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Laponite-based Nanomaterials for Biomedical Applications: A Review

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Current Pharmaceutical Design, 2019, 25, 1-20 1
REVIEW ARTICLE

Laponite-based Nanomaterials for Biomedical Applications: A Review

Sabya Sachi Das1, Neelam2, Kashif Hussain3, Sima Singh4,*, Afzal Hussain1, Abdul Faruk5 and
Tebyetekerwa Mike6

1
Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi-835215, Jharkhand, India;
2
Department of Pharmaceutical Sciences, NIMS University, Jaipur-303121, Rajasthan; 3Gyani Inder Singh Institute of Professional
Studies, Dehradun-248003, Uttarakhand, India 4School of Health Sciences, College of Health Sciences, University of KwaZulu-Natal,
Durban 4000, South Africa; 5Department of Pharmaceutical Sciences, Hemwati Nandan Bahuguna Garhwal University, Srinagar,
Uttarakhand, India; 6State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Material Science,
Donghua University, P. R. China

ARTICLEHISTORY
Received: December 8, 2018
Accepted: March 20, 2019
DOI:
10.2174/1381612825666190402165845
  fication of new promising research directions.
Abstract: Laponite based nanomaterials (LBNMs) are highly diverse regarding their mechanical, chemical, and
structural properties, coupled with shape, size, mass, biodegradability and biocompatibility. These ubiquitous
properties of LBNMs make them appropriate materials for extensive applications. These have enormous potential
for effective and targeted drug delivery comprised of numerous biodegradable materials which results in en-
hanced bioavailability. Moreover, the clay material has been explored in tissue engineering and bioimaging for
the diagnosis and treatment of various diseases. The material has been profoundly explored for minimized toxic-
ity of nanomedicines. The present review compiled relevant and informative data to focus on the interactions of
laponite nanoparticles and application in drug delivery, tissue engineering, imaging, cell adhesion and prolifera-
tion, and in biosensors. Eventually, concise conclusions are drawn concerning biomedical applications and identi-

Keywords: Laponite (LAP), Laponite-Based Nano-Materials (LBNMs), Applications, Composition and characteristics, Drug delivery and
biosensor.

1. INTRODUCTION leading to the formation of octahedral or tetrahedral nano-clay

Exhaustive research has been carried out for the detection, di-
agnosis, and treatment of several diseases prevailing around us
today. However, trends and advances in science and technology,
keep availing new areas of research [1]. In the recent past, various
researchers have witnessed extraordinary attention and innovations
to exploit nanomaterials and mitigate several issues in drug delivery
[2]. Currently, numerous nanomaterials of different sizes, structure,
morphology and origin (natural and synthetic) have been synthe-
sized for prime application in various biomedical areas such as
biosensing, medical diagnosis, standardized catalysis, and other
usage [3] Some of these nanomaterials include multifunctional
liposomal nanoparticles, [4]functionalized fullerenes, [5,6] func-
tionalized nanotubes,[7,8] iron oxide nanoparticles, [9,10] polym-
eric micelles, [11,12] dendrimers,[13,14] nanoshells, [15] and po-
lymeric microspheres [16]. Unquestionably, nanomaterials have
found ubiquitous uses in various areas of biomedical application
owing to innate biosafety and biocompatible concern [17,18]. This
may be due to the additional unique properties which include ad-
justable size, increased drug/material loading, ease in adjusting
surface properties, stimuli-responsive drug release kinetics, and
better pharmacokinetics [19-21]. A wide range of nanomaterials
with some of the above properties have been investigated and em-
ployed in various biomedical and pharmaceutical fields [22-25],
such as clay-based nanoparticles [26,27].
Clay minerals are typically layered silicate structures (phyl-
losilicates) of plate-like morphology. Their arrangements are estab-
lished on coatings fabricated through cationic ligands octahedrally
or tetrahedrally synchronized to hydroxyl and oxygen linkages
*Address correspondence to this author at the School of Health Sciences,
College of Health Sciences, University of KwaZulu-Natal, Durban 4000,
South Africa; E-mail: simasingh87@gmail.com
sheets [28]. They have recently provided new opportunities for
improved hybrid materials due to their proven capacity to interre-
late with drugs and other biological molecules during synthesis and
use [29]. These silicates are used as fundamental units to assemble
organic moieties in the nanometer array. The amassing approaches
depend on the clay features which comprise, i) coated clays (ver-
miculites, kaolinites and smectites) can easily get adsorbed in leni-
ent experimental circumstances, altered ions and molecules; nano-
composites and polymers resilient interlinked complexes and nano-
combinations, and ii) microfibrous clay minerals such as palygor-
skite and sepiolite, can produce hybrid and complex materials via
the interface with diverse kinds of organic moieties by the periph-
eral planes and, in certain situations, the interior planes of these
nano-structured particulate solids [30].
Amongst the various clay mineral nanomaterials, synthetic clay
material Laponite® (Table 1) has stood out as the most commonly
used nanoclay in biomedical applications. Laponite®, therefore,
forms the basis of our current review, given its various appreciable
properties, limitations, advantages and disadvantages along with
preparation methods. The review also gathered comparative data of
various clay nanomaterials (natural and synthetic) which would be
very informative for scientists or researchers working in the same
domain.
2. LAPONITE
Laponite (LAP) is a synthetic nano clay smectite with a struc-
ture and composition closely related to the natural clay mineral
hectorite (Fig. 1) [31,32]. The activities and utility of LAP for dif-
ferent purposes depend upon its grades (Table 2). It has a distinct
layered structure with a permanent negative surface charge on every
single face and aspect of the molecules and positive charge distribu-
tions along the surface edges [32,33], enhancing LAP nanoparticle
properties such as high aqueous stability and shear thinning fea-

1381-6128/19 $58.00+.00 © 2019 Bentham Science Publishers

2 Current Pharmaceutical Design, 2019, Vol. 25, No. 00 Das et al.

Table 1. Composition, characteristics and synthesis conditions of laponites.

Composition % (on dry weight basis)

1. Silicone dioxide ( SiO 2 ) : 60.4
2. Ferric oxide ( Fe 2 O 3 ) : 0.02
3. Magnesium oxide ( MgO ) : 26.0
4. Calcium oxide ( CaO ) : 0.20
5. Sodium oxide ( Na2 O) : 3.0
6. Water ( H 2 O) : 6.9
7. Carbon dioxide ( CO 2) : 0.29
8. Sulphur trioxide ( SO 3 ) : 0.10
9. Lithium oxide ( Li 2O) : 1.1
Sum of mass : 98.01
Physicochemical characteristics
a) Molecular f ormula : H 12 Li 2Mg 16 Na 2 O 72 Si 24
b) IUPAC Name : D ilithium;hexadecamagnesium;disodi um;1,3,5,7 -
tetraoxido - 2,4,6,8,9,10 -hexaoxa -1,3,5,7 -
tetrasilatricyclo[3.3.1.13,7]decane;dodecahydroxide
c) Molecular weight (g/mol ) 2286.804
:
d) Morphology : Fine white powder; swells to produce a clear
colorless thixotropic gel when dispersed in water
e) Cation exchange capacity ( ! /g) : 0.79
f) Size of average primary particle : 40 _ 10 _ 1
(nm 3)
g) Moisture ( % at 105 °C) : 8
h) pH ( 2 % aqueous dispersion ) : 8.5
-3)
i) Measured density ( g cm : 2.53
j) Refractive index : 1.54

! Starting Material Conditions Remarks

Mg salts, Na 2SiO 3 Na 2 CO 3 or NaOH 1 bar, boiling or reflux, 10 -2- h; 185 - Commercially available as
Li salt, HF or LiF 265°C at 10 -50 bar, " 8 h Laponite material

MgCl 2 , Na 2 SiO 3, HNO 3 , NH 4 OH, 125 -300 °C, P H2O , 1 -24 h Less structural Li with increasing
NaOH, LiOH temperature, layer charge due to
octahedral vacancies

Talc, Li 2 CO 3 (calcinated at 760 - 185°C, P H2O Laponite like material; talc is

980°C), Na 2 SiO 3 Na 2 CO 3 relatively cheap and readily
available source

K 2 SiF 6, LiF, Li 2CO 3 MgO, SiO 2 1420 °C, 2h Li-laponite; very small flakes as
byproduct

Established reaction and conditions for the synthesis of pure laponite material:

Na 0.7 Si 8 Mg 5.5 Li0.3 O 20 (OH) 4 +12H ++8H 2 O_ 0.7Na ++8Si(OH) 4 +5.3Mg 2+ +0.4Li +

(pH of dissolution medium - 6-9)

!
tures, with improved drug loading capacity and drug interactions
[34,35]. In LAP, the metal cationic inter-layer is intercalated be-
tween two tetrahedral silica layers, giving a 2:1 smectite layered
structure resemblance. The LAP-nanocomposite plane has a poor
net negative charge due to the cationic exchange, and the conse-
quential unstable charges generate a net positive charge distribution
on the surface end of each LAP nanoparticle. Therefore, the feeble-
ness of charges on the surface end of the nanoparticles associated
with alike clays makes LAP as a significant clay for biomedical
applications. Minor surface charges on LAP provide delamination
into single nanosheets, which is a simple procedure that signifi-
cantly enhances the surface area and interactions with different!
biomolecules [36].
At suitable concentration, LAP forms gels in aqueous systems
by electrostatic interactions amongst negatively charged surfaces
and positively charged edges of the nanodiscs of radius 12.5 nm
and a width of 1 nm, giving outstanding suspension thixotropy to
systems, in addition to other unique properties [37-39] (Fig. 2).
Special characteristics of LAP include the potential interactions
with organic molecules on LAP modified planes, inter-film
Laponite-based Nanomaterials for Biomedical Applications Current Pharmaceutical Design, 2019, Vol. 25, No. 00 3

Fig. (1). a) Schematic and b) TEM images of LAP nanoparticles showing shape and size. c) Molecular structure of LAP, smectite 2:1 (TOT where T stands for
Tetrahedral and O for Octahedral) phyllosilicate (Image reproduced with permission from RSC in ref. 36)

Fig. (2). a) LAP, [(Si 8 Mg 5.5 Li 0.3 ) O 20 (OH) 4] − 0.7) has a permanent negative surface charge due to the isomorphic substitutions in the crystal structure and a
pH dependent edge charge from unsatisfied valences in the disrupted crystal lattice. b) Potential interactions between organic molecules and the clay particle
surfaces, inter-layer pores, and inter-particle spaces give many mechanisms. (Image reproduced with permission from John Wiley and Sons in ref. 29)
4 Current Pharmaceutical Design, 2019, Vol. 25, No. 00 Das et al.

Table 2. Different grades of laponite and their benefits/limitations.

Laponite Temporary Permanent sol

Gel forming Features Benefits and limitations
grade name sol forming forming

Universal application and high efficiency in water based sys-

RD X General purpose grade tems; rheology control in surface coatings, household products
and general and industrial fields

As for LAPONITE RD, universal application and high effi-

ciency in water based systems, recommended for use in formu-
RDS X General purpose sol grade
lations that have low levels of free water. Suitable for use in soft
and hard water up to 20 °dH/ 20 °E/ 350ppm CaCO3

Aqueous dispersions of this grade will remain as stable liquids

for very long periods of time. Recommended for use in highly
filled surface coatings that have low levels of free water.
S482 X Very high sol stability grade
Also for use in non-rheology applications, such as electrically
conductive, antistatic and barrier films.
Suitable for use in all levels of water hardness

Ready-for-use, simply mix into a readymade formulation. Rec-

ommended for use in highly filled surface coatings. Also for use
A long term stable aqueous dis-
SL25 X in non-rheology applications, such as electrically conductive,
persion of Laponite antistatic and barrier films.
Suitable for use in all levels of water hardness.

Functions well in formulas with very high or very low pH level.

Organic modification for extra
Recommended for systems containing higher levels of dissolved
EP X performance in “difficult” sys-
solids. Very efficient stabilization of emulsions and suspended
tems
solids.

Optimized for use in non-rheology applications such as electri-

JS X High sol stability grade
cally conductive, antistatic and barrier films

Personal care grades:

High purity, certified low heavy
For rheology control in personal care and cosmetic applications,
XLG X metal and low microbiological
used to stabilize emulsions, lotions and creams.
content.

High purity, certified low heavy

For rheology control in personal care and cosmetic applications,
XLS X metal and low microbiological
often used in rinse-off products containing surfactants.
content.

High purity, certified low heavy For rheology control in personal care and cosmetic applications,
XL21 X metal and low microbiological optimized for use in skincare formulations stabilized at pH 5.5
content. or lower.

Optimized for rapid dispersion in

D X For rheology control in toothpaste formulations.
sorbitol solution.

apertures and inter-molecule spaces. These interactions show viable
mechanisms such as hydrogen bonding, cation linking, cation
altercation, hydrophobic interactions, anion interchange and proton
transference; all dependant on pH of the medium, electrostatic
characteristics and size of the adjoining molecule [28,36,40,41].
The characteristic précised surface area property coupled with this
unique charge distribution provides numerous excellent interaction
behaviors between LAP nanodisks and other biomolecules [42,43].
The high edge area to surface ratio of LAP is suitable for edge
modifications. Apart from grafting, surface modifications can also
be performed by ion exchange, leading to the production of LAP
with a wide range of properties. Furthermore, other properties of
LAP such as biocompatibility and inertness have strongly enabled
its study and further applications in drug delivery [44-49],
immobilization of DNA or proteins for bio-sensing [50-54] and
synthesis of inorganic nanoparticles with biomedical functionalities
[55-58]. This review discusses the application of LBNMs in differ-
ent areas of biomedicine; including drug delivery, tissue engineer-
ing, imaging, biosensors and cell adhesion and proliferation. Lastly,
we advance prospects conclusion on the adoption of LBNMs in
various medical fields. LBNMs have had an explosion of
publications in recent years, and therefore our review could not
cover all these excellent published works.
3. APPLICATIONS OF HYBRID LAPONITE-BASED
NANOMATERIALS
Nanoscale LAP materials can be treated with lipophilic mole-
cules (Fig. 2 a,b) and hence, provide a broad array of hybrid mate-
Laponite-based Nanomaterials for Biomedical Applications Current Pharmaceutical Design, 2019, Vol. 25, No. 00 5

Table 3. Laponite-drug hybrids used for biomedical applicationsa.

Drug Polymer/s Application Form References

Doxorubicin Enhanced solubility, sustain release and therapeutic efficacy. Nanodisk [44]

Doxorubicin (DOX) Complex inhibited tumor growth more significantly than free Nanodisk [45]
DOX

Doxorubicin PEG, PLA pH-enhanced drug release behavior in a sustained manner, Nanohybrid [46]
DOX-loaded nanocarriers effectively internalized by CAL-72
cells (an osteosarcoma cell line).

Doxorubicin (DOX) PAMAM Effectively inhibited the proliferation of KB cells (a human Nanodisk-dedrimer [47]
epithelial carcinoma cell line) than free DOX complex

Folic acid (FA)-DOX APMES Specifically target cancer cells overexpressing high-affinity FA Nanodisk [48]
receptors

Doxorubicin (DOX) PEG-LA Targeted carrier for efficient loading and specific delivery of Nanodisk [49]
different anticancer drugs to liver cancer cells.

Dexamethasone Sodium hyaluro- Enhanced controlled release Gel [70]

nate

Bone Morphogenic Safely harnessed BMP2 for bone induction. Gel [71]
Protein 2 (BMP2)

Silicate nanoparticles PVA, alginate Wound healing Interpenetrating network [72]

(IPN) hydrogel

Tetrazine Alginate Enhanced controlled release Cryogel [73]

Silicate nanoparticles Si-HPMC Cartilage tissue engineering Interpenetrating network [74]

(IPN) hydrogel

Bovine serum albumin Chitosan, PVA Improved the adsorption capacity of BSA hydrogel nanocomposite [75]
(BSA) beads

Donepezil Eudragit® E-100 Enhanced encapsulation efficiency and controlled release Nanoclay hybrid [76]

Doxorubicin (DOX) Alginate Diminished the effect of DOX ion-trapping in the acidic ex- Hydrogels [85]
tracellular environment of the tumor.

Itraconazole Eudragit®E-100, Release of effect of drug was effected by the type of cation and Nanohybrid [86]
aminoal- pH of system.
kylmethacrylate

Doxorubicin PAH-PSS Polyelectrolyte multilayers improved the sustained release Multicoated nanohybrids [89]
properties.

Doxorubicin PLGA) Enhanced the sustained release characteristic with reduced Nanocomposite [91]
cytotoxicity at targeted cells.

Dexamethasone PEG Enhanced physiological stability and sustained pH-responsive Nanoplates [92]
release properties.

Doxorubicin Alginate Enhanced the anticancer activity Nanohybrid [93]

a
Abbreviations: Polyethylene oxide (PEO); Four-armed poly(ethylene glycol) (PEG-D4); Poly(N-isopropylacrylamide) (PNIPAM); Polyvinyl alcohol,
(PVA)-alginate (LAP:PVA-Alginate); Silated hydroxypropylmethyl cellulose (Si-HPMC); Polylactic acid (PLA); poly(amidoamine) (PAMAM); polyethylene
glycol-linked lactobionic acid (PEG-LA); 3-aminopropyldimethylethoxysilane (APMES); poly(allylamine) hydrochloride, poly(sodium styrene sulfonate)
(PAH/PSS); Poly(lactide-co-glycolide) (PLGA)

rials with distinctive properties for several potential applications
[35,59-63]. The treated nanoscale LAP materials can be used in
several applications which include drug delivery, tissue engineer-
ing, biosensors and cell adhesion and proliferation. In biomedical
applications (Table 3), particularly in nanomedicine, this material
embraces great potential since it acts as a relevant drug carrier for
sustained release of poorly aqueous soluble materials and also for
refining their bioavailability.
3.1. Drug Delivery
LAP has numerous vital technical applications, which go be-
yond the conventional usage of clays in pharmaceutics and cosmet-
6 Current Pharmaceutical Design, 2019, Vol. 25, No. 00
ics. The high chances of probable interactions amongst LAP and
biological molecules induce exciting opportunities for LAP loaded
biomolecule or drug delivery systems. In the perspective of oral
drug/biomolecule delivery, distinctive pharmacological formula-
tions include diffusing LAP molecules in aqueous or oil mediums
entailing drug moiety and, succeeding stabilization, and then re-
gaining of LAP-drug hybrid as a compact segment, further embed-
ded into tablet form. Thus, the intercalation of itraconazole [64],
donepezil [76] and amoxicillin [44] into LAP composites has been
considered for controlled drug distribution applications [60,64-76].
Jung et al. [64] prepared an Itraconazole-Laponite (ITA-LAP)
hybrid by intercalating ITA in between interlayer space of LAP and
de-intercalating in the ionized state. The LAP clay was used as a
solubility controller and the intercalation of drug molecules into
interlayer space in LAP conjugates improved the dissolution rate of
ITA. Gaharwar et al. [65] investigated the capability of LAP cross-
linked polyethylene oxide (PEO) nanocomposites as bioactive scaf-
folds by studying the in vitro cytocompatibility of LAP-PEO cross-
linked nanocomposite layers using MC3T3-E1 mouse preosteoblast
cells. Calabrese et al. [66] designed a surfactant-modified organo-
clay (OC) based delivery system for the oral intake of cinnamic
acid (CA). The existence of LAP (bio-surfactant) improved the
drug loading efficacy by about 2 times. The drug-LAP hybridiza-
tion method can be responsible for a novel way of formulating nano
drug delivery devices with controlled release and solubility utilities.
It also acts as an innovative drug delivery carrier with controlled
release features. The half-release time (t1/2) and drug encapsulation
efficiency of the drug depend directly upon the LAP content in the
formulation. Liu et al. [67] prepared a novel injectable nano-
complex tissue adhesive hydrogel entailing of dopamine (DOPA)
impregnated with (Polyethylene glycol- LAP) PEG/LAP matrix.
Incorporation of 2 wt % LAP favorably amplified the bulk me-
chanical assets, the rate of curing, and adhesive property of the
adhesive hydrogel due to its robust interfacial binding with DOPA,
ascertaining it as an effective method for endorsing bioactivity in a
bioinert. Stempfle et al. [68] examined the dispersion of LAP
nanoparticles, that aided as a cross-linking agent to attain enhanced
particle properties in poly-N-isopropylacrylamide (PNIPAM) LAP
complex hydrogels. The main tactic of the study was to envisage
the gesture of nanoparticles in hydrogels which would allow re-
searchers for an improved consideration of the dynamics within
these complex systems. Ghadiri et al. [69] formulated Laponite-
Mafenide (LAP-Maf) hydrogel by solution an improved intercala-
tion method and LAP-Maf-Alginate (LAP-Maf-Alg) complex was
formulated by incorporating LAP-Maf hydrogel complex into stable
alginate base. Cytotoxicity tests showed that the diffusion of mag-
nesium (Mg2+) ions from the surface of LAP-Maf hydrogel reduced
the cytotoxic effects of Maf, which can further enhance the wound
curative process. Studies showed that the LAP-Maf-Alg film could
be used to absorb wound exudates and LAP-Maf hydrogel could be
used as a potential wound dressing material. Fraile et al. [70] re-
ported that dexamethasone (DEX) could be retained on LAP, pri-
marily through hydrogen bonding formation and complexation with
sodium counter ions. LAP could be used as a carrier for controlled
release and delivery of DEX for the treatment of ophthalmic disor-
ders. Gibbs et al. [71] confirmed that the adsorptive properties of
LAP nanoparticle gels were capable to confine bone morphogenic
protein 2 (BMP2) activities that persuaded ectopic bone and signifi-
cantly reduced the effective therapeutic dose in the concentration
range of sub-microgram per ml that was able to intervene os-
teogenesis compared to current methods. Golafshan et al. [72] de-
veloped an interpenetrating polymer network (IPN) complex hy-
drogel comprising LAP-polyvinyl alcohol-alginate (LAP-PVA-Ag).
The varying concentration (0, 0.5, 1 and 2 wt. %) of LAP signifi-
cantly effected the physical, mechanical and biological characteris-
tics of complex IPN hydrogels and the mechanical strength of LAP-
PVA-Ag considerably improved (upon 2 times) compared to PVA-
Ag. LAP: PVA-Ag hybrid could act as an ultimate hydrogel for
Das et al.
wound curative applications at ideal concentration of LAP (0.5%).
Furthermore, these LAP complexes show appropriate swelling,
improved blood coagulation activity and mechanical properties.
Koshy et al. [73] prepared an injectable nanocomposite hydrogel
system by incorporating LAP into hydrogel containing encapsulated
protein. This strategy of simple and versatile controlled release of
recombinant proteins prominently simplifies the design of hydrogel
systems for sustained drug delivery and therapeutic protein release
applications. Boyer et al. [74] developed a hydrogel system by
mixing LAP clay with silated hydroxypropylmethyl cellulose (Si-
HPMC) for procuring hybrid IPN of Si-HPMC-LAP. The use of Si-
HPMC-LAP hydrogels, combined with chondrocytes in subcutis of
nude mice, exhibited their impending usage for cartilage tissue
engineering, prominently in the treatment of articular cartilage de-
fects. Mahdavinia et al. [75] developed Chitosan-PVA-LAP mag-
netic hydrogel beads by the solution-mixing method and were used
for the adsorption of bovine serum albumin. Magnetic Fe3O4 nano-
composites were initially restrained on LAP sheets with decent
dispersing aptitude in order to evade any accumulation of nanopar-
ticles in chitosan-PVA matrices. Furthermore, the addition of LAP
nanoparticles to the nanocomposite substrates enhanced diversity
and propagation of cells.
The most important property is the two discrete positions on the
LAP nanodisk surfaces and the edges of the LAP nanoclays which
contributes to their multi-functionality as markers and transporters.
Functional groups are essential for further bio-conjugation or cova-
lent add-on of functional moieties that can be familiarized via cova-
lent bonding of sensitive molecules like the propylsiloxanes shown
in Fig. (2a), at the edge –OH groups [37,80,81]. Co-adsorption of
polyethylene glycol (PEG) and alkylammonium ions in the clay
layers or on the clay surfaces can modify the rheological properties
and solubility [82,83] and similarly, the pyrophosphate ions (Fig.
2c) are used as supplementary stabilizers in the arrangement of high
ionic strength dispersions [84]. Furthermore, the capacity of LAP to
perform as a DOX drug moiety carrier was established as a speci-
men of a diagnostically pertinent application [44,85] and this is
because the LAP interlayer voids can be used for effective drug
encapsulation with enhanced retaining capacity. In particular, nano-
clays have demonstrated to be excellent candidates for drug deliv-
ery carriers as they show the ability to accommodate bulky particles
or functional groups into their interlayer voids of 2-D alumino-
silicate sheets and finally release the drug complexes by ion ex-
change system [27].
A cutting-edge hybrid drug carrier system employing LBNMs
was developed by Takahashi et al. [83] using porous and spongy
nanocrystals of a bulge LAP, conjugated to a di-block copolymer
enclosing PEG and polyamine segment. LAP altered with complex
of (ɑ-acetal-poly(ethylene glycol)-block-[poly(2-(N, N-
dimethylamino) ethyl methacrylate)] formed a standardized or-
ganic-inorganic hybrid dispersion in the water medium. Due to the
high affinity between the drug moiety and LAP surface, LAP-PEG
mixture was used as a carrier for sustained release of poorly water-
soluble compounds. Surface modification with PEG remarkably
enhanced the dispersion steadiness of high ionic strength. However,
their consequences led to only a few pharmaceutical requirements
which included, a drug carrier mode for sustained release of drug
and the enhancement of bioavailability when pyrene, a typical
molecule for a poorly water-soluble drug was incorporated for tar-
geted drug delivery. To improve their findings, hydrophilic drugs
together with the smectite nanoclays were instead employed to form
new effective delivery systems.
Park et al. [76] successfully used donepezil (DNZ) and different
clay nanoparticles (LAP, saponite, and montmorillonite) as organic
guest molecules and inorganic matrices, respectively and formed
DNZ-nano clay hybrids. Their results indicate that DNZ molecule
was effectively interlinked by cation exchange reaction deprived of
any weakening of their conjugated functional groups. The cation
Laponite-based Nanomaterials for Biomedical Applications
exchangeability of the LAP regulated the captivation extent and
molecular prearrangement of drug particles in the interlayers of
matrices, and the release of sequences of DNZ. The thermal con-
stancy of drug fragments was also enhanced after the hybridization
with clay (LAP) particles. The release rate was improved by using
Eudragit® E-100 (bulky cationic polymer); nanocomposites layered
with this polymer showed a quicker drug release in a shorter time
period. Consequently, the LAP molecules were recommended as an
innovative drug delivery carrier moiety with controlled release
features.
Similar to Park et al. [76], Jung et al. [86] followed the works
of Takahashi et al. [83] but focused on the enhanced release rate of
the low-water-soluble drug, itraconazole (ITA) in a controlled man-
ner. The former had worked on changing from the use of hydro-
phobic drugs to the hydrophilic based drug. Jung's research group
employed LAP as a drug carrier, with which ITA was conjugated to
study its drug release patterns. Janssen Pharmaceuticals developed
ITA as an antifungal agent with a wide spectrum of treatments, and
now with pervasive acceptance [87]. ITA is also used for the treat-
ment of Aspergillus sp. and Candida sp., the most common fungal
pathogens [88]. It is known that water-insoluble drugs, such as ITA
show complications of low bioavailability due to their poor rate of
release in aqueous media. Numerous types of cations were involved
to control the release rates so as to accelerate the ion exchange reac-
tion and to curtail the recrystallization of released drug molecules.
Fig. (3). Schematic illustration of the intercalation of DOX into LAP (Image reproduced with permission from RSC in ref. 44)
Current Pharmaceutical Design, 2019, Vol. 25, No. 00 7
In their reported results, the drug release mechanisms of ITA–LAP
were explained; depending upon the kind and variety of cations in
the dissolution media, the entire quantity of ITA release varied
during the first 72 hours. So, such an LBNM, when incorporated
with suitable cations, could be employed as a drug delivery system
with a wide range of consequences.
With an improved drug release profile, Wang et al. [44] em-
ployed and studied LAP induced nano-carrier system for anticancer
drug delivery and cancer treatment applications. LAP nanodisks
were employed to carry DOX molecule to the cancer cells for can-
cer treatment applications as shown in Fig. (3). The resultant LAP-
DOX complex showed a high loading of DOX and exhibited a sus-
tained release profile of DOX molecules (Fig. 4). Significantly, the
LAP-DOX complex enhanced the ability to deliver DOX efficiently
to the cancer cells with considerably improved therapeutic efficacy.
Following the work of Wang et al. [44], Xiao et al. [89] reported a
simple method to modify DOX-loaded LAP nanoparticles by alter-
nate deposition of cationic polyallylamine hydrochloride and ani-
onic polysodiumstyrene sulfonate (PAH/PSS) polyelectrolytes over
the surface of DOX-loaded LAP nanoparticles. The multilayer-
coated DOX-LAP nanohybrid effectively inhibited the growth of
MCF-7 cancer cell lines and could be used in the treatment of
breast cancer. Similar work with DOX was followed through Nair
et al. [90], who developed a noble method for the controlled release
of DOX using LAP-polylactide-co-glycolide (PLGA) complex
8 Current Pharmaceutical Design, 2019, Vol. 25, No. 00
Fig. (4). Confocal laser scanning microscope images of human epithelial carcinoma cells treated with phosphate buffered saline (PBS), free DOX, and
LAP/DOX nanodisks with a DOX concentration of 0.6 µM for 2 h at 37 °C. (Image reproduced with permission from John Wiley and Sons in ref. 44)
(LPC) vesicles, through a single step double-emulsion method
which showed exfoliated morphology and improved the thermal
stability. The LPC vesicles could be used for controlled drug deliv-
ery with enhanced encapsulation of other hydrophilic and hydro-
phobic drugs. Li et al. [91] explored a unique anticancer drug deliv-
ery system by means of LAP-DOX nanodisks. The in vivo antitu-
mor efficiency and systemic toxicity of LAP-DOX nanodisks was
illustrated using a tumor-bearing mouse model. Outcomes of the
study revealed that at similar DOX concentration, LAP-DOX nano-
disks were able to constrain the tumor growth more expressively
than free DOX as well as the survival time of mice treated with
LAP-DOX complex was more than the mice treated with free DOX.
Roozbahani et al. [92] developed DOX-LAP nanoplates (DL-NPs)
by encapsulating DOX into the interlayer surfaces or voids of LAP
nanoplates through a modified intercalation technique. The con-
trolled release of DOX from LAP nanoplates exhibited pH-sensitive
behavior. Cytocompatibility with enhanced control release of DL-
Das et al.
NPs makes it an apt carrier for bone-tissue engineering application.
Goncalves et al. [93] prepared DOX-loaded LAP-Alginate (LAP-
AG-DOX) hybrid hydrogels with enhanced stability by integrating
nanodisks of biocompatible LAP into AG hydrogels using calcium
as a crosslinker. Results showed that the LAP-AG-DOX hybrid
hydrogels enhanced the antitumor activity of DOX with good cyto-
compatibility.
3.2. Tissue Engineering
The major concern of tissue engineering is to advance numer-
ous artificial 3-dimensional shells or scaffolds with suitable chemi-
cal and physical properties that can diligently imitate the natural
extracellular medium [94]. These shells should be biodegradable,
wholly blend after implantation, and be absorptive in nature to pro-
vide a greater surface area to volume ratio for cell proliferation,
attachment, and differentiation (Table 4). New tissue should
quickly form, and no additional surgical procedures should be per-
Laponite-based Nanomaterials for Biomedical Applications Current Pharmaceutical Design, 2019, Vol. 25, No. 00 9

Table 4. Laponite-drug/polymer hybrids used for tissue engineering, bioimaging and other significant applicationsa.

Drug/ polymer Application Form References

Tetracycline; PLGA Reduced burst release of the drug and significantly improved the tensile Nanofibres [94]
strength of the polymer nanofibrous mats.

PEG Viability of encapsulated hMSCs was improved Hydrogel [97]

PEG-DTT Adjusted polymer quantity tailored both the degradation rate and modulus of Hydrogel [99]
hydrogels

5-aminovaleric acid; ChiPgA Enhanced the porosity of composite, biocompatible. Scaffold [100]

Gelatin Significantly improved mechanical properties Foam [101]

PLA Supported neovascularization (integral for nutrient transport). Nanocomposite film [102]

BAAm Enhanced the rheological properties of hydrogel. Hydrogel [105]

PEG-DA Significantly enhanced both the compressive and tensile properties Hydrogel/ [107]
Scaffold

PNIPAM Enhanced the mechanical and biological properties. Hydrogel [108]

Strontium ranelate; PCL Enhanced alkaline phosphatase (ALP) activity and maintained cell viability. Scaffold [110]

Sodium alginate, Sodium exhibited excellent adsorption capacity on heavy metal ions, which enhanced Hydrogel [111]
acrylate the adsorption of Ni2+, Cu2+, Zn 2+ and Cd2+ ions by 10.4, 8.0, 23.0,and 14.3 fold
compared to active carbon (AC).

Gellan gum methacrylate; Enhanced gel mechanical properties, formed gels withstand steam sterilization. Nanocomposite hy- [113]
polyethylene glycol di- drogel
methacrylate

PEG; iron oxide (maghemite – Magnetic iron oxide nanoparticles embedded in the laponite matrix exhibited Ferrogel [129]
γ-Fe2O3) strong T2-weighted MRI (magnetic resonance imaging) contrast.

PNIPAM Tissue engineering and bioimaging applications. Hydrogel [130]

PNIPAM; polystyrene Tissue engineering, wound healing and bioimaging applications. Hydrogel [132]

Chitosan; PEO Enhanced tuning of cellular adhesion and control biomineralization. Nanocomposite [133]

Aequorin; PEG Sol–gel encapsulated aequorin protein offers potential as a one shot biolumi- Sol-gel matrix [139]
nescence based biosensor for the determination of Ca2+.
a
Abbreviations: Poly(lactide-co-glycolide) (PLGA); Poly (ethylene glycol) (PEG); Dithiothreitol (DTT); chitosan/polygalacturonic acid (ChiPgA); Polylactic
acid (PLA); N,N‘-methylenebis(acrylamide) (BAAm); Poly(ethylene glycol) diacrylate (PEGDA); Poly(N-isopropylacrylamide) (PNIPAM); Polycaprolactone
(PCL); polyethylene oxide (PEO).

formed after implantation for them to be removed out of the body
[95]. Exceptional contenders for soft-tissue engineering scaffolds
include hydrogels, which are polymer networks extensively swollen
with water [96]. However, extensive application of hydrogels as
ideal scaffolds is limited owing to their bio-inertness [81], reduced
mechanical properties [82] and their fragile behavior after getting
dried [83]. To create mechanically robust hydrogels, nanoclays
have been employed as cross-linkers to make nanocomposite hy-
drogels with improved mechanical properties such as compressive
strength and stiffness (modulus) [100-103].
Owing to the high interfacial area, nanoclays offer enhanced
mechanical properties due to strengthening when used in a polymer
matrix. Along this line, Haraguchi et al. [104] prepared a modified
elastic nanocomposite hydrogel by in situ polymerizations of N-
isopropyl acrylamide (NIPA) monomer with existing LAP nano-
clays (Fig. 5). The resulting hydrogel was capable of overcoming
the limitations of conventional chemically cross-linked polymer
networks. The incorporation of LAP nanoclays into poly(NIPA)
(PNIPA) hydrogels gave highly stable and structurally homogene-
ous materials with extraordinary mechanical properties. These dis-
tinct properties were found suitable and useful for application in
biomedical tissue engineering. In addition to PNIPA, LAP-based
nanocomposite hydrogels have been synthesized using other classes
of monomers such as acrylamide [105] and acrylic acid [106].
To further improve the mechanical properties of the nanocom-
posite hydrogels for use in tissue engineering, Chien et al. [107]
synthesized biocompatible poly(ethylene glycol) diacrylate
(PEGDA)-LAP hybrid hydrogels which supported both two-
dimensional and three-dimensional (2D and 3D) cell cultures of
human mesenchymal stem cell. Incorporation of LAP nanoparticles
successfully enhanced the mechanical properties (flexible and com-
pressive) of PEGDA hydrogels. The improved mechanical proper-
ties of PEGDA/LAP hydrogels highlighted their possible applica-
tions in tissue engineering.
In spite of these noticeable advances in flexible modulus, the
toughness and durability attained still had an extent less than that of
lenient biological tissues. In 2012, Wang et al. [108] improved the
mechanics of PNIPA-LAP nanocomposites by making gel com-
10 Current Pharmaceutical Design, 2019, Vol. 25, No. 00 Das et al.

Fig. (5). Nanocomposite hydrogels for enhanced mechanical properties. In contrast to a) organically cross-linked (OR) PNIPA polymer gels b,c) gels cross-
linked with clay nanoparticles (NC) display marked improvements in strength, elongation, and toughness (numbers represent relative crosslink density). d) The
large degree of spacing between clay cross-linkers allows for long and flexible polymer chains. (Image reproduced with permission from John Wiley and Sons
in ref. 88)

plexes with a suitable coated structure imitating control release of
the drug. The well-arranged nanoscale complex permitted the inte-
gration of LAP composites of up to 30 wt%, accomplished a 360-
fold upsurge in elastic modulus (collectively with a six-fold growth
in hardness and five-fold rise in strength) in contrast to the ortho-
doxly produced PNIPA-LAP nanocomposite gel complexes. The
modulus value of 1.5–43 MPa of these PNIPA-LAP nanocomposite
gels signifies the utmost testified worth for a polymeric hydrogel to
date, and, analytically, attains mechanical characteristics similar to
that of hard biological tissues such as cornea and cartilage [108].
Wang et al. [109] studied the applicability of LAP bioceramic
for potential and enhanced bone-tissue engineering applications. In
their work, LAP bioceramic with a smooth surface and somewhat
systematic holey arrangements was formed. The LAP bioceramic
showed an admirable surface hydrophilicity and protein adsorption
activities. With the decent bone healing effect revealed by in vivo
experiments, and also excellent biosafety, the synthesized LAP
bioceramic held an abundant potential for applications in bone tis-
sue engineering (Fig. 6). Similarly, Nair et al. [110] recently, were
able to synthesize a complex of strontium ranelate (SRA) with LAP
in the presence of polycaprolactone (PCL) for bone tissue
engineering applications.
Numerous polysaccharides such as chitosan, alginate and meth-
ylcellulose have been blended with LAP to overcome the brittleness
of their single-network hydrogels, hence yielding biomaterials with
enhanced properties [111,112]. Attempting to form a novel
nanocomposite hydrogel, recently, Pacelli et al. [113] mixed a
functionalized gellan gum (GG-MA), with LAP. A biocompatible
polysaccharide, GG-MA has received increased consideration due
to its extensive applicability, ranging from drug delivery
applications to cartilage tissue engineering applications [114]. The
amalgamation of LAP in GG-MA network was able to form robust
and stable hydrogels with practically unvaried or integral mechani-
cal features after thermal treatment. The thermal behavior was reli-
ant on the quantity of nano-clay presented in the polymeric net-
work, with respect to the solo matrices of GG-MA, which cannot
sustain decontamination deprived of degradation. This property
signifies an important fact towards the design of biomaterials poten-
tially beneficial as wound dressing covering or any other significant
biomedical application where a sterile system is required.
LAP can be established as tissue matrices for engineering a
diverse class of tissues, perhaps for craniofacial (dental) and ortho-
pedic (soft–hard interfaces) applications. In this context, Gaharwar
et al. [115] explored the structural and mechanical properties of
Laponite-based Nanomaterials for Biomedical Applications Current Pharmaceutical Design, 2019, Vol. 25, No. 00 11

Fig. (6). In vitro osteogenic differentiation of rMSCs and in vivo bone repair evaluation.
a) ALP activity (normalized for the DNA content, nmol of transformed substrate per unit of time and per mass of DNA) of rMSCs cultured onto different
substrates in growth medium after 14 days culture. Insert of (a) shows the picture of alizarin red staining of rMSCs cultured onto TCP (left) and LAP ceramic
(right) in growth medium without any inducing factors on day 14. (b–f) show the macroscopic appearance of bone defects (A 2-mm bone defect was created in
the middle of the tibia, which was implanted with LAP ceramic as shown in (d)). (b) and (e) show the macroscopic appearance of defects without and with
implantation for 24 weeks, a trace of LAP ceramic residual is observed in (e) as pointed by an arrow. (c) and (f) show the radiographic images of bone defects
without and with LAP implantation after 24 weeks. (Image reproduced with permission from Elsevier in ref. 93)

covalently as well as physically cross-linked nanocomposite hydro-
gels comprising of silicate/LAP nanoparticles and polyethylene
glycol (PEG). Nair et al. [116] prepared polycaprolactone (PCL)
composite scaffolds comprising LAP-strontium ranelate (LAP-SR)
complex for the controlled release of strontium ranelate. Results
from the in vitro study using human osteosarcoma cells showed that
the complex PCL-LAP-SR was used in the treatment of osteoporo-
sis and for bone tissue engineering applications. Wu et al. [117]
prepared polyethylene glycol-silicate (PEG-Si) based hydrogels that
were tangibly cross-linked by silicate nanoparticles, LAP and cross-
linked by either Pluronic F127-diacrylate or PEG-diacrylate. The
ensuing networks resisted uniaxial extensions up to 2000%, signify-
ing that the hydrogel networks can absorb considerable amounts of
energy during alteration and so it could be used as a matrix for tis-
sue engineering application, pressure sensitive adhesives and
wound dressing uses. Ordikhani et al. [118] prepared chitosan–
Laponite (CS-LAP) nanocomposite films by an electrophoretic
deposition technique. The intercalation of the CS-LAP and drug
macromolecules, vancomycin (VCM), into silicate matrix enhanced
the controlled release of VCM. The cellular outcomes showed that
the presence of LAP affected cell viability, attachment and alkaline
phosphate activity of MG-63 osteoblast-like cells, applicable in
bone-tissue engineering applications. Paula et al. [119] developed a
method comprising a self-assembled, polymer-centered conformal
coating, assembled by an aqueous-based layer-by-layer (LbL)
method, as a dual-purpose biomimetic implant surface which pro-
vided sustained release of an antibiotic agent trailed by an active
growth factor for orthopedic implant applications. The multi-
layered coating entails two parts: a base osteoinductive agent con-
taining a bone morphogenetic protein-2, recombinant human bone
morphogenic protein (rhBMP-2), below an antibacterial constituent,
enclosing gentamicin (GEM). LAP barrier layers improved the
sequential separation amongst the release of the two drugs and ex-
tended the release of the core rhBMP-2 growth factor, ensuring
more physiologically significant dosing of rhBMP-2. Wang et al.
[120] prepared LAP bioceramics by sintering LAP powder compos-
ites. These LAP bioceramics persuaded the osteoblast differentia-
tion of rat mesenchymal stem cells (rMSCs) in growth medium
deprived of inducing factors and hence could be used for the treat-
ment of bone defects and bone-tissue engineering applications.
3.3. Bioimaging
The principle of all imaging techniques, single-photon-emission
computed tomography (SPECT) and optical imaging), (X-ray or
computed tomography (CT), echography, positron emission tomo-
graphy (PET), magnetic resonance imaging (MRI), is to build a 2D
12 Current Pharmaceutical Design, 2019, Vol. 25, No. 00 Das et al.

Fig. (7). T2-Weighted MR images (a) and linear fitting of 1/T2 (b) of LAPFe3O4 and Fe3 O4 NPs at different Fe concentrations (0.005, 0.01, 0.02, 0.04, and 0.08
mM). 1 and 2 represent LAP-Fe3O4 and Fe3O4 NPs, respectively. MR imaging of cancer cells in vitro. T2-Weighted MR images (c) and MR signal intensity
analysis (d) of HeLa cells after treated with PBS, LAP-Fe3O 4 NPs at different Fe concentrations for 6 h. In vivo T2-weighted images (a) of tumor (red circle),
liver (red arrow) and kidney (red star) after intravenous injection of LAP-Fe3O4 NPs (930 µg mL−1 Fe, in 0.1 mL PBS) for 0 h, 2 h, 4 h, and 6 h. In vivo MR
signal intensity (b) of liver, kidney and tumor after intravenous injection of LAP-Fe3O4 NPs at different times. (Image reproduced with permission from RSC in
ref. 33)

Fig. (8). Improved adhesion and proliferation of MSCs on PEO gel films with increasing incorporation of LAPNPs. (Image reproduced with permission from
Elsevier in ref. 143)
Laponite-based Nanomaterials for Biomedical Applications
Fig. (9). Protein interaction with the nanoclay hybrids. Fluorescence enhancement (F/F0) of Nile Red on LAP in aqueous dispersion (left) and SternVolmer
quenching plot (F0/F) of Eu(ttfa) 3(topo)2 on LAP in aqueous dispersion (right) after addition of BSA (solid squares) and β-lactoglobulin (open circles), meas-
ured after 16 h of equilibration time. (Image reproduced with permission from RSC in ref. 122)
or 3D image comprehending information that can be used to under-
stand the physiology or metabolism of the organisms. However,
sometimes contrast is naturally present in the obtained images. To
improve this, contrast agents are administered and their dynamic
behavior in the body facilitate the observation of the anatomic or
pathologic structure, invisible without contrast agent. Recently, NPs
have increasingly been considered as promising contrast agents
because of their unique physical, chemical, and biological proper-
ties [121-123] (Fig. 9), particularly in MRI imaging. This is because
currently, MRI is one of the most influential imaging tools for envi-
sioning the anatomical arrangements of soft tissues with cellular
and even sub-cellular 3D resolutions [124,125]. MRI is extensively
used for the diagnosis and identification of diseases such as tumors,
cerebrovascular and cardiovascular diseases [126,127].
Despite wide use, the sensitivity of MRI in distinguishing the
healthy tissues and malignant tissues is lagging. Therefore, en-
hanced efficacy of MRI diagnosis is a current [31] urgent task in
the currently designed advanced MRI contrast agents. LAP based
composite nanomaterials have recently been employed in an at-
tempt to study and expound a possible solution to this problem.
Modified LAP technology could act as improved recognition sensi-
tivities in bioimaging, bioanalysis and biosensing. Felbeck et al.
[128] investigated different approaches for the superficial function-
alization of LAP and formulated 25 nm core-sized nanoparticles
(disk-shaped), as nano-carriers for altered fluorophores. The Si−OH
functional groups at the edges of these nanodisks were significantly
embedded with 3-aminopropyldimethylethoxysilane (APES). The
robust effect of charge on the dye and accumulation affinity on the
illumination of the inevitable dyes at the edges of nanodisks was
noticed from the consequences during formulation.
Tzitzios et al. [129], by a single step precipitation method,
synthesized laponite-gamma-iron oxide (LAP/γ-Fe2O3) composite
nanomaterials. The blended nano-composites were investigated by
a sequence of corresponding methods to further explain the struc-
tural arrangement and configuration, and also to reveal the mag-
netic properties of the final material. Fe2O3 nanoparticles interca-
lated in the LAP matrix exhibited strong T2-weighted MRI diver-
gence, which was practically 2-fold higher as compared to mono-
dispersed Fe2O3 nanoparticles (core sizes of ~13 nm). However, no
in vivo MRI divergence augmentation effect of the attained LAP-γ-
Fe2O3 was present until recently when Ling et al. [31] exploited a
simplistic co-precipitation method to formulate a novel water-
dispersible LAP-Fe3O4 nanoparticles with enhanced control release
effect. The MRI performance of LAP-Fe3O4 nanoparticles was as-
Current Pharmaceutical Design, 2019, Vol. 25, No. 00 13
sessed both in vivo and in vitro by means of a human cervical carci-
noma cell line, the HeLa xeno-grafted tumor model and the HeLa
cells, respectively. In both, in vitro tumor cell MRI and in vivo tu-
mor grafted nude mice MRI, there was a noticeable signal intensity
alteration in the presence and with the administration of LAP-Fe3O4
nanoparticles (Fig. 7) respectively owing to the cellular uptake of
the nanoparticles. This exhibits the potential of using LAP-Fe3O4
nanoparticles as a T2-weighted divergence agent for MRI.
3.4. Cell Adhesion and Proliferation
In response, primarily, to the opportunities afforded by LBNMs
in biomedicine, an evolving cluster of studies has also explored the
interface of cells with these nanomaterials. The application of
LAPNPs and composites in cell adhesion and proliferation was
previously coined more into in vitro categorization of cellular reac-
tions and responses [29]. Notwithstanding lingering questions re-
garding cytocompatibility, numerous studies have revealed not only
usual cellular signals and responses but also on clay-reliant aug-
mentations, predominantly on cell adhesion and propagation upon
gel substrates and polymeric matrices.
Haraguchi et al. [130] studied the consequences of the amount
of clay in LAP nanoparticle merged with PNIPA hydrogels on cel-
lular feasibility, linkage and propagation. With earlier investiga-
tions [131,132], organically polymer based PNIPA hydrogels alone
were incompetent to keep up the linkage of the multiplying cells.
Furthermore, LAP-clay associated PNIPA hybrids were competent
to sustain both the bonding and propagation of HepG2 (immortal-
ized cell line comprising of human liver carcinoma cells), human
umbilical vein endothelial cells (HUVECs) and skin fibroblast that
are intensely related with the concentration of LAP in the formu-
lated hydrogel. Haraguchi’s group tagged the sharp dependence of
cellular linkage on LAP quantity in the aforementioned system, to
the i) anionic surface charges consulted by the LAP, ii) hydropho-
bicity of the fine PNIPA substrate by the hydrophilic LAP nano-
composites and iii) amended protein adsorption. A similar LAP
dependent effect on cell adhesion and propagation was studied.
Chang et al. [107] found it sufficient to add 2.5 wt% LAP to endure
the linkage and propagation of human mesenchymal stromal/stem
cells (hMSCs) on below par cell linked PEG hydrogel films. The
researchers still recommended conceivable importance of LAP
nanocomposites in establishing adhesive sites for cellular linkage,
attachment and in allowing protein site-specific adsorption.
14 Current Pharmaceutical Design, 2019, Vol. 25, No. 00 Das et al.

The series of studies by Gaharwar et al. [59, 132-133] and Table 5. Pharmaceutical and non-pharmaceutical applications
Schexnailder et al. [134] on LAP-PEO nanocomposite films fo- of laponite in various fields.
cused on the utility and potential of LAP nanoclays in enabling
adhesion and proliferation of cells on polymeric gels. Like many
biopolymers, PEO is non-fouling and hydrophilic moiety; and is Personal care • Skincare and sunscreen emulsions
thus resilient to the cellular linkage. Yet still, PEO is frequently products • “Emulsifier-free” emulsion systems
used to synthesize physically cross-linked PEO–LAP hydrogels and
• Alphahydroxy acid creams
(PNIPA)-based polymers employed to amalgamate mostly cova-
lently cross-linked LAP-polymer films or hydrogels [135-137]. The • Toothpaste
adhesion of NIH3T3 fibroblasts [133, 134], mesenchymal stem • Color cosmetics
cells (MSCs) [110] and MC3T3-E1 preosteoblasts [59] was found
to be extremely reliant on the ratio of PEO added to LAP. At no- • Gelled skin cleansers and Depilatory creams
ticeable ratios of LAP to PEO of 40% and beyond, fibroblasts were • Exfoliant and astringent cleansers
noticed to attach accurately and multiply significantly (Fig. 8). In-
• Nail lacquers and Shampoos
creasing the nanoclay amount up to 70% further improved cell
proliferation. Prominently, these results were constantly perceived Paper and • Static dissipative (antistatic) coatings
in the growth phase and also in the overall amount of cells polymer films
delivered at the plateau phase, signifying the presence of bonding • Electrographic paper and film
edges and sites afforded by the LAP, signifying LAP nano- • Inert barrier films
composites as a governing factor [134,135].
• Anti-blocking coatings
3.5. Biosensors • Paper coating colours
Most results in biology are complex, nonlinear, transient and • Ink jet coatings
very indistinct. Conversely, improved speed, quantity and sensitiv-
• Industrial specialty papers
ity are a prerequisite in biomedicine [138]. Extensively optical sen-
sors that use hybrid NPs center on the recognition of analytes and • Microparticle for retention and drainage systems
molecules that either absorb or radiate light. These sensors signifi-
cantly depend on the involvement of biomolecules that comprises Surface coat- • Decorative & architectural finishes
fluorescent or chromophoric groups (i.e. hemeproteins, flavopro- ings • Textured coatings
teins, and fluorescently-labeled proteins). These biomolecules can
• Water-in-water multicolor paint
also be primed by co-entangling a biomolecule along with a fluoro-
phore or chromophore that reacts specifically to the protein- • Automotive OEM and refinish
reconciled reaction (i.e. variation in O2 levels, pH change,). On the • Clearcoats and varnishes
other hand, bioluminescence can be utilized as a signal to specify
the existence of species that modify or change the function of lumi- • Industrial and protective coatings
nescent proteins such as aequorin [139]. LAP hybrid NPs together • Rust conversion coatings
with the already established technologies can act as analytical
• Water reducible alkyds
probes to improve efficiency.
• Wood stains
The protein corona [140-142] and nanoparticle cytotoxicity are
among the most important factors considered while establishing • Decking stains
hybrid nanoparticles in biophotonics. Felbeck et al. [143] recently • Wood varnishes
carried out optical studies on the interaction of LAP nanocompo-
sites or hybrids with β-lactoglobulin and bovine serum albumin • Printing inks
(BSA). In their study, LAP hybrids were loaded with Eu-complex- • Artist’s & children’s paints
Eu (ttfa)3(topo)2 and with Nile Red (fluorescent solvatochromic
• Pigment suspensions
dye). Fluorescent solvatochromic dye Nile Red (NR) was already
previously studied with proteins [144-146], and Eu-complex had House prod- • Oven cleaners and degreasers
also been successfully incorporated into LAP hybrids earlier [147]. ucts
Their investigation suitably followed the behavior of proteins by • Gelled bleach cleaners
using LAP-based nanohybrids. The LAP complex of both the dyes • Sprayable cleaners and spray-with-cling formu-
optically responded to the existence of β-lactoglobulin and BSA. lations
Conversely, while Nile Red manages to express a noticeable emis-
sion enhancement, the Eu-complex somewhat lost emission • Tablet disintegranting agent
strength. Moreover, the emission strength of the NR-LAP-BSA • Carpet shampoos
hybrid was more than for the analogous LAP-β-lactoglobulin com- • Acidic and alkali toilet cleaners
plex. This was attributed to the higher quantity of hydrophobic
positions in BSA, which lead NR molecules to prolix into. These • Hard surface cleaners and air fresheners
results suggest that the performance of proteins can appropriately • Liquid automatic dishwashing detergents
be trailed using dye-LBNMs.
• Antistatic products and anti-redeposition agent
Further, there are lots of general applications of laponite as
multifunctional material including personal care products, paper Agricultural • Seed germination gels
and polymer films, surface coatings, house products, agricultural • Plant rooting gels
usages (Table 5). In the present review, brief compilations of bene-
fits and limitations including general information of various clay • Agrochemical flowables – herbicides, pesticides
nanomaterials have been illustrated in Table 6. Moreover, Table 7 • Essential element suspensions
summarized various preparation techniques followed with
Laponite-based Nanomaterials for Biomedical Applications Current Pharmaceutical Design, 2019, Vol. 25, No. 00 15

Table 6. Classification of different types of clay nanomaterials: Benefits and Limitations.

Type of clay Formula Origin Substitution Layer Routes of ad- Dosage form Benefits and Limitations
mineral charge ministration

Montmorillo- Mx(Al2−xMgx) Natural Octahedral Negative Oral Solid (tablets, cap- Low pH yielded; accompa-
nite Si4O10(OH)2 sules, powders); nying minerals depend
·nH2O Liquid (suspensions, mainly on pressure and
emulsions) temperature conditions;
additional minerals depend
Topical Creams, ointments
upon starting compositions.
and powders

Transdermal Films and pathches

Rectal Suspensions, tablets

Vaginal Ointments, creams

and gels

Hectorite Mx(Mg3−xLix) Natural Octahedral Negative Oral Solid (tablets, cap- It is commercially available
Si4O 10(OH) 2 sules, powders); as laponite and talc; talc is
·nH2O Liquid (suspensions, relatively cheap and readily
emulsions) available source.

Saponite Mx Mg3(Si4−xAlx ) Natural Tetrahedral Negative Oral Solid (tablets, cap- Poor crystallinity at ≤ 200
O10(OH) 2·nH2O sules, powders); °C; no complex formation
Liquid (suspensions, during gel preparation;
emulsions) amount of amorphous mate-
rial depends on time and
amount of NH4OH; addition
of Mg improves the forma-
tion of saponite.

Flurohectorite Mx(Mg3−xLix) Synthetic Octahedral Negative Oral Solid (tablets, cap- Very small flakes as by-
Si4O 10 F2·nH2O sules, powders); products; excess LiF (start-
Liquid (suspensions, ing material) needed to
emulsions) form flurohectorite.

Laponite Mx(Mg3−x Lix) Synthetic Octahedral Negative Oral Solid (tablets, cap- Very much useful in phar-
Si4O 10(OH) 2 sules, powders); maceutical, tissue engineer-
·nH2O Liquid (suspensions, ing and biomedical applica-
emulsions) tion due to its smooth deg-
radation. Used as rheology
Topical Creams, ointments
modifier. Thermal and
and powders
pressure sensitive.
Transdermal Films and pathches

Fluromica NaMg2.5 Si4O 10 F2 Synthetic Octahedral Negative Topical Film and patches Impurities from starting
material zeolite stuff re-
mains; < 10% amorphous.

Kaolinite Al2Si2O5 (OH)4 Natural - Neutral Oral Solid (tablets, cap- Na-gel resulted in degrada-
sules, powders); tion at 350 °C to byprod-
Liquid (suspensions, ucts.; many metal substitu-
emulsions) tions are shown to be possi-
ble.
Topical Film and patches

Local Powder and polymer

mixtures

(Table 6) Contd....
16 Current Pharmaceutical Design, 2019, Vol. 25, No. 00 Das et al.

Type of clay Formula Origin Substitution Layer Routes of ad- Dosage form Benefits and Limitations
mineral charge ministration

Halloysite Al2Si2O5 (OH)4 Natural - Neutral Oral Solid (tablets, cap- Forms dilute solutions;
·2H2O sules, powders); better result with NH 4 and
Liquid (suspensions, F.
emulsions)

Topical Film and patches

Local Powder and polymer

mixtures

Kanemite Na2Si4 O9 Natural/ Tetrahedral Negative Oral Solid (tablets, cap- Identical to montmorillo-
·5H2O Synthetic sules, powders); nite.
Liquid (suspensions,
emulsions)

Makatite NaHSi2O 5 Natural/ Tetrahedral Negative Rectal Suspensions, tablets Not specific.
·7H2O Synthetic

Octasilicate Na2Si8 O17 Synthetic Tetrahedral Negative Local Powder and polymer Exact structural elucidations
·9H2O mixtures could not be identified.

Magadiite Na2Si14O29 Natural/ Tetrahedral Negative Topical Film and patches Used for electrochemical
·10H2O Synthetic studies specifically.

Kenyaite Na2Si20O4 Synthetic Tetrahedral Negative Local Powder and polymer Not specific.
·10H2O mixtures

Table 7. Various preparation techniques of clay nanocomposites: advantages and disadvantages.

Preparation Technique Driving Force Advantages Disadvantages

In-situ polymerization
Interaction strength between mono-
mer and clay surface; Enthalpic
evolvement during the interlayer
polymerization.
Suitable for low or non-soluble poly-
mers; A conventional process for ther-
moset nanocomposites.
Clay exfoliation depends on the extent of
clay swelling and diffusion rate of
monomers in the gallery; Oligomer may
be formed upon incompletely polymeri-
zation.

Solution exfoliation Entropy gained by desorption of Prefer to water-soluble polymers. Compatible polymer-clay solvent system
solvent, which compensates for the is not always available; Use of large
decrease in conformational entropy quantities of solvent; Co-intercalation
of intercalated polymers. may occur for solvent and polymer.

Melt intercalation Enthalpic contribution of the poly- Environmental benign approach; No Slow penetration (transport) of polymer
mer-organoclay interactions. solvent is required; Nanocomposites can within the confined gallery.
be processed with conventional plastic
extrusion and molding technology

advantages and disadvantages of the various clay nanomaterials.
Thus, these clay nanomaterials need to be explored further as safe
drug delivery carriers for challenging molecules with obvious ad-
vantages. Natural and synthetic need much attention of the research
scientists working on nanomedicine as drug carrier for the recent
era.
4. FUTURE PROSPECTIVE
LAP as formulation additives and drug carriers are applied by a
variety of routes including oral, transdermal, and local administra-
tions. The amount of LAP, depending on the routes of administra-
tion for biomedical applications, can be selected in order to control
key parameters including size, swellability, mucoadhesiveness,
dispersibility, and drug-release rate. In addition, the hybridization
reaction of the drug with LAP, whatsoever the physical adsorption
or intercalation, results not only in improved solubility and phys-
icochemical stability of drug molecules, but also offers a controlled
and sustained drug-release rate, and eventually achieves improved
bioavailability due to efficient drug delivery. In various drug deliv-
ery systems, LAP-drug hybrid systems or LBNM’s show admirable
biocompatibility, greater anion exchange ability, and pH-sensitive
solubility interrelated with drug load content. Furthermore, it is
established that the significant inorganic materials such as LAP and
their intercalated hybrids or nanocomposite hybrids would allow for
the development of novel polymer hybrids or composite materials
with advanced mechanical properties, applicable for biomedical
applications. The advanced developments of LAP-drug hybrid sys-
tems or LBNM, via various routes of administration, will allow the
Laponite-based Nanomaterials for Biomedical Applications
medication to be lodged to specific targeted parts of the body (or-
gans or cells). Although the field of clay-drug hybrid systems has
attained significant attention over the past decade with many chal-
lenges remained. From general prospects, LAP-drug hybrid systems
or LBNM’s seemed to be very effective and to work well in vitro,
but some failed in in vivo performance due to complications in-
volved in real physiological conditions. Furthermore, toxicological
studies are required to determine whether the LAP-drug hybrid
systems or LBNM’s can be applied with judiciously rationalized
clinical outcomes. The gene delivery and programed DDS (tar-
getability and/or environmental stimuli responsiveness, with clay
minerals) are further challenges. The innovative design in terms of
formulations with clay-drug hybrids advance clinical use and con-
sequently, open new drug-delivery markets. Finally, research on
clay minerals will expand their applications in biomedical fields,
such as regenerative tissue engineering, theranaustics, personalized
medicine, and implants.
CONCLUSION
As documented by a large number of papers and books,
HLBNMs have been widely studied and applied in the biomedical
field. LAP is an excellent material for biomedical applications,
coupled with cost and excellent properties ranging from chemical to
mechanical properties. There is immense potential for their study
and use in biomedicine. Important still, is their use with polymeric
additives which presents new LAP–drug interaction, release
mechanisms and strength characteristics. These are essential for the
formulation of drug delivery systems, tissue engineering materials,
cell imaging, adhesion and proliferation mechanisms, and as bio-
sensors. In each application, new opportunities are arising from the
need for ideal materials to further commercialization for use on a
large scale. Furthermore, the synthesis of these materials at
nanoscale and incorporation with other materials, make LBNMs
signals possible future breakthroughs in biomedicine.
However, in spite of the quick improvement in respect to
LBNMs, these novel nanocomposites must be prudently and wholly
assessed for biocompatibility to be applicable for biomedical
applications. Their novelties in biomedicine are fairly well-
established and are peculiarly understood regarding their physio-
logical interactions with different living tissues. Additionally,
among the numerous research articles mentioning the adoption of
LBNMs, no systematic estimation and evaluation of the biocom-
patibility of any LBNMs have been accomplished or published.
With this done, in the future, we can anticipate further extensive
translational research on LAP, mainly in the areas of immune
modulation, imaging, and cancer research. The therapeutic advan-
tages, bioactive ness and surface properties of modified LBNMs in
biomedical applications are a requirement, and the question as to
whether these materials can become a center of focus as a field of
investigation for high-priority development.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
  [23]
None.
 
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or other-
wise.
ACKNOWLEDGEMENTS
Declared none.
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