2 h, while pH above their isoelectric point, one can have them predomi-
their time-extended release from clay nanotubes takes ca. nantly negative and efficiently load inside the tubes. There are

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Figure 4. a) Release profile of dexamethasone, furosemide and nifedipine; water, pH 6.5, sink conditions (a), and TEM image of aqueous dispersion
of the loaded nanotubes (b).

surprisingly few publications on halloysite tubes loaded with In the opposite experiment (positive proteins), we saw faster
proteins,[51,52,55] and other published work deals with non-spe- desorption kinetics of 4–6 h. When processed at low pH (below
cific protein adsorption on halloysite–polymer or halloysite– the isoelectric point), the loading efficiency was significantly
lipid composites, where the location of proteins is not confined higher than the lumen volume, of ca. 25 wt%. Obviously a lot
within the tube lumens.[53,54] of positive proteins are adsorbed on the tube’s negative outer-
With thermogravimetric analysis, one can determine a total surface. This external adsorption is more common for different
mass of loaded proteins and with UV techniques to measure clays (e.g., montmorillonite and bentonite) and less interesting
the kinetics and the amount of the proteins capable of being for tubule halloysite composites.
released. For many negatively charged proteins, halloysite We have immobilized laccase from Trametes veriscolor and
loading consisted of 7–8 wt%, but only about half, 3–4%, of lipase from Candida rugosa into clay nanotubes. The enzymes
these proteins were released within 8–20 h, while another were loaded using incubation in solution and vacuum treat-
ca. 3% remained bound in the tube and were functional for ment. Lipase, when adsorbed in halloysite, can be described with
a longer time as compared with free enzymes in solution a Langmuir adsorption isotherm, whereas laccase is described
(Figure 5).[51,52] with a linear adsorption. Both enzymes displayed enhanced

Figure 5. a) TGA results after loading lipase (solid line) and after releasing the loaded protein (dashed line). The line representing the protein before
release was offset one unit to account for the extra water that was in the sample (this is the weight percent lost in the first 100–150 °C). b) Release
kinetics of laccase from halloysite, pH 6.5. Results by J. Tully, Y. Lvov and R. Yendluri, Louisiana Tech University.

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Figure 6. a) A TEM image of halloysite nanotubes loaded with laccase. b) Extended biocatalytic stability of laccase samples at 25 °C; round dots:
halloysite-loaded enzymes; squares: free enzyme in solution.

pH stability at acidic pH when immobilized into the tubes. Lac- longer release is needed; thus drug release has to be efficient for
case shows greater biocatalytic stability at acidic pH and no dif- 1–3 days, antimicrobial formulations for weeks, anticorrosion,
ference at basic pH. From this, one can conclude that halloysite flame-retardant. and antioxidant composites for many months
can be used as an immobilization tubule substrate providing and even years. We have to indicate that if clay nanotubes loaded
long-term enzymatic stability, especially in acidic pH. Glucose oxi- with dry functional compounds (antimicrobial, anticorrosion,
dase temperature stability was essentially increased (up to 70 °C). etc.) are doped into melted polymers, then the tube ends are
We assume that an extension of storage time for halloysite-immo- clogged and release is stopped. Only after such polymeric mate-
bilized enzymes may be a general feature (see Figure 6). rials are decomposed or have cracks and defects, this enhances
Another interesting application of tubular nanoreactors chemical release, exposing healing and protective properties.
is when one could load enzymes into a clay tube and then In many cases, one need to design additional nanotube coating
“feed” them with a substrate through the tube opening, real- with thin polymeric layers or forming tube-end stoppers to
izing confined biocatalysis. The fact that enzymatic catalysis slow down release.[5–7,58–60] A straight-forward (though difficult)
occurs only inside the hollow tubular lumen was shown by the approach is the sequential adsorption of polycations and poly-
urease-catalyzed hydrolysis of urea, which, in turn, resulted anions on charged clay nanotubes through so-called layer-by-
in a higher pH inside the tubes and enhanced the internal layer (LbL) encapsulation (Scheme 8 and Figure 7).
precipitation of Ca2+ and CO32− ions.[51] Synthesized CaCO3 Polycation/polyanion multilayers form a shell on the hal-
completely fills inner halloysite lumens and exhibits the meta- loysite providing a diffusion barrier slowing the release. Hal-
stable vaterite phase. This CaCO3 formation was not observed loysite readily adsorbs polycations, such as chitosan, polyeth-
to occur on the outer surface of the halloysite nanotube nor yleneimine (PEI), polylysine, or polyallylamine hydrochloride
in solution. Recently, in a similar approach, urease-loaded hal- forming a molecularly thin positively charged layer. Then, nega-
loysite sustained a higher pH in the halloysite lumen, which tively charged polyelectrolytes, sodium polystyrene sulfonate
induced magnetite synthesis inside the tube.[57] The “enzy- (PSS), and poly(acrylic acid) or heparin may be deposited,
matic” approach may be utilized either for loading the interior forming strong polycation/polyanion complexation. In Figure 7a,
of the halloysite with different compounds or with bioactive halloysite nanotubes LbL-coated with PEI/7 nm silica are
material. The suggested technique may find application as a shown. The halloysite surface was first covered with PEI/PSS/
means of fabricating complex inorganic core–shell type nano- PEI with a 5 nm thickness. Such precursor treatment signifi-
materials composed of two completely different substances cantly enhanced next silica nanoparticle adsorption. Coating
ensuing from the biomineralization reaction demonstrated halloysite nanotubes with large-molecular-weight polyelectro-
above. The idea of using halloysite nanovolume lumens lyte shells allowed for an extension of the release time of the
as nanoreactors offers promising possibilities for studying drug dexamethasone from 8 to 16 h.[56]
crystal engineering and fundamental aspects of the biominer- Another approach is based on the formation of a urea–for-
alization process. maldehyde (UF) coating on the halloysite surface. Halloysite
was exposed to urea–formaldehyde prepolymer solution (par-
tially polymerized oligomer as described in ref. [59]. Due to
3.3. Time-Extended Release from Nanotubes with Encapsulation its abundant N–H functional groups, prepolymer adsorbs on
and the End-Stoppers the halloysite external surface via hydrogen bonding and with
enhanced adsorption at the lumen ends. Rapid crosslinking of
A typical release time of water-soluble chemical agents from the the prepolymer causes formation of a thin polymer shell that
clay nanotubes is 5–10 hours. However, for many applications also plugs tube endings.

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decomposition inside biological cells, making targeted drug

delivery, as will be discussed in the following section.[61]

4. Biological Cell Delivery and Cytotoxicity

4.1. Drug Delivery with Intracellular Activation

Due to the high loading capacity and biocompatibility, halloysite

nanotubes are a good candidate for the fabrication of intracel-
lular drug-delivery vehicles. Halloysite has been suggested as a
versatile nanosized hollow carrier[42,62] which combines effec-
tive drug loading from solution or melt into the lumen and
straightforward approaches for surface chemistry modification.
Halloysite nanotubes have aqueous colloidal properties
similar to silica nanoparticles of comparable sizes. However,
the inner halloysite lumen is positively charged, allowing the
selective loading of negatively charged drug molecules.[40,48]
Recently, several reports have demonstrated anticancer drug-
delivery formulations based on halloysite. Doxorubicin was
successfully loaded into nanotubes followed by wrapping
of the nanotubes with DNA to improve the dispersability in
water.[50] Doxorubicin-loaded halloysites were tested in vitro
using human cancer model cells (A549). Sustained release of
Scheme 8. a) Layer-by-layer polycations/polyanions/silica tube encapsu- the encapsulated drug for over two weeks without an initial
lation. b) Formation of the tube-end Cu-benzotriazole stoppers. burst secured strong effects on the cytoskeleton of the cancer
cells.
Another report demonstrates the enzyme-activated drug
In the third technique, an extended benzotriazole corrosion delivery based on halloysite employed as transmembrane car-
inhibitor release was based on the formation of copper-inhib- riers, which is regarded as a promising alternative to conven-
itor clogs due to the chelation of Cu(II) ions by released inhibi- tional diffusion-controlled systems. The triazole dye, brilliant
tors (predominantly at the tube ends).[58] Corrosion inhibitors green (BG), which is known to suppress mitochondria in
form a 2D polymeric network that covers the entire halloysite malignant cells[63] was utilized. As shown in Figure 8a, BG is
surface and effectively seals the tube ends and other leakage localized inside the tube lumens. Next, halloysite loaded with
tube defects. As a development of this technique, halloysites BG was supplemented with dextrin stoppers (Figure 8b) prone
were rinsed sequentially with benzotriazole and 0.1 M CuSO4 to be cleaved by intercellular glycosyl hydrolases for controlled
solutions for about 30 s for the formation of the stoppers. This release inside cells.
allowed for adjustment of the release of the antimicrobial, bril- BG-loaded HNTs penetrate through the cellular membranes,
liant green, between 5 and 100 h.[60] as shown in TEM images (Figure 8c), while their uptake effi-
In the fourth approach (Figure 7c), we were able to make ciency depends on the cell proliferation rate. Decomposition
the tube-end stoppers by deposition of glycogen or dextrin. of the dextrin tube-end stoppers mediated by glycosyl-hydro-
This tube encapsulation can be controlled by enzymatic lases triggers the release of the lumen-loaded BG, allowing for

(a) (b) (c)

Figure 7. a,b) TEM image of halloysite nanotubes encapsulated in polyethyleneimine – silica shell (a) and with tube opening clogged with glycogen
stoppers (b). c) Comparison of benzotriazole release curves from pristine halloysite, halloysite encapsulated with urea-formaldehyde encapsulation,
and with copper end-tube stoppers.

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Figure 8. a) TEM image of brilliant-green-loaded halloysite. b) SEM image of a dextrin cap on the end of the functionalized nanotube. c) TEM images
of A549 cell incubated with dextran-coated clay nanotubes. d) Resazurin assay results demonstrating the LD50 value of BG-loaded halloysite for A549
cells. The insets show AFM images of the distribution of DX-halloysite in the A549 cells. Reproduced with permission.[61] Copyright 2015, Nature
Publishing Group.

effective destruction of human lung carcinoma cells (A549) on the relative sizes of the cells (i.e., smaller bacteria are
(Figure 8d), whereas the hepatoma cells (Hep3b) were more coated with chaotically organized bundles of nanotubes,
resistant, indicating selective drug delivery. Exploiting tubule while yeast and microalgae are covered by tile-resembling
clay instead of mesoporous silica nanoparticles typically used layers of halloysite). The electrostatic interactions secure the
in the fabrication of enzyme-activated drug-delivery carriers[64] nanotubes within the LbL-formed layers, preventing the dis-
might be more efficient because it offers more room for drugs assembly of the shells. Importantly, no penetration of nano-
in the lumens, unlike silica having a small pore size of 2–3 nm tubes into the cell interior has been detected. The approach is
and potential in vivo toxicity. universal and can be applied to most microbial cells (bacteria,
microalgae, microfungi). Nanotube-decorated micro-organ-
isms may find applications as versatile templates for the fab-
4.2. Cell Surface Deposition via LbL Polymer Assembly rication of core–shell inorganic microcapsules obtained after
the calcination of cells. Other applications are found with live
Cell-surface engineering is one of the vibrantly developing cells carrying a cargo of halloysite loaded with biomacromol-
multidisciplinary research areas.[65–68] Cell-surface engineering ecules, such as nutrients, antibiotics, biocides, nucleic acids
aims at tailoring nanomaterials to cell surfaces (cell walls or and enzymes.
membranes) to provide the coated cells with novel functionali-
ties. Also known as “cyborg cells”, these biocomposite micro-
particles have become an important tool and a promising 4.3. Low Toxicity of Halloysite
biomaterial.[42] Living cells may be coated with magnetic nano-
particles, which allows for effective spatial manipulation using Halloysite clay nanotubes unquestionably are a promising
an external magnetic field.[62] Among the many other types of natural nanomaterial. Recently, halloysite nanotubes have
nanomaterial, halloysite nanotubes have also been employed been found applicable for the fabrication of novel biomedical
to decorate cell walls of yeast,[64] microalgae,[40] and bacte- materials. The rapidly expanding use of halloysite nanotubes in
rial cells[65] via layer-by-layer (LbL) deposition with oppositely the porcelain and polymer composite industry suggests a high
charged polymers (Figure 9a–d). probability of undesired release of these clay nanotubes into the
After deposition on cells, the nanotubes form randomly environment, bringing them into the direct contact with organ-
positioned monolayers on the microbial cell walls, depending isms in their natural habitats, which may potentially cause

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Figure 9. Above: polyelectrolyte LbL-mediated deposition of halloysite nanotubes onto yeast and fabrication of hollow microparticles (a). Below: TEM
(b) and SEM (c) images of single yeast cells coated with AH/PSS/PAH/halloysite/PAH; (c) SEM image (false-colored) demonstrating halloysite-free
daughter-cell budding from halloysite-coated mother cell. All adapted with permission.[67] Copyright 2013, The Royal Society of Chemistry.

unwanted damage to cells, tissues, and organs. Therefore, the within the last four decades, including for nanotoxicity assays.
elucidation of the toxicity of halloysite nanotubes toward living Our study demonstrated that these nanotubes were found
organisms is crucially important. Halloysite has a good bio- exclusively in the intestines of the worms (Figure 10a–d).
compatibility, which was assessed for both cell cultures[66] and Halloysite was detected along the whole intestine, starting
invertebrate models.[68–70] from the buccal cavity to the anus, and the aggregated areas
The uptake and toxic effects of halloysite have been inves- were located in interior bulb and terminal bulb (Figure 10a).
tigated using human cell lines (breast cancer cells and epi- Importantly, we did not detect nanotubes outside the intes-
thelial adenocarcinoma cells).[66] This study suggests that the tines of the nematodes. As a result, no significant effect on
viability of the human cells was preserved at relatively low con- the fertility of the microworms, or the reduction of the egg
centrations (up to 0.075 mg mL–1), (70% of viable cells); with number in pregnant animals was detected (Figure 10e–g).
increasing concentrations (>1 mg mL–1), the viability was con- Apparently, halloysite within a wide range of concentrations
siderably decreased. As well as free clay nanotubes, chitosan does not damage the organism of the nematodes, inflicting
scaffolds for tissue engineering doped with halloysite were only mechanical stress onto the alimentary system. The
found to induce no significant adverse effects on attachment microworms intentionally avoid taking up the nanotubes,
and development of fibroblasts. Composite halloysite-doped therefore the only effective way of delivery is based on clay-
dental scaffolds stimulated the growth of fibroblast cells.[35,36] nanotube-modified cells. Based on these findings, halloysite
To supplement the observation of morphology and moni- clay nanotubes appear unlikely to have toxic effects at mod-
toring of cell growth, proteomic analysis has been applied,[71] erate levels of exposure.
detecting exposure-specific changes in protein expression In conclusion, first, halloysite has very low cell toxicity and
associated with the pro-inflammatory effects induced by the is safe up to very high concentration of 0.5 mg mL–1 of culture.
halloysite (ca. 1 mg mL–1), suggesting that halloysite induces It is also safe for soil worms, which are the first organisms
cell growth and proliferation, stimulates subtle responses to encountering possible halloysite pollution. Second, it is biocom-
infection, irritation, and injury, and demonstrates enhanced patible, which means that tissue contact with halloysite is not
antioxidant capability. However, a study with a mouse primary harmful; moreover, being included in polymeric composite hal-
peritoneal macrophage model demonstrated anti-inflammatory loysite improves biological cell proliferation and coating micro-
activity of the nanotubes, which increased with lumen volume organisms with halloysite does not harm their functionality.
and space, and decreased with average pore size.[69] The overall However, halloysite is not biodegradable, there are no biological
toxicity of halloysite on yeast and bacteria has been found to be mechanisms to degrade this alumosilicate clay in the body, and
negligible.[66,68] it cannot be injected in the blood intravenously, but rather may
We have evaluated the in vivo toxicity of halloysite on free- be used for external medical treatment with slow release of
living nematodes (worms) Caenorhabditis elegance.[68] These encapsulated drugs (e.g., in creams, implants, or wound treat-
nematodes have been extensively used in biomedical research ment of tissues).

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Figure 10. Above) Dark-field microscopy imaging of distribution of halloysite in C. elegance worms: a) inside the foregut; b,c) in the midgut (no nano-
tubes in embryos, uterus, and vulva were detected); d) inside the hindgut. Below) in vivo effects on C. elegance growth and fertility: a) the cumulative
curves of body length of nematodes treated with increasing concentrations of halloysite (mg mL−1); b) the influence of tube concentration on fertility in
adult hermaphrodites; c) cumulative survival curve for increasing concentrations of halloysites (mg mL−1). Reproduced with permission.[68] Copyright
2015, The Royal Society of Chemistry.

5. Halloysite as an Adsorbent Halloysite is a biocompatible and safe nanomaterial that

can be used in water-filtration systems. The removal efficiency
Like many other clays, halloysite is a good adsorbent with of the halloysite is higher than most conventional mineral
ca. 60 cm2 g–1 porosity in untreated form; after acid/base adsorbents and may be further improved with acidic etching
processing, its porosity may be increased 6 to 7 times. If we as described above. Halloysite can be regenerated by burning
compare halloysite with kaolin, which has the same chemical adsorbed organics. Even more efficient water purification may
composition, or bentonite, one can see that adsorption of be reached in practical filters by complexation of halloysite
water-soluble molecules on the halloysite is approximately two- nanotubes with polycations, such as polyethyleneimine or chi-
times higher, especially for negatively charged molecules.[72–76] tosan, or by doping halloysite into standard polyethersulfone
This may be explained by the dual nature of the halloysite sur- porous membranes.[74,75] However, mechanisms of chemicals
face: outside it is negative, adsorbing positive impurities, and adsorption in such complex filtration systems are not com-
the inner lumen is positive, adsorbing negative impurities pletely understood.
(Figure 11).[73] Amine-grafted halloysite has been shown to demonstrate
An adsorption study using cationic rhodamine 6G and ani- reversible CO2 capture from ambient air. The adsorption of atmos-
onic chrome azurol S showed two times better removal of these pheric CO2 followed a fractional-order kinetic model. The high
dyes for halloysite as compared with kaolin. Halloysite filters efficacy of CO2 capture, easy regeneration and reuse, and excellent
have been effectively regenerated up to 100 times by burning stability of the surface modified halloysite make the procedure
out the adsorbed dyes at 400 °C. The overall removal efficiency robust, environmentally friendly, and sustainable. The preferen-
of anionic chrome azurol S exceeded 99.9% for the 5th regener- tial adsorption of three major abundant isotopes of CO2 (12C16O2
ation cycle of halloysite, showing a great advantage of halloysite and 13C16O2,) from ambient air has been demonstrated.[76]
for the removal of negatively charged impurities. Its adsorption Halloysite has been used for the treatment of animals. An
capacity decreases with an increase of ionic strength, tempera- efficient oral formulation of halloysite to adsorb in the stom-
ture, and pH, when the internal positive charge of the tubes achs of chickens and piglets and remove dangerous myco-
declines. For cationic rhodamine 6G, a higher ionic strength, toxins (zearalenone, deoxynvalenol) present in grain feed has
temperature, and initial solution concentration are favorable been demonstrated.[77,78] Though it was demonstrated that
toward enhanced adsorption with an optimal pH of 8. Lang- halloysite is safe for micro-organisms, worms, fish, and small
muir and Freundlich isotherms have been used to describe the animals,[66–68] it has to be considered with a great caution for
equilibrium adsorption data.[73] human treatment.

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Figure 11. a–d) Dye filtration from 2nd-generation kaolinite and halloysite filters: chrome azurol S (a) and rhodamine 6G (b) solution passed through
halloysite filters; chrome azurol S (c) and rhodamine 6G (d) solution passed through kaolinite filters. The concentrations of the dyes were 300 mg L−1
in all the cases. e) Adsorption of rhodamine 6G and chrome azurol S onto halloysite and kaolinite.

6. Halloysite Mesoporous Templates for Catalytic i) first, to carry out nanoparticle synthesis in the presence of
Nanoparticles halloysite nanotubes, which results in seeding the surface of
the tubes with 3–5 nm diameter catalytic particles. The for-
Nanotubes of different natures, coated or intercalated with metal mation of the nanoparticles on the halloysite surface may be
and metal oxides, are efficient mesoporous media for advanced initiated at external defects in the crystalline wall structure.
catalysis. To deposit metal nanoparticles onto the clay-tube sur- Vacancies in the halloysite crystal lattice create enhanced
face, standard metal-particle-formation reactions were carried charges that attract metal ions, followed by their growth to
out in the tube dispersion. There are two approaches elaborated: nanoparticles.[7,79–81]

Figure 12. a,b) SEM of silver nanoparticles synthesized onto clay nanotubes (a) and silver nanorod synthesized inside the tube (b). c,d) Fe2O3 particles
synthesized onto halloysite (c) and within its lumen (d). e) Scheme of internal silver synthesis in halloysite lumen. Reproduced with permission.[82]
Copyright 2012, American Chemical Society.

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ii) Second, to load reactor components into
the nanotube lumen, wash these tubes’
outermost and to carry out particle syn-
thesis exclusively inside the tube interior,
producing round or rod-like nanoparticles
(Figure 12).[7,82]

With the reaction volume being restricted

to the nanoscale, one can produce metal
nanoparticles that fit within the tube lumen.
We have synthesized 5–10 nm diameter par-
ticles of Ag, CoO, Cu/Ni, and Fe3O4 encased
into such core–shell nanostructures.[7]
There is an example of formation of silver
nanorods inside the halloysite (aqueous
silver acetate was loaded into the tubes and
reduced by thermal decomposition:[82] for
loading, halloysite was mixed with a satu-
rated solution of the target compound. The
suspension was stirred and sonicated for 20
min to disperse the halloysite. Then, a beaker
containing the suspension was transferred
to a vacuum jar, which was then evacuated
using a vacuum pump. Slight fizzing of the
solution under vacuum indicates that air is
being removed from the tubule lumen. Once
the vacuum is broken, chemicals are pulled
into the pores. The resultant mixture was
kept stirring and heated on a hot plate at 100
°C until it was completely dry. The resultant
material was washed to remove externally
attached material and heated to 300 °C for
one hour to decompose the silver acetate to
silver. High-resolution TEM and X-ray anal-
ysis indicated oriented rod-like silver crystal
in the tube interiors (Figure 12b).
Figure 12c,d also presents halloysite nano-
tubes with Fe2O3 nanoparticles on the tubes Figure 13. a) Schematic illustration for the selective dispersion of Cu–Ni over halloysite
and in the lumen, respectively. Iron oxide without or with citrate (CA). b,c) TEM images of the Cu–Ni onto halloysite (b) and Cu–Ni into
was deposited using Fe-acetyl acetonate halloysite lumen (c). d–i) Annular-dark field image of the Cu–Ni into halloysite (d) and the cor-
salt, which was decomposed by heating in a responding elemental-mapping images (e–i) Reproduced with permission.[83] Copyright 2015,
nitrogen atmosphere, yielding corresponding Royal Society of Chemistry.
nanoparticles, char, and products of oxalate
thermal degradation. possibility to design two-component catalytic system when one
Figure 13 demonstrates the synthesis of agglomeration- type of nanoparticles will be located inside the clay nanotubes
tolerant exhaust catalyst with copper–nickel nanoparticles pro- and another outside the tubes.
duced inside (more-efficient catalyst) or outside the clay nano- The nanocatalysts produced are supported on high-sur-
tubes (less-efficient catalyst). The 20-times-enhanced nitrogen face-area alumosilicate tubule clay, which may be helpful for
monoxide and carbon monoxide purification with Cu–Ni into the production of the optimal alkane length in the Fisher–
halloysite lumen (as compared with external Cu–Ni nanopar- Tropsch reaction. The described above nanoconfined catalyst
ticles) was attributed to the inherent topology of the material, synthesis may be scaled up to hundreds of kilograms of the
where the Cu–Ni nanoparticles are strongly immobilized on composite nanomaterial. Natural halloysite clay is available
the Al2O3 interior and protected from particle agglomeration in thousands of tons at a low price, making it an excellent
at elevated temperatures (300 °C). The demonstrated enhanced mesoporous carrier for large-volume reactors, especially for
functionality of halloysite as an efficient support at high tem- the petroleum industry. In the 1960s, raw halloysite was used
perature can be expanded to different catalysis-requiring as an alumosilicate catalyst for oil cracking, but later it was
harsh conditions, desulfurization of petroleum, and methane- replaced with more-efficient zeolites.[84] Even pristine hal-
steam re-formation, helping to meet current environmental loysite has some advantages for the cracking of heavy oil frac-
and energy challenges.[83] Finally, we would like to indicate a tions or recycled vegetable oil,[85] and its modification with

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(pectin, starch), chitosan, cellulose, and humic acid.[96–101]

REVIEW

metal nanoparticles may essentially enhance these catalytic

capabilities. Halloysite loading in water-soluble polymers may be as high
as 50–60 wt%, producing solid organic–inorganic composites,
as is shown in Figure 14d,e. The densest composites may be
7. Polymeric Nanocomposites obtained by the LbL method by sequential alternate adsorp-
tion of anionic clay with polycations, for example, polyeth-
There are many publications on doping polymers with clay yleneimine (PEI).[1] Remarkably, with this method, one can
nanotubes.[6–8,86–111] Doping of halloysite into melted poly- produce architectural nanocomposite coatings with layers of
mers may be done using industrial double-screw extruders clay nanotubes and silica or other spherical nanoparticles
or by admixing halloysite during the polymerization pro- arranged in a pre-determined order (Figure 14f).
cess, allowing for composites with well-dispersed clay tubes Surprisingly, halloysite mixes well with medium-polarity
(Figure 14). Water-soluble polymers can be directly mixed polymers such as poly(vinyl chloride) and even with low-
with halloysite. The strength of the halloysite tubes them- polarity polymers, like polyethylene and polypropylene.[102–104]
selves has been estimated from direct bending experiments. The reason for this is not clear and may be related not only to
The Young’s modulus of single clay tubes is about 130 GPa, the surface chemistry, but also to the nanoscale relief (rough-
and they have a high flexibility.[87] Halloysite tubes can be ness) of the tubes producing hydrophobic spots.
bent to 90° without obvious failure or damage. Typically, Recently, a detailed analysis of the usage of halloysite nano-
the addition of 3–5 wt% halloysite into polymers doubles tubes for motor-vehicle-industry composites was performed.
the composite’s tensile strength and essentially increases Polylactide–halloysite nanotube composites modified by the
its adhesivity to solid substrates or the interlayer material’s co-addition of a plasticizer (tributylcitrate), reached mechan-
integrity (Figure 15). Doping clay nanotubes into a poly- ical properties suitable for use in automotive applications.[106]
meric matrix provides a kind of ceramic “skeleton” within the Polymers doped with 5–10 wt% halloysite possess much better
material, enhancing its strength, and these “skeleton bones” flame-retardancy; usually, the burning speed was decreased 2–3
may be loaded with functional chemicals (like real bones are times in such composites.[107,108]
loaded with marrow).[7,86] Clay nanotubes were also doped into inorganic alumosili-
Halloysite tube’s silica exterior surface and its alumina inte- cate geopolymers.[109] First, positively charged fly-ash micro-
rior, are both polar, providing good hydrophilicity, and, con- particles were evenly coated with anionic halloysite nanotubes,
sequently, good dispersion in polar polymers such as epoxy, and then such core–shell nanocomposites were processed with
polyamides,[88–91] polyethyleneimine, poly(vinyl alcohol), an alkali dissolution accompanied with –Si–O–Al–O–Si–O–Al–
polyacrylates,[92–95] and biopolymers such as polysaccharides polymerization. Such polymeric concrete had a three-times-longer

Figure 14. SEM images of polyethylene doped with 5 wt% and low-density polyethylene doped with 15 wt% halloysite (images (a–c) provided by and
used with permission from A. Zeitoun, Applied Minerals Inc.). d,e) Pectin doped with 30 and 50% halloysite. Reproduced with permission.[100] Copyright
2011, American Chemical Society. f) Cross-section of (halloysite-PEI-silica-PEI)4 superlattice-film on a silver electrode. The film is bound together via
the electrostatic interactions of anionic and cationic species Reproduced with permission.[7] Copyright 2002, Elsevier.

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3
10 wt% Halloysite
2.5 5 wt% halloysite
2 wt% Halloysite
Stress (MPa) 2 Without halloysite

1.5

0.5

0
0 0.1 0.2 0.3 0.4
Strain
a b
Figure 15. a,b) Stress–strain characterization of polymers doped with halloysite, poly(methyl methacrylate) (a) and epoxy resin (b).

setting time and higher flexibility. More-detailed analysis of the remix and redistribute the enhancements after every thermal
mechanical properties of halloysite with polymers can be found loading. The thermal properties of the composite were con-
in the reviews in refs.,[6–8] and we will further concentrate on sistent for at least 100 thermal cycles. This indicates the
the composite functionality based on combinations with carbon potential for real-world applications of these materials, as no
nanotubes and loading chemical inhibitors inside the clay external containment is required and long-term property sta-
nanotubes. bility is achieved. To study the real-world application of this
phase-change material, double-layer structures with different
doping have been tested. This multilayer organization allows
8. Functional Composites preferable vectorial heat transfer in the chosen direction over
a 24-hour heating/cooling cycle (day/night). A composite
8.1. Phase-Change Materials (PCMs) for Thermal-Energy for a smart building roof is suggested, which can maintain
Storage the interior temperature of the building by the appropriate
arrangement of the layers. Due to the good thermal stability,
Other interesting composites were obtained by halloysite the high thermal conductivity, the ability to preserve shape
mixing with paraffin and wax. These wax compounds melt at during wax melting, and the abundant availability of this nat-
72 °C and transform to liquid. However, composites containing ural tubule clay, phase-change insulation composites based
40–50 wt% of halloysite allow for a material to preserve its on halloysite could be used to conserve energy in large-scale
shape during wax melting (Figure 16).[110,111] The capability of applications.[111]
the new wax–nanoclay composites of maintaining their form Unfortunately, to counter the exciting prospects of polymer–
even above the wax melting temperature with the binding of halloysite nanocomposites, there is one dark feature: the
melted tiny droplets of wax with the halloysite ceramic car- possibility of catalytic decomposition of the polymers with hal-
cass was demonstrated. Such capability of phase-change heat- loysite alumina. We have observed a high-temperature decom-
transfer materials could lead them to become a potential choice position (140–170 °C, 10–20 hours) of poly(dimethylsiloxane)
for application in buildings or other systems as part of an doped with halloysite, and have attempted to modify the tubes
overall energy-efficiency improvement. Phase-change insula- with hexamethyldisiloxane to prevent this.
tion materials include the mixed blend of naturally occurring
halloysite nanotubes with low-cost paraffin of unique charac-
teristics. In addition to the inclusion of halloysite, conductivity- 8.2. Antimicrobial Composites (Bone Implants
enhancement materials such as graphite nanoparticles and and Tissue Scaffolds)
multiwall carbon nanotubes have also been added to make
such phase-change materials thermally conductive while main- Halloysite loaded with simple antiseptics such as brilliant green,
taining their shape. providone iodine, or chlorhexidine allows for extending the time
The thermal-conductivity test presented values from 0.5 that these antibacterial agents will function from minutes to
to 1.4 W m–1 K–1 as conductivity enhancement ranged from 5–10 hours. Halloysite encapsulation of antibiotics (tetracycline,
3 to 10% . Maximum thermal conductivity was demonstrated gentamicin, and ciprofloxacin) are even more efficient, their
for a mixture of 45:45:10 (wax:halloysite:graphite). Inclusion sustained release for 100–200 h allows them to fight even multi-
of the halloysite provided a structural support for the mate- drug resistant (MDR) bacteria such as gangrene. In Figure 17
rial to maintain its shape after undergoing phase change. we present results on the release of ciprofloxacin from clay
Such a unique characteristic would allow phase-change com- nanotubes and the use of such nanoformulation to destroy a
posites to maintain the distribution of thermal conductivity gangrene colony in a Petri dish. An equal amount of the anti-
enhancement within themselves, eliminating the need to biotic was applied to white tablets and the dark rings around

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Figure 16. Photographs of the wax composites maintaining their shape at 60 and 80 °C (left to right in each group): a) for wax; b) 90 wt% wax + 10 wt%
carbon nanotubes; c) 60 wt% wax + 40 wt% halloysite; d) 50 wt% wax + 40 wt% halloysite + 10 wt% carbon nanotubes.

them demonstrate the area of inoculation. One can see that non- composite adhesiveness to bone and titanium implants over
encapsulated ciprofloxacin has a very low antibacterial efficiency, pure poly(methyl methacrylate) (PMMA) or calcium phosphate
while halloysite–ciprofloxacin efficiently kills gangrene bacteria. (CP) has been demonstrated. Decrease of the PMMA poly-
In the next step, drug loaded halloysite was embedded into merization temperature from 72 to 50 °C minimized tissue
polymers to make stronger and functional bone implants, damage. Antibiotics encased in clay nanotubes were isolated by
dental filler formulations, tissue scaffolds, and for structural a free-radical polymerization process during cement solidifica-
reinforcement of microvascular networks.[112–118] We pro- tion to allow a wider drug selection (e.g., ciprofloxacin). Prepa-
duced halloysite composites for bone implants with extended ration of combinations of clay nanotubes loaded with different
2–3 week antibacterial protection needed for surgery spot antibiotics (halloysite cocktail) with long-time release will syn-
healing[114] ergistically increase the efficiency of fighting of drug-resistant
Clay tubule containers allow for bone-cement composites infections.[114]
with sustained 200–300 h antibiotics release without compro- With a halloysite powder formulation, 95 wt% of loaded
mising the material strength; 2–3 times enhancement of the gentamicin was released within 48 h; however, the gentamicin

Figure 17. Release of ciprofloxin (vertical axis in%) from halloysite, and efficent suppression of gangrene with this nanoformulation (dark circles of
dead bacterial around white antibiotic tablet). Collaborative results by Y. Lvov and K. Lews, Northeastern University, Boston.

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Figure 18. a,b) Sustained release of ciprofloxacin (a) and gentamicin (b) from 7–10 wt% halloysite doped into PMMA bone cement.

release time was dramatically extended when the halloysite infection.[119] This nanoarchitecture of electrospun micro-
was incorporated in PMMA cement. Release from PMMA fibers with tubular nanocontainers may include a variety of
composites reached 60% in 250 h (Figure 18b), with enhanced drugs, allowing for drug cocktails for fighting multidrug-
gentamicin release in implant defects such as cracks. We have resistant infections.
also elaborated a “cocktail” of nanotubes loaded with 2–3 dif- The physico-chemical and mechanical properties of
ferent antibiotics and tested its efficiency on drug-resistant such microfibers with aligned clay nanotubes may have
bacteria. interesting features, and one of them is inducing the ori-
An interesting application of halloysites is their inclusion entation of poly(glycolic acid) polymeric chains along hal-
into electrospun microfibers.[119–121] Often, such polymeric loysite nanotubes.[122] The molecular chain and crystallite
fibers have a diameter of ca. 400 nm, which forces 800-nm- ordering achieved the highest orientation degree at 5 wt%
long halloysite tubes to orient along the fibers, making them halloysite loading. Clay nanotubes act as nucleating agent
stronger.[119] Such inclusion of halloysite loaded with drugs for poly(glycolic acid) and increase the crystallinity of the
into the fibers allows drug release to be extended from the 10 fibers.
to 20 h, typical for polymeric electrospun fibers, to hundreds
of hours. The guided tissue regeneration (GTR) technique
has become standard in therapy; however, infections in many 8.3. Corrosion Coating
cases cause failure of clinical applications. A nano–micro-
composite electrospun membrane with sustained 3-week Doping these clay nanotubes into paint (polyurethane, epoxy,
drug delivery was developed using metronidazole-loaded and polystyrene latex) coatings at 5 wt% provides sustained
halloysite clay nanotubes doped into poly(caprolactone)/ release of anticorrosion agents, resulting in longer-term
gelatin fibers (Figure 19). A hierarchical nano–micro system metal protection, as well as in 50–100% increase in the
was constructed as follows:[117] Clay tubes with a diameter coating strength and adhesivity. Such enhanced coating is
of 50 nm and a length of 800 nm were incorporated at especially important for operation in extreme conditions.
8 vol% into the polymeric fibers with a diameter of 400 nm, Comparative tests have shown an advantage of this coating
which resulted in the alignment of the tubes and provided technology for sea-water operations as compared with
enhanced anisotropic mechanical properties of the tissue existing coatings.[58,59,123–125] Cracks developed in polymer
membrane. coating materials doped with tubule nanocapsules will also
The metronidazole-loaded halloysite incorporated be self-healed. Doping loaded clay nanotubes into a poly-
in the microfiber membranes allowed for an extended meric matrix will provide sustained inhibitor release and
release time of 20 days as compared with 4 days for direct a ceramic “skeleton”, enhancing the composite material
admixing of the drug into the microfibers. In Figure 19, strength.
one can see two different increment areas: the first 4 days – Polymer composites used for coating, containing 5 wt% of
mostly drug release from the bulk polymer, and the second clay nanotubes were loaded with standard anticorrosion agents
region, 5–20 days – a slower release from the nanotubes. specific for copper, aluminum, and steel (benzotriazole, hydrox-
A longer sustained release of metronidazole from the com- yquinoline, and dodecylamine). An encapsulation of these
posite membranes prevented colonization of anaerobic agents in a clay tube will allow a longer anticorrosion protective
bacteria, while cells could adhere to and proliferate on the function with enhanced action at the coating defects. Figure 20
drug-loaded composite membranes without toxic effects. demonstrates scanning electron microscopy (SEM) images of
The biocompatibility of the nanotubes was demonstrated bulk clay nanotubes, their location in the polyurethane paint
with mouse cells, while the halloysite–drug formula- layer, and the efficiency of anticorrosion protection for steel and
tion has been shown to efficiently suppress Fusebacterium aluminum.

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Figure 19. Scheme of the composite fiber formation and drug release. TEM images of poly(caprolactone)/gelatin fibers with embedded halloysite tubes
and metronidazole release curves from such composite (blue dots) as compared with usual fibers (red). Reproduced with permission.[119] Copyright
2015, American Chemical Society.

8.4. Anti-Aging Rubber Nanocomposites through intermediated linkages (grafting/complexation

mechanism).[126]
It is relatively easy admixing halloysite with natural water- We proposed doping clay nanotubes loaded with antioxi-
based latexes; however, the challenge is to dope clay nano- dants into SBR to prevent rubber aging.[128] Elastomer aging
tubes at 10–20 wt% into industrial styrene–butadiene rubber is caused by high temperature, oxygen, oil, acids, alkalis, and
(SBR) before its crosslinking. For this, one need to make the other active chemicals. This process leads to the deterioration
tubes more hydrophobic, changing its contact angle in water of the chemical and mechanical properties of the rubber, and
from 10 to 50–60°; usually this is reached through silaniza- makes it less elastic, harder, and mechanically unstable. Since
tion.[126–128] Methacrylic acid (MAA) has been used to improve thermal-oxidative aging is the most common type of rubber
the performance of styrene–butadiene rubber (SBR)/halloysite aging, chemical antioxidants are added into elastomer com-
nanocomposites by direct blending. The strong interfacial pounds to extend the lifetime of the product by binding with
bonding between the halloysite and the rubber matrix results oxygen/ozone. Maintaining a supply of antioxidants in bulk

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Figure 20. a) Clay nanotube location in paint. b–e) Corrosion development on scratched polyurethane painted metal samples after 9 months in simu-
lated sea water: steel, usual paint coating, and paint/halloysite composite loaded with dodecylamine (b,c); aluminum-2024 alloy coated with usual
paint, and paint/halloysite loaded with benzotriazole (d,e).

Figure 21. a) Antioxidant 4010NA release from halloysite rubber composite at 25 °C. The inset images arethe EDS spectra of the sample after
2 months and the schematic of the release of antioxidant in rubber matrix. b,c) SEM image of the section surface of SBR-halloysite composite (b) and
TEM image of SBR-halloysite composites (c).

rubber is important; however, antioxidants often diffuse toward antioxidant blooming. From this research, we concluded that
the surface of rubber products in an event called “blooming”. this functionalized halloysite can improve the SBR composite
Blooming results in microdefects, loss of antioxidant protec- mechanical properties and aging resistance without blooming.
tion, and contaminates the environment. Because of this, only This approach for fabricating functional rubber–halloysite
about 1 wt% antioxidant can be added to an elastomer formula- nanocomposites may be extended to other “smart” elastomers,
tion, which provides only limited aging resistance, and is not for example, for sustainable antimicrobial rubber protection
high enough to illicit blooming.[129] using halloysite fillers loaded with antiseptics.
An aging-resistant SBR composite was prepared by the addi-
tion of 27 wt% halloysite clay nanotubes loaded with the anti-
oxidant 4010NA.[125] Silanized halloysites were well dispersed 9. Conclusions
in the SBR matrix, which provided the synergistic effect of
improved mechanical properties and sustained release of the Halloysite clay tubes with a diameter of ca. 50 nm and a
antioxidant. Encapsulating the antioxidant in the nanotubes length of 1 µm have been used as natural nanocontainers
allowed for an antioxidant concentration of 3.2 wt% (which for loading and sustained release of chemical agents. The
tripled the amount compared with the traditional process), halloysite inner lumen can store and release molecules in a
without any indication of surface blooming. The release of controllable manner, making these tiny containers attractive
4010NA from the halloysite nanotubes in water and nonpolar for applications in drug delivery, antimicrobial materials, self-
cyclohexane varies from four hours to days, but, after burying healing polymeric composites, and regenerative medicine.
the tube-encapsulated antioxidant into bulk rubber, it was The halloysite lumen capacity may be adjusted between 10
extended to more than nine months (66 wt% was released in and 40 vol% with selective etching, and its porosity may be
the first five months (see Figure 21)). After incubation at 90 °C varied from 60 to 400 m2 g–1. Halloysite has no in vitro or
for seven days, the SBR and antioxidant-loaded halloysite com- in vivo toxicity, which allows it to be used for drug-delivery
posite showed stable tensile strength and little decrease in systems capable of releasing bioactive agents in a sustained
elongation at break when compared with a control sample. The manner from hours to months. It may be useful for oral drug
test occurred at 90 °C and incubation for 15 days showed no formulations, skin care, medical implants, and dentistry,

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though halloysite cannot be used for intravenous injection [8] M. Liu , Z. Jia , D. Jia , C. Zhou , Prog. Polym. Sci. 2014 , 39 ,
because it is not biodegradable. 1498 .
Halloysite tubes can encase enzymes for longer storage, [9] G. Cavallaro, G. Lazzara, S. Milioto, J. Phys. Chem. C 2012, 116,
higher temperature, and extended functionality, while the tube’s 21932.
[10] G. Cavallaro, G. Lazzara, S. Milioto, F. Parisi, V. Sanzillo, ACS
opening allows for delivery of small substrate molecules into
Appl. Mater. Interfaces 2014, 6, 606.
the tube interior for biocatalysis. Loading DNA into halloysite [11] G. Cavallaro, G. Lazzara, S. Milioto, G. Palmisano, F. Parisi, J. Col-
is another prospective research direction. As functional nano- loid Interface Sci. 2014, 417, 66.
blocks, halloysite tubes may be used for building on biological [12] Y. Zhao, G. Cavallaro, Y. Lvov, J Colloid Interface Sci. 2014, 440, 68.
cells, like the formation of spore-like microbial shells providing [13] B. Singh, Clays Clay Miner. 1996, 44, 191.
microorganisms with additional functions. [14] B. Singh, I. Mackinnon, Clays Clay Miner. 1996, 44, 825.
These clay nanotubes have good mixability with biopolymers [15] K. Tazaki, Clays Clay Miner. 2005, 53, 224.
(e.g., polysaccharides, polyacrylates), with high-, medium- or [16] J. Kirkman, Clays Clay Miner. 1981, 29, 1.
low-polarity polymers (e.g., polyamides, epoxy, poly(vinyl chlo- [17] Y. Kuroda, K. Ito, K. Itabashi, K. Kuroda, Langmuir 2011, 27, 2028.
ride), polyethylene), and can be doped into plastics providing [18] K. Wada, Chem. Geol. 1987, 60, 17.
[19] P. Quantin, J. Gautheyrou, P. Lorenzoni, Clay Miner. 1988, 23,
good dispersions. These ceramic nanotubes form a “skeleton”
423.
in the bulk polymers, enhancing the composite strength and [20] K. Nicolini, C. Fukamachi, F. Wypych, A. Mangrich, J. Colloid Inter-
adhesivity. These “skeleton bones” may be loaded with active face Sci. 2009, 338, 474.
compounds, like real bones are loaded with marrow, providing [21] E. Abdullayev, A. Joshi, W. Wei, Y. Zhao, Y. Lvov, ACS Nano 2012,
additional functionality for polymers (antimicrobial, anti-aging, 6, 6887.
anticorrosion, and flame-retardancy). Halloysite–rubber nano- [22] R. White, D. Bavykin, F. Walsh, Nanotechnology 2012, 23, 1.
composites have improved strength and elongation limits, as [23] A. Zhang, L. Pan, H. Zhang, S. Liu, Y. Ye, M. Xia, X. Chen, Colloids
well as enhanced anti-aging and flame-retardant properties due Surfaces, A 2012, 396, 182.
to the nanotube loading/sustained release of corresponding [24] C. Li, J. Wang, X. Lu, S. Ding, J. Colloid Interface Sci. 2014, 420, 1.
chemical inhibitors. Halloysite is nontoxic, abundantly avail- [25] W-O. Yah, A. Takahara, Y. Lvov, J. Am Chem Soc 2012, 134,
1853.
able from natural deposits: a “green” nanomaterial that does
[26] W-O. Yah, H. Xu, H. Soejima, W. Ma, A. Takahara, Y. Lvov, J Am
not require exfoliation or other complicated energy-consuming Chem Soc 2012, 134, 12134.
processing. [27] H. Jing, W-O. Yah, Y. Higaki, H. Otsuka, Y. Lvov, A. Takahara,
Chem. Lett. 2013, 42, 121.
[28] Y. Fu, D. Zhao, W. Wang, Y. Lvov, IOP Mater. Sci. Eng. J. 2014, 64,
Acknowledgements #012047.
[29] P. Yuan, P. Southon, Z. Liu, C. Kepert, Nanotechnology 2012, 23,
Y.L. acknowledges support by the U.S. Department of Energy under
275705.
EPSCoR Grant DE-SC0012432 with additional support from the
[30] G. Cavallaro, G. Lazzara, S. Milioto, Langmuir 2011, 27,
Louisiana Board of Regents and an Alexander von Humboldt Foundation
Prize. W.W. and L.Z. acknowledge support from the National Natural 1158.
Science Foundation of China (51320105012 and 81330043) and the [31] Z. Luo, H. Song, X. Feng, M. Run, H. Cui, L. Wu, J. Gao, Z. Wang,
Beijing Nova Program (Z131102000413015). R.F. acknowledges support Langmuir 2013, 29, 12358.
from the Russian Science Foundation grant No 14–14–00924. The [32] Z. Luo, A. Wang, C. Wang, W. Qin, N. Zhao, H. Song, J. Gao,
authors thank A.S. Dubkova for technical help with pictures. J. Mater. Chem. A 2014, 2, 7327 .
Note: Figure 4b in the originally published manuscript did not show the [33] L. Onsager, Ann. N.Y. Acad. Sci. 1949, 51, 627.
tube loading as described in the caption. On February 8, 2016, the image [34] J. Adams, J. He, G. McPherson, A. Bose, R. Gupta, V. John, Lang-
was replaced with a higher resolution image wherein the tube loading is muir 2014, 30, 13533.
demonstrated. [35] A. Hughes, M. King, Langmuir 2010, 26, 12155.
[36] D. Kommireddy, S. Sriram, Y. Lvov, D. Mills, Biomaterials 2006, 27,
4296.
Received: May 16, 2015 [37] H. Wu, H. Watanabe, W. Ma, A. Fujimoto, T. Higuchi, K. Uesugi,
Revised: June 22, 2015 A. Takeuchi, Y. Suzuki, H. Jinnai, A. Takahara, Langmuir 2013, 29,
Published online: October 6, 2015 14971.
[38] R. Price, B. Gaber, Y. Lvov, J. Microencapsulation 2001, 18, 713.
[39] Y. Suh, D. Kil, K. Chung, E. Abdullayev, Y. Lvov, D. Mongayt,
J. Nanosci. Nanotechol. 2011, 11, 661.
[1] P. Podsiadlo, A. Kaushik, E. Arruda, A. Waas, B. Shim, J. Xu, [40] N. Veerabadran, R. Price, Y. Lvov, Nano 2007, 2, 215.
H. Nandivadu, B. Pumplin, J. Lahann, A. Ramamoorthy, N. Kotov, [41] Y. Lvov, R. Price, B. Gaber, I. Ichinose, Col Surf Eng. 2002, 198, 375.
Science 2007, 318, 80. [42] Y. Lvov, A. Aerov, R. Fakhrullin, Adv. Colloid Interface Sci. 2014, 207,
[2] Y-C. Li, J. Schulz, S. Mannen, C. Delhom, B. Condon, S-C. Chang, 189.
M. Zammaran, J. Grunlan, ACS Nano 2010, 4, 3325. [43] S. Levis, P. Deasy, Int. J. Pharm. 2002, 243, 125.
[3] E. Ruiz-Hitzky, M. Dardera, F. Fernandes, B. Wicklein, A. Alcântar, [44] S. Levis, P. Deasy, Int. J. Pharm. 2003, 253, 145.
P. Aranda, Prog. Polym. Sci. 2013, 38, 1392. [45] H. Kelly, P. Deasy, E. Ziaka, N. Claffey, Int. J. Pharm. 2004, 274, 167.
[4] E. Joussein, S. Petit, J. Churchman, B. Theng, D. Righi, B. Delvaux, [46] C. Ward, S. Song, E. Davis, J. Nanosci. Nanotechnol. 2010, 10, 6641.
Clay Miner. 2005, 40, 383. [47] J. Forsgren, E. Jämstorp, S. Bredenberg, H. Engqvist, M. Strømme,
[5] Y. Lvov, D. Shchukin, H. Möhwald, R. Price, ACS Nano 2008, 2, 814. J. Pharm. Sci. 2010, 99, 219.
[6] M. Du, B. Guo, D. Jia, Polym. Int. 2010, 59, 574. [48] V. Vergaro, Y. Lvov, S. Leporatti, Macromol. Biosci. 2012, 12, 1265.
[7] Y. Lvov, E. Abdullayev, Prog. Polym. Sci. 2013, 38, 1690. [49] M. Shami, K. Geckeler, Nanotechnology 2008, 19, 075604.

1248 wileyonlinelibrary.com © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Adv. Mater. 2016, 28, 1227–1250
 www.advmat.de
www.MaterialsViews.com

REVIEW
[50] Y. Lee, G-E. Jung, S. Cho, K. Geckeler, H. Fuchs, Nanoscale 2013, 5, [84] H. Robson, (Exxon Research & Development Co.), US Patent
8577. 4,098.676, 1978.
[51] D. Shchukin, R. Price, Y. Lvov, Small 2005, 1, 510. [85] E. Abdullayev, V. Abbasov, Y. Lvov, J. Petrochem. Oil Ref. 2010, 23,
[52] J. Tully, R. Fakhrullin, Y. Lvov, in NATO Science Series – C: Envi- 234.
ronmental Security. Nanomaterials and Nanoarchitectures (Eds: [86] E. Abdullayev, Y. Lvov, J. Nanosci. Nanotechnol. 2011, 11,
T. Wagner, M. Bardošová), Springer 2015, Ch. 6. 10007.
[53] R. Zhai, B. Zhang, L. Liu, Y. Xie, H. Zhang, J. Liu, Cat. Commun. [87] D. Lu, H. Chen, J. Wu, C. Chan, J. Nanosci. Nanotechnol. 2011, 11,
2010, 12, 259. 7789.
[54] C. Chao, J. Liu, J. Wang, Y. Zhang, B. Zhang, Y. Zhang, X. Xiang, [88] M. Liu, B. Guo, M. Du, X. Cai, D. Jia, Nanotechology 2007, 18,
R. Chen, ACS Appl. Mater. Interfaces 2013, 5, 10559. 455703.
[55] C. Chao, B. Zhang, R. Zhai, X. Xiang, J. Liu, R. Chen, ACS Applied [89] S. Deng, J. Zhang, L. Ye, Comp. Sci. Tech. 2009, 69, 2497.
Mater. Interfaces 2013, 5, 10559. [90] Y. Ye, H. Chen, J. Wu, L. Ye, Polymer 2007, 48, 6426.
[56] N. Veerabadran, Y. Lvov, R. Price, Macromol. Rapid Commun. 2009, [91] B. Guo, Q. Zou, Y. Lei, M. Du, M. Liu, D. Jia, Thermochim. Acta
24, 99. 2009, 484, 48.
[57] P. Zheng, Y. Du, X. Ma, Mater. Chem. Phys. 2015, 151, 14. [92] M. Liu, B. Guo, M. Du, D. Jia, Appl. Phys. A: Mater. Sci. Proc. 2007,
[58] E. Abdullayev, Y. Lvov, J. Mater. Chem. 2010, 20, 6681. 88, 391.
[59] A. Joshi, E. Abdullayev, A. Vasiliev, O. Volkova, Y. Lvov, Langmuir [93] M. Du, B. Guo, M. Liu, D. Jia, Polym. J. 2007, 39, 208.
2013, 29, 7439 [94] B. Lecouvet, J. Gutierrez, M. Sclavons, C. Bailly, Polym. Degrad.
[60] W. Wei, R. Minullina, R. Fakhrullin, E. Abdullayev, D. Mills, Y. Lvov, Stabil. 2011, 96, 226.
RCS Adv. 2014, 4, 488. [95] W. Wei, E. Abdullayev, A. Hollister, Y. Lvov, D. Mills, Macromol.
[61] M. Dzamukova, E. Naumenko, A. Badrutdinov, Y. Lvov, Mater. Eng. 2012, 297, 645.
R. Fakhrullin, Sci. Rep. 2015, 5, 10560. [96] Y. Xiea, P. Chang, S. Wang, J. Yua, X. Maa, Carbohydr. Polym. 2011,
[62] M. Guo, A. Wang, F. Muhammad, W. Qi, H. Ren, Y. Guo, G. Zhu, 83, 186.
Chin. J. Chem. 2012, 30, 2115. [97] H. Voon, R. Bhat, A. Easa, M. Liong, A. Karim, Food Bioproc. Tech.
[63] X. Zhang, Y. Zheng, L. Fried, Y. Du, S. Montano, A. Sohn, Free Rad- 2012, 5, 1766.
ical Biol. Med. 2011, 50, 811. [98] M. Liu, B. Guo, Q. Zou, M. Du, D. Jia, Nanotechnology 2008, 19,
[64] A. Bernardos, L. Mondragón, E. Aznar, M. Marcos, R. Martínez- 205709.
Máñez, F. Sancenón, J. Soto, J. Barat, E. Pérez-Payá, C. Guillem, [99] Y. Lvov, S. Eadula, Z. Zheng, Z. Lu, G. Grozdits, Nor. Pulp Paper
P. Amorós, ACS Nano 2010, 4, 6353. Res. J. 2006, 21, 552.
[65] E. Naumenko, M. Dzamukova, G. Fakhrullina, F. Akhatova, [100] G. Cavallaro, G. Lazzara, S. Milioto, Langmuir 2011, 27, 1158.
R. Fakhrullin, Curr. Opin. Pharmacol. 2014, 18, 84. [101] G. Lazzara, G. Cavallaro, R. Fakhrullin, Y. Lvov, ICE Green Mater.
[66] V. Vergaro, E. Abdullayev, R. Cingolani, Y. Lvov, S. Leporatti, Bio- 2014, 2, 232.
macromolecules. 2010, 11, 820. [102] M. Liu, B. Guo, M. Du, D. Jia, Polym. J. 2008, 40, 1087.
[67] S. Konnova, I. Sharipova, T. Demina, Y. Osin, D. Yarullina, [103] M. Du, B. Guo, M. Liu, D. Jia, Polym. J. 2006, 38, 1198.
O. Ilinskaya, Y. Lvov, R. Fakhrullin, Chem. Commun. 2013, 476. [104] M. Du, B. Guo, M. Liu, D. Jia, Polym. Polym. Compos. 2007, 15,
[68] G. Fakhrullina, F. Akhatova, Y. Lvov, R. Fakhrullin, Environ. Sci.: 321.
Nano 2015, 2, 54. [105] H. Ismail, P. Pasbakhsh, A. M. N. Fauzi, A. A. Bakar, Polym. Test.
[69] J. Cervini-Silva, A. Nieto-Camacho, E. Palacios, J. A. Montoya, 2008, 27, 841.
V. Gómez-Vidales, M. T. Ramírez-Apán, Colloids Surfaces, B 2013, [106] A. Notta-Cuvier, M. Murariu, J. Odent, R. Delille, A. Bouzouita,
111, 651. J.-M. Raquez, F. Lauro, P. Dubois, Macromol. Mater. Eng. 2015, 6,
[70] M. Bottino, G. Yassen, J. Platt, N. Labban, L. Windsor, K. Spolnik, 254.
A. Bressiani, J. Tissue Eng. Regen. Med. 2013, 1712. [107] M. Du, B. Gao, D. Jia, Eur. Polym. J. 2006, 42, 1362.
[71] X. Lai, M. Agarwal, Y. Lvov, C. Pachpande, K. Varahramyan, [108] J. Zhao, C.-L. Deng, S.-L. Du, L. Chen, C. Deng, Y.-Z. Wang, J. Appl.
F. Witzmann, J. Appl. Toxicity 2013, 33, 1316. Polym. Sci. 2014, 131, 40065.
[72] A. Kilislioglu, B. Bilgin, Radiochim. Acta 2002, 90, 155. [109] A. Joshi, C. Montes, E. Allouche, Y. Lvov, J. Inorg. Organomet.
[73] Y. Zhao, E. Abdullayev, A. Vasiliev, Y. Lvov, J. Colloid Interface Sci. Polym. Mater. 2015, 25, 282.
2013, 406, 121. [110] J. Zhang, X. Zhang, Y. Wan, D. Mei, B. Zhang, Sol. Energy 2012, 86,
[74] J. Zhang, Y. Zhang, Y. Chen, L. Du, B. Zhang, H. Zhang, J. Liu, 1142.
K. Wang, I&ES Res. 2012, 51, 1082, [111] Y. Zhao, S. Thapa, L. Weiss, Y. Lvov, Adv. Eng. Mater. 2014, 16,
[75] Y. Zheng, A. Wang, J. Macromol. Sci. A: Pure Appl. Chem. 2010, 47, 33. 1391.
[76] S. Jana, S. Das, C. Ghosh, A. Maity, M. Pradhan, Sci. Rep. 2015, 5, [112] E. Abdullayev, Y. Lvov, J. Mater. Chem. B 2013, 1, 2894.
8711. [113] Y. Lvov, A. Aerov, R. Fakhrullin, Adv. Colloid Interface Sci. 2014, 207,
[77] Y. Zhang, R. Gao, M. Liu, C. Yan, A. Shan, Archives Animal Nutri- 189.
tion 2014, 68, 320. [114] W. Wei, E. Abdullayev, A. Hollister, D. Mills, Y. Lvov, Macromol.
[78] Y. Zhang, R. Gao, M. Liu, B. Shi, A. Shan, B. Cheng, Theriogenology Mater. Eng. 2012, 297, 645.
2014, 12, 1. [115] W. Zhou, B. Guo, M. Liu, R. Liao, A. Bakr, M. Rabie, D. Jia,
[79] Y. Fu, L. Zhang, J. Solid State Chem. 2005, 178, 3595. J. Biomed. Mater. Res. A 2009, 1574.
[80] Y. Zhang, X. He, J. Ouyang, H. Yang, Sci. Rep. 2013, 3, 2948. [116] Q. Chen, Y. Zhao, W. Wu, T. Xu, H. Fong, Dental Mater. 2012, 28,
[81] R. Wang, G. Jiang, Y. Ding, Y. Wang, X. Sun, X. Wang, W. Chen, 1071.
ACS Appl. Mater. Interfaces 2011, 3, 4154. [117] M. Liu, C Wu, Y. Jiao, S. Xiong, C. Zhou, J. Mater. Chem. B 2013,
[82] E. Abdullayev, K. Sakakibara, K. Okamoto, W. Wei, K. Ariga, Y. Lvov, 1, 2078.
ACS Appl. Mater. Interfaces 2011, 3, 4040. [118] S. Olugebefola, A. Hamilton, D. Fairfield, N. Sottos, S. White, Soft
[83] N. Sanchez-Ballester, G. Ramesh, T. Tanabe, L. Shrestha, Matter 2014, 10, 544.
E. Koudelkova, Y. Lvov, K. Ariga, H. Abe, J. Mater. Chem. 2015, 3, [119] J. Xue, Y. Niu, M. Gong, R. Shi, D. Chen, L. Zhang, Y. Lvov, ACS
6614. Nano 2015, 9, 1900.

Adv. Mater. 2016, 28, 1227–1250 © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim wileyonlinelibrary.com 1249
 www.advmat.de
www.MaterialsViews.com
REVIEW

[120] K. El-Refaie, G. Bowlin, K. Mansfield, J. Layman, D. Simpson, [125] D. Fix, D. Andreeva, H. Möhwald, Y. Lvov, D. Shchukin, Adv. Funct.
E. Sanders, G. Wnek, J. Controlled Release 2002, 81, 57. Mater. 2009, 19, 1720.
[121] M. Makaremi, R. De Silva, P. Pasbakhsh, J. Phys. Chem. 2015, 119, [126] B. Guo, Y. Lei, F. Chen, X. Liu, M. Du, D. Jia, Appl. Surf. Sci. 2008,
7949. 255, 7329.
[122] D. Tao, Y. Higaki, W. Ma, H. Wu, T. Shinohara, T. Yano, [127] V. Raman, S. Rooj, A. Das, K. Stockelhuber, F. Simon, G. Nando,
A. Takahara, Polymer 2015, 60, 1894. G. Heinrich, J. Macromol. Sci. A 2013, 50, 1091.
[123] D. Shchukin, H. Moehwald, Small 2007, 3, 926. [128] Y. Fu, D. Zhao, P. Yao, L. Zhang, W. Wang, Y. Lvov, ACS Appl.
[124] E. Abdullayev, R. Price, D. Shchukin, Y. Lvov, ACS Appl. Mater. Mater. Interfaces 2015, 7, 8156.
Interfaces 2009, 2, 1437. [129] G. Li, J. Koenig, Rubber Chem. Technol. 2005, 78, 3.

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