Chemical Engineering Journal 391 (2020) 123823

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Chemical Engineering Journal

journal homepage: www.elsevier.com/locate/cej

Review

Alginate-based nanomaterials: Fabrication techniques, properties, and T

applications
⁎
Ilekuttige Priyan Shanura Fernandoa, WonWoo Leeb, Eui Jeong Hanc, Ginnae Ahna,c,
a
Department of Marine Bio-Food Sciences, Chonnam National University, Yeosu 59626, Republic of Korea
b
Freshwater Biosources Utilization Bureau, Bioresources Industrialization Support Division, Nakdonggang National Institute of Biological Resources (NNIBR), Sangju
37242, Republic of Korea
c
Department of Food Technology and Nutrition, Chonnam National University, Yeosu 59626, Republic of Korea

H I GH L IG H T S G R A P H I C A L A B S T R A C T

• Alginate is a renowned biopolymer

extensively explored in nanomaterial
research
• It’s a biocompatible, hydrophilic,
polymer ideal for therapeutic applica-
tions
• Alginate nanomaterials are mainly
2+
prepared by Ca gelification & iono-
tropic gelation
• Major applications; nanotheranostics,
nanoremediation and regenerative
engineering

A R T I C LE I N FO A B S T R A C T

Keywords: Alginate is a biopolymer extensively utilized in numerous applications. Hydrogel forming property, chemical
Alginate structure with hydroxyl and carboxylate moieties, biocompatibility, biodegradability, and solubility of alginate
Nanoencapsulation in water have broadened up research perspectives in material, and biomedical sciences. Study of alginate-based
Nanoaggregates nanoparticles, nanoaggregates, and nanofibers initiated recently. These materials have gained increased atten-
Nanocomposites
tion for their potential industrial and biomedical applications. The present review broadly describes the
Fibrous scaffolds
synthesis, structural and physicochemical characteristics, recent advancements of processing and functionali-
Nanotheranostics
zation of alginate-based nanomaterials. The potential applications of alginate-based nanomaterials in numerous
fields such as drug delivery, tissue engineering, environmental remediation, developing bioanalytical markers,
disinfectants, and gene therapy are described. Existing limitations and solutions are underscored with future
research scopes. The strategies employed in extracting alginates from algae, fabrication methods of alginate-
based nanomaterial, and the commonly used analytical techniques of characterizing nanomaterials are dis-
cussed.

1. Introduction
Following its first discovery in 1980, alginate-based micro-
encapsulation particles have extensively studied for developing nano-
materials and other functional materials [1,2]. Hydrogelling ability of
alginates has expanded its uses and research perspectives in biomedi-
cine and multiple disciplines, including the food industry, sewage
treatment, and as an adsorptive material for heavy metal removal from
contaminated water [3–5]. Biocompatible and biodegradable polymers
are extensively explored, targeting their potential biomedical and

⁎
Corresponding author at: Department of Marine Bio-Food Sciences, Chonnam National University, Yeosu 59626, Republic of Korea.
E-mail addresses: shanurabru@gmail.com (I.P.S. Fernando), 21cow@naver.com (W. Lee), iosu5772@naver.com (E.J. Han), gnahn@jnu.ac.kr (G. Ahn).

https://doi.org/10.1016/j.cej.2019.123823
Received 19 July 2019; Received in revised form 9 December 2019; Accepted 13 December 2019
Available online 14 December 2019
1385-8947/ © 2019 Elsevier B.V. All rights reserved.
I.P.S. Fernando, et al.
pharmaceutical applications. Chemical structures of biopolymers clo-
sely resemble macromolecules of the native extracellular environment.
Hence, the majority of biopolymers are compatible with living systems
compared to synthetic polymers [6]. Alginate polymers are biode-
gradable, biocompatible mucoadhesive, hemocompatible and have not
been found to accumulate in biological systems [7]. Thus, alginates
could be utilized in multiple applications due to its inert nature. With
the rapid advancements in nanotechnology, many inorganic and or-
ganic nonmaterial are synthesized through the control of matter and
investigated for desirable functional properties [8]. Currently, a vast
number of nanomaterials are available with different sizes, shapes,
textures, and compositions. Alginate-based nanomaterials have become
one of the major interests in modern-day scientific research. Different
types of alginate-based nanomaterials with different sizes, shapes, and
compositions have now been synthesized [9–11]. They are particularly
attractive for biomedical and pharmaceutical applications as well as for
food packaging and environmental remediation. Among the wide range
of techniques used in fabricating nanomaterials, controlled gelification
by Ca2+ ions, ionotropic gelation with positively charged polymers,
electrospinning, self-assembly of structurally modified alginate into
nanoaggregates, thermally-induced phase separation, and microfluidics
are extensively studied for alginate-based nanomaterials. Fabricating
different types of nanoparticles and nanofibers using biopolymers
especially for biomedical applications, is a challenging process, which
involves maintaining stability and biocompatibility. Considering food
packaging and environmental remediation, some of the currently used
materials are undesirable considering their nondegradable nature,
which creates environmental issues. Alginate is an environmentally
friendly component that can be recycled and undergo degradation.
Alginate nanomaterials is a broadly and rapidly developing field tar-
geting both industries and academia. The use of alginate-based nano-
material in specific biomedical and other applications has extensively
been reviewed with respect to its physicochemical properties [12–14].
Production techniques of alginate gel particles have also been reviewed
[2,15]. The present review attempts to provide an overall view of the
current state of knowledge and how the physicochemical properties of
alginate-based nanomaterials would associate with its wide-ranging
uses in different applications. It is our sincere hope that this will pro-
vide an insight to further advancement of the field of biomaterials en-
gineering.
1.1. Alginate
Alginates are naturally occurring anionic, chain-forming, hydro-
philic, colloidal heteropolysaccharides with randomly arranged linear
unbranched chains of α-l-guluronate (G block) and β-d-mannuronate
(M block) residues which are C5-epimers. The arrangement of G and M
blocks in alginates could be consecutive (repeating units of GGGG or
MMMM blocks), alternating (GMGMGMGM) or random depending on
their natural source [4,16]. The unperturbed dimensions of the polymer
chains increase based on the order of their monomeric substitution
pattern (MG-blocks < MM-blocks < GG-blocks). Alginates contain
many free hydroxyls (−OH) and carboxyl (−COOH) groups enabling
them to form intramolecular hydrogen bonds. FTIR studies of alginic
acid clearly explain these molecular features [17]. Alginates from sea-
weeds occasionally contain attached sulfate groups whereas, alginates
found in some bacteria such as Azotobacter vinelandii contain acetyl
groups [18]. Physicochemical characteristics of alginate much depend
on the monomeric composition sequence, molecular weight, and at-
tached functional groups. These features could vary depending on their
natural source, location in the plant, and varies based on geographical
location and season. The crystal structure of alginate fibers prepared
from Fucus vesiculosus has been recorded as an orthorhombic unit cell
structure with 7.6 Å, 10.4 Å (fiber axis), and 8.6 Å for a two dis-
accharide chain unit cell with space group P212121 [17]. However, X-
ray diffraction patterns could vary depending on the monomer
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Chemical Engineering Journal 391 (2020) 123823
composition and attachment pattern in alginic acid samples.
1.2. Sources of alginates, extraction, and purification methods
Alginate is a renowned polysaccharide, a component of the cell
walls of brown algae and an exopolysaccharide of some bacteria
(Pseudomonas and Azotobacter) [18]. Commercially alginate is produced
using Laminaria hyperborea, Laminaria digitata, Macrocystis pyrifera, As-
cophyllum nodosum, Eclonia maxima, Laminaria japonica, Lessonia ni-
grescens, Durvillea antarctica, and Sargassum spp. [19,20]. Alginate
chains are composed of mannuronic and guluronic acid units whose
pKa values are published as 3.38 and 3.65, respectively. Alginic acid
forms a precipitate generally below pH 3.6 at ambient temperature
[10]. Hence alginates are purified from the powdered brown algae
under alkaline extraction conditions using sodium carbonate, sodium
hydroxide, or gelatinous aluminum hydroxide (above pH 6.0). Subse-
quently, alginates are precipitated out from the filtrate by techniques
such as acidification, the addition of Ca2+ ions (forms calcium algi-
nate), or by adding ethanol (lowering dielectric constant) [21,22].
Depigmentation of algae powder prior extraction is essential to reduce
brown discoloration of the final product. Another impurity, which al-
ters the purity and rheological properties of alginate is polyphenols.
Phenolic compounds form strong dipolar forces with polysaccharides
[23]. Hence, algae powder after depigmentation is soaked in for-
maldehyde or formaldehyde in ethanol to facilitate formaldehyde
crosslinking of phenolic compounds, making them insoluble in the ex-
traction solvent [21,22]. Fluorescence spectroscopy at an emission
wavelength of 450 nm could be generally used to estimate the poly-
phenolic levels in the final product isolated during the extraction pro-
cess [24]. Diluted acid pretreatment before the alkaline extraction
seems to increase the yield of alginate and reduce phenolic content.
Diluted mineral acids could convert calcium alginate into alginic acid
which could increase the extraction efficiency with alkali than using the
original calcium alginate [22]. Further, it has shown to remove any
soluble phenolic compound after the formalin treatment [25].
2. Methods used in synthesizing alginate-based nanomaterials
Numerous nanomaterial fabrication methods are being applied for
synthesizing alginate-based nanomaterials. Below we have discussed
few prominent methods of formulating alginate-based nanomaterials.
Fig. 1 illustrate the principles behind each method, which are pro-
foundly explained in upcoming subsections. According to many pub-
lications, low molecular weight and partially oxidized alginates without
significant alteration to its basic alginate structure have shown better
degradation and clearance from the body compared to native alginate,
which has a prolonged degradation rate that causes difficulties being
cleared off from the body [26]. Our previous review discloses a com-
prehensive description of favorable reaction conditions for functiona-
lizing alginate helpful in clarifying some of the reaction schemes
mentioned herewith [27].
2.1. Controlled gelification using Ca2+ ions
Alginates being anionic polymers with carboxylate groups, readily
form gels in the presence of calcium ions and other divalent cations
(Fig. 1, A). The ionic and coordination crosslinking between alginate
and divalent cations proceed favored by the interactions between G
blocks and the cations. Thus, alginates with a high guluronate content
could yield stronger gels. The famous “Egg box” model initially de-
scribed by Grant et al. [28] explains the structure of the junction zones
in calcium alginate hydrogels (Fig. 2). The formation of calcium-algi-
nate nanocomposites should be done under controlled conditions. Many
studies regarding calcium-alginate nanocomposites rely on the func-
tionalization of the composites by encapsulating different materials
such as metal and metal oxide nanoparticles, drugs, or bioanalytical
I.P.S. Fernando, et al. Chemical Engineering Journal 391 (2020) 123823

Fig. 1. Techniques used in synthesizing alginate-based nanomaterials.

markers. Motshekga et al. [29] describe the synthesis of Bentonite
supported ZnO nanoparticle (20–90 nm) encapsulated alginate nano-
composites via Ca2+ mediated controlled gelification process. The en-
capsulation technique follows the incorporation of an alginate solution
containing a homogeneous dispersion of Bentonite supported ZnO na-
noparticles to a solution of Ca2+. The continuous stirring of the gelation
medium (Ca2+ solution) ensures uninterrupted bead formation while
preventing bead aggregation. Moreover, the dispersion of the
nanoparticles on the Bent support reduces their agglomeration. Another
approach of fabricating nanoshell carrier (250 nm) is the encapsulation
of drug-loaded nanoparticles in calcium alginate nano hydrogel shell by
water-in-oil microemulsion templates [30]. Herein the core, gold na-
norods (50 nm) conjugated porous silicon nanoparticles, and drugs are
encapsulated in calcium alginate hydroshells by mixing a nanoemulsion
of alginate, core nanoparticles and AOT-isooctane with a nanoemulsion
of diluted CaCl2 and AOT-isooctane at 25°C. This method could be

Fig. 2. Gelation of alginate by calcium, the “egg‐box” model.

3
I.P.S. Fernando, et al.
optimized for achieving a higher encapsulation efficiency with a high
loading capacity while having a low cellular toxicity. Photothermal
sensitivity to local temperature increase is desirability for the con-
trollable release of therapeutics by near-infrared laser photothermal
therapy. In relation to other nanomaterial fabrication methods men-
tioned herewith, controlled gelification using Ca2+ ions is the simplest
method, which could be easily implemented. The stability of the intra/
inter-molecular crosslinking resulting particles is comparatively higher
due to the strong crosslinking with Ca2+ ions.
2.2. Formation of polyionic complexes through ionotropic gelation via
intermolecular interactions
Alginates being an anionic polymer, has widely investigated for the
production of nanocomposites by ionotropic gelation with positively
charged polymers (Fig. 1, B). Among the various types of alginate-
polycation complexes reported in the literature, chitosan-alginate
polyion nanocomplexes are considered to be of higher interest. Chit-
osan-alginate complexes are synthesized through the ionic crosslinking
between positively charged amino groups of chitosan (pKa = 6.2–7)
with negatively charged carboxylate groups of alginic acid [31]. The
complex formation should be done under carefully monitored condi-
tions using low concentration solutions of either species. Several studies
investigate the efficacy of chitosan/alginate nanoparticles to en-
capsulate curcumin derivatives such as curcumin diethyl diglutarate
[32] and curcumin diglutaric acid by water-in-oil emulsification
(~215 nm) and ionotropic gelification (226 ± 23–334 ± 12 nm)
[33]. Herein the drug is fist dispersed in alginate solution containing
Pluronic®F-127 with continuous stirring and sonication to achieve the
emulsification. Then a CaCl2 solution is dropwise added to obtain an
emulsion with the pre-gel property (ionic and coordination cross-
linking). The resulting emulsion adjusted to pH 4.9 is then combined
with chitosan solutions adjusted to pH 4.6 at different dose ratios to
optimize the conditions for obtaining the nanoparticles (ionotropic
gelation). A recent study describes curcumin loaded layer-by-layer as-
sembly of chitosan and sodium alginate platforms (~200 nm) around
citrate coated MnFe2O4 magnetic nanoparticles (~12 nm) [34]. Herein
the MnFe2O4 nanoparticles have been synthesized by a thermal de-
composition method by initially capping with citrate. Layering has been
done under monitored conditions at room temperature to prevent the
overwhelming complexation of chitosan and alginate in bulk. Following
subsequent depositions, the nanoparticles precipitate had decanted
magnetically, suspended in ultrapure water, and centrifuged at
10,000 rpm to remove excess biopolymers in the supernatant. After
each washing, the pH levels of all solutions have been re-adjusted to ~5
prior to the next biopolymer assembly.
The preparation of a nontoxic, reduced drug-releasing insulin
coated alginate-C18 conjugates nanoparticles encapsulated chitosan-
oleic acid beads (522.50 ± 66.47 nm) has been described by Alfatama
et al. [35]. Herein alginate-C18 conjugates are prepared by reacting
tetrabutylammonium alginate with 1-bromoctadecane followed by the
addition of a sodium chloride aqueous solution. This follows the
dropwise addition of insulin with continuous stirring. These insulin
coated alginate-C18 conjugate nanoparticles in solution adjusted to pH
4–4.5 are then processed into beads by extruding through an en-
capsulator integrated with a vibrating nozzle to a continuously stirred
solution of calcium acetate at 25°C. Beads are then coated by simulta-
neously extruding the bead solution containing sodium tripolypho-
sphate with a chitosan-oleic acid conjugate solution adjusted to pH 5.5,
which enables the coacervation of the chitosan and alginate. Further
consolidation and coating were promoted with crosslinking of chitosan
with tripolyphosphate ions and reaction of alginate with calcium ions.
Other than chitosan, cationic polymers such as poly-L-lysine
(pKa = 9–10.5) and Eudragit E100 (pKa = 7.0–7.3) have been used
with alginate to form polyionic complexes [10]. Antigen (BSA) en-
capsulated ε-polylysine-sodium alginate nanoparticles
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Chemical Engineering Journal 391 (2020) 123823
(133.2 ± 0.5 nm) have been self-assembled by ionotropic complexa-
tion. Here the ionic interaction forms between positively charged
–NH3+groups of ε-polylysine and negatively charged –COO– of alginate
at a pH of 7.4 [36]. The conjugation of targeting ligands (monoclonal
antibodies, peptides, or small molecules) to the surface of alginate na-
noparticles allows the active targeting of these drugs encapsulated na-
nomaterial to be accumulated in the tissues of interest [37]. Zimet et al.
[38] describe a modified two-step method of fabricating Nisaplin
loaded nanoparticles (60–70 nm). Initially, a pre-gel of alginate is
prepared at pH 5.2 by adding a minor amount of Ca2+ to the alginate
solution, which contains Nisaplin. Successively it is cross-linked with
poly-l-lysine and chitosan at 25°C.
Formulation of rifampicin loaded alginate/cellulose nanocrystals
(55 ± 20 nm) by the ionotropic gelation technique has been studied by
[39]. Cellulose nanocrystals possess excellent compaction properties,
which makes it an ideal carrier of pharmaceuticals. Herein, cellulose
nanocrystals have been dispersed in a solution of alginate containing
natural honey, which acts as the capping and stabilizing agent. A so-
lution of Ca2+ is then incorporated into the above medium with con-
tinuous agitation. Cellulose nanocrystals are described to enhance
mechanical stability while being a stable drug carrier with a high
loading efficiency [40].
A zein/caseinate/alginate nanoparticle (208 nm) fabrication
method has been described by [41]. Zein is a prolamine protein with
hydrophobic characteristics. Zein-based nanoparticles are increasingly
studied for drug delivery applications due to their biocompatibility,
biodegradability, and slower digestibility. It is reported as an ideal
carrier for lipophilic bioactives. A well-blended alkaline solution con-
taining deprotonated propolis, zein (dissolved in ethanol), sodium
caseinate micelles, and alginate is gradually acidified by adding citrate
buffer (pH 3.8), which results in the formation of composite nano-
particles. The acidification increases the electrostatic complexation
improving the aggregation of zein, caseinate, and alginate.
A novel study describes the synthesis of aggregation-induced emis-
sion active polymeric nanoparticles (226 ± 63.3 nm) by conjugating
oxidized sodium alginate with aggregation-induced emission (AIE)-ac-
tive dye, 2-(4-aminophenyl)-3-(10-hexadecyl-4H-phenothiazin-3-yl)ac-
rylonitrile (PhE-NH2) using pyruvic acid as the molecular “bridge” by
microwave-assisted Döbner reaction [42]. Oxidized alginate has been
added to a solution of phenothiazine and pyruvic acid, which is dis-
solved in DMSO. The mixture is then reacted in a microwave reactor at
120°C. The dropwise addition of acetone precipitates the product na-
noparticles. The synthesis of AIE-active carbohydrate polymers remains
challengeable due to the reduced solubility of carbohydrates in organic
solvents. However, the described reaction scheme provides a successful
approach to develop fluorescent polymeric nanoparticles in a fast, cost-
effective manner under mild reaction conditions. Polyionic complexa-
tion is a relatively complex fabrication method which should be carried
out under controlled conditions. However, it allows the incorporation
of different properties which is useful for different applications.
2.3. Spray drying followed by crosslinking
Spray drying is a widely used technique of nano/microencapsula-
tion of therapeutics to alter pharmacokinetics while improving stabi-
lity. The method involves the atomization of a liquid slurry and rapid
drying by a gas (Fig. 1, C). Spray drying at sub-ambient temperatures
(Spray freeze-drying) is suitable for thermo-sensitive compounds [43].
Drug loaded nanoparticles generated via spray drying are coated by
crosslinking with a suitable ion or by polyionic complexation. In one
study, caffeine-loaded peptides (pepsin hydrolysate of whey proteins)
nanoparticles (100–300 nm) fabricated via emulsification in ethanol
and vacuum, drying is homogeneously dispersed in the sodium alginate
and spray dried obtaining microparticles (4 μm). These are then dis-
persed in a CaCl2 aqueous solution to cross-link microparticles. Cross-
linked particles are separated by centrifugation [44]. Erdinc and
I.P.S. Fernando, et al.
Neufeld [45] describe the preparation of Protein (subtilisin) na-
noencapsulates (2.2 to 4.5 µm) by spray drying a solution of protein
loaded alginate, which is set to a pre gelling state by incorporating
glycol-chitosan or Ca2+. The volume reduction during spray drying
stiffens the partially cross-linked pre-gelled nanoparticles. Regulation of
feeding rate of sample, feed spraying pressure, air pressure, aspirator
speed, temperature of drying gas and dryer chamber controls the par-
ticle size.
2.4. Alginate nanoaggregates through self-assembly
This method does not utilize Ca2+ induced gelification or cationic
polymers to form the aggregates. The methodology includes self-as-
sembly of polymeric material through intra/inter-molecular cross-
linking with other polymers or compounds. Chang et al.[46] describe
the synthesis of disulfide cross-linked nanospheres (170 nm) by a so-
dium alginate derivative. Herein sodium alginate is first oxidized with
periodate at room temperature, which is then thiolated with 4-ami-
nothiophenol at room temperature forming amphiphilic molecules that
undergo self-assembly into reverse micelles. These undergo disulfide
bond cross-linking and subsequent air oxidation following ultra-
sonication (Fig. 3). Hollow nanospheres (487–974 nm) have been fab-
ricated via self-assembly of alginate-graft-poly(ethylene glycol) and α-
cyclodextrin in aqueous solution [47]. Here, the bonding of poly
(ethylene glycol) oligomers on the alginate backbone construct a rigid-
coil system, which is then mixed in α-cyclodextrin, a complexing agent
that increases aqueous solubility resulting in the formation of inclusion
molecules that self-assemble into hollow spheres. Stable micelles
(50–300 nm) by self-assembly of amphiphilic alginate graft copolymers
have been prepared by single electron transfer-living radical poly-
merization (SET-LRP) [48]. Here tetrabutylammonium salt of low mo-
lecular weight fragments of native alginate is esterified with bromoi-
sobutyric acid by activating alginate hydroxyl groups with
carbonyldiimidazole followed by methyl methacrylate grafting. The
self-assembled product undergoes radical polymerization in the pre-
sence of Cu(0) and Tris[2-(dimethylamino)ethyl]amine as the catalyst.
Above micelles with outer-shell containing alginate with preserved
carboxylate moieties could have significant potential in targeted and
controlled delivery of drugs. Intra/inter-molecular crosslinking reac-
tions in the above approaches are carried out under controlled reaction
conditions to prevent any undesirable degradation.
2.5. Fabrication of nanocomposite fibrous scaffolds and nanoparticles
respectively by electrospinning and electrospraying
Electrohydrodynamic methods, namely electrospinning and elec-
trospraying, respectively allow the fabrication of fibrous membranes
Fig. 3. Fabrication of alginate nanoaggregates through self-assembly.
5
Chemical Engineering Journal 391 (2020) 123823
and particles at micron, submicron, and nanoscale levels (Fig. 1, D).
Fibrous membranes obtained by electrospinning are having a high
surface area to volume ratio with interconnected pore structure prop-
erties, which are desirable for cellular attachment, proliferation, and
migration. The electrospinning technique uses an electric field to gen-
erate nanofibers from a charged polymeric solution. A jet of polymeric
material is sprayed on a surface driven by the application of an elec-
trical potential between a capillary needle and the surface. Electrospun
jet undergoes extensive stretching and rapid drying with the evapora-
tion of the solvent. This process leads to the deposition of a porous non-
intertwined 3D network of nanofibrils. Based on the disable properties
of the nanofibrous mesh, it could mimic the natural extracellular matrix
of animal tissues [49]. Electrospun alginate fiber membranes cannot be
fabricated in aqueous solutions by only itself due to the low breaking
strength of the fibers and brittleness which limits its applications [50].
Hence non-toxic synthetic polymers are used in combination to obtain
nanofibers possessing better mechanical properties and thermal stabi-
lity. Chae et al. [51] describe an approach to fabricate hydroxyapatite/
alginate-based nanocomposite fibrous scaffolds (average diameter of
141 ± 45 nm) for bone tissue regeneration using the electrospinning
technique. A mixture of sodium alginate, polyethylene oxide, and
Triton X-100 dissolved in dimethyl sulfoxide have been used to cast the
nanocomposite fibers. Sodium phosphate has been used as the pre-
cursor ions for the in situ synthesis of hydroxyapatite. The electrospun
nanofibers collected at the rotating grounded drum is stirred in a cal-
cium nitrate solution for forming hydroxyapatite, while it assists to
crosslink alginate. Udaseen et al. [52] describe the fabrication of na-
nofibrous scaffolds (diameter range 100 nm − 1000 nm) through a
nozzle (needle) free electrospinning of a blend of polyvinyl alcohol and
alginate. Herein, Nozzle-free electrospinning, compared to needle-
based electrospinning techniques, enables the rapid production of na-
nofibrous mats. The formation of hydrogen bonds between polyvinyl
alcohol and alginate supposedly improves the thermal stability and
mechanical properties of electrospun fiber membranes. Based on novel
findings, the incorporation of inorganic nanoparticles such as Nano-
hydroxyapatite during the fabrication is found to improve mechanical
stability, cell adhesion, and proliferation [50]. Further, it stabilizes the
electrospun solution preventing agglomeration and precipitation of
suspended components in the aqueous spinning solution. Hu et al. [53]
use polycaprolactone and alginate co-electrospinning using a dual-jet
system for fabricating composite nanofibers (691 ± 116 nm) for in situ
transfection applications. Polycaprolactone is a biocompatible polymer
that can improve cell adhesion. Here DNA is first incorporated with
polyethyleneimine, which condenses DNA into positively charged par-
ticles, facilitating ionic crosslinking with the alginate matrix. Electro-
spun nanofibers are immersed in absolute ethanol containing 2% CaCl2
to promote the crosslinking of alginate fibers.
I.P.S. Fernando, et al.
In contrast, electrospraying is a liquid atomization process induced
by electrical forces. The difference between the two techniques elec-
trospinning and electrospraying relies on the concentration of the
polymer solution. The formation of a Taylor cone could be observed
with a high solution concentration, which results in polymer elongation
due to whipping instability, which results in the fiber formation. With a
low solution concentration, fine droplets are formed due to the in-
stability of the jet. Consequently, self-dispersing of these highly charged
droplets cause particle formation. Moreover, it prevents droplet ag-
glomeration and coagulation [54]. Further, the solvent evaporation
cause droplet contraction and solidification giving solid polymeric
particles in the grounded collector. Coaxial electrospinning is another
recent advancement, whereas the electrospraying setup contains a dual
nozzle spinneret with an inner and outer capillary respectively for core
and wall material of the fabricated articles. A cost-effective fabrication
method for paclitaxel loaded sodium alginate-Ca2+/egg white nano-
particles (200 ± 18 nm) using an electronic spray method is described
by [55]. Here the alginate and paclitaxel formulated liquid are elec-
trosprayed to a grounded beaker containing egg white and calcium
chloride solution under a voltage of 15.0 kV. Qiusheng et al. [56] de-
scribe the fabrication of porous calcium alginate beads (1.969 mm) by
electrospraying CaCl2 solution to an air perforated blend of sodium
dodecylbenzene sulfonate, CaCO3, and NaHCO3. They are then soaked
in Zr(NO3)4 to facilitate the partial exchange of Ca2+ ions with Zr4+
producing zirconium alginate. Electrospray particles are seen as ideal
nanoscaled drug delivery vehicles due to improved drug loading, con-
trolled/sustainable drug-releasing capabilities over a long period, and
the ability to aggregate at target locations [55]. Such biomaterials could
have potential applications in tissue regeneration, tissue engineering,
drug delivery systems, and wound dressings [50].
2.6. Fabrication of nanocomposite fibrous scaffolds by thermally-induced
phase separation
TIPS could be defined as the transformation of a homogenous
polymer solution prepared at elevated temperature to two phases as a
polymer-rich phase and a polymer lean phase through the rapid re-
moval of thermal energy. As summarized in Fig. 1, E, this technique
utilizes a low melting point, miscible, and hygroscopic solvent that
could dissolve the polymer of interest. The phase separation is achieved
with the addition of water followed by rapid mixing to obtain an
emulsion. The emulsion is then cast into a mold and rapidly frozen
using liquid nitrogen. Then it is freeze-dried to obtain the porous
scaffolds [57]. As Zhang, Liu, Yang and Zhu [9] describe, silk fibroin/
sodium alginate composite nanofibrous scaffolds (diameter 50–500 nm)
prepared through the TIPS method could be used as a promising ex-
tracellular matrix for tissue engineering. According to the procedure, a
mixture containing degummed and regenerated silk fibroin solution
and sodium alginate solution have blended at 60°C and homogeneously
mixed with a dioxane/water mixture to obtain the emulsion. After
casting, the emulsion has been frozen at −80°C and freeze-dried for
24 h. Thermally-induced phase separation (TIPS) is a promising tech-
nique for fabricating 3D nanofibrous scaffolds.
2.7. Formation of alginate nanoparticle using a microfluidics- aided
polyelectrolyte complexation
Microfluidic-assisted fabrication offers the ability to control the size
and polydispersity of nanoparticles, a significant advantage over the
conventional methods [58]. Fig. 1, F illustrate typical examples of mi-
crofluidics flow systems. Huang et al. [59] describe a process of de-
vising relatively uniform Na-alginate microdroplets (200 µm) in oil
using a microfluidic chip, which in turn gelatinized by colliding with a
Ca2+ rich phase. Although this method offer convenience over the
other described methods, extremely sensitive instrumentalization is
required. At present, uniform alginate nanoparticles of sizes ranging
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Chemical Engineering Journal 391 (2020) 123823
from 10 to 300 nm have been fabricated using this method [58]. The
particle size could explicitly be controlled by controlling the physical
parameters and chemical composition. In a much recent study, Kim
et al. [60] describe the generation of alginate-based nanoparticles
(380–520 nm) by mixing Ca-alginate pre-gel solution with poly-L-lysine
in a microfluidic mixing device. These nanoparticles have shown en-
hanced stability against aggregation with control over the particle size
by controlling the flow rates. The synthesis of Poly lactic-co-glycolic
acid /MgO-alginate core–shell microspheres has been described by Lin
et al. [61] using an oil/water emulsion approach. A specially designed
microfluidic capillary device with coaxially aligned injection and col-
lection capillaries within a square capillary has been used to produce
poly lactic-co-glycolic acid /MgO-alginate core–shell droplets. Much of
the previous processes described the formation of polydispersed nano-
particles without proper control over the partial size and homogenous
nature. Since they could limit their use in biomedical applications. In
contrast, with the developments in microfabrication and microreaction
technologies and novel microfluidic devices, the ability to produce
monodisperse water droplets in oil have modernized the fabrication of
monodisperse polymer-based nanoparticles.
3. Alginate-based magnetic nanoparticles
Magnetic nanoparticles demonstrate properties such as super-
paramagnetism, high saturation field, high field irreversibility, extra
anisotropic effects, and exhibit loop shifting after field cooling. The
occurrences of such phenomena depend upon the finite size and the
surface properties that control the magnetic behavior of individual
nanoparticles [62]. In this regard, magnetic alginate nanoparticles
could offer additional benefits over the nonmagnetic alginate nano-
material. The magnetic property is simply achieved by incorporating
ferri and ferromagnetic material such as Fe3O4 (magnetite), Fe2O3
(maghemite), MnFe2O4 (jacobsite), SrFe12O19, Fe-C and alloys such as
SmCo5 during the fabrication process [62,63]. Gao et al. [64] describe
the synthesis of sodium alginate assisted iron oxide nanoparticles
(~24.5 nm) with ferromagnetic properties via a redox-based hydro-
thermal process using urea and FeCl3·6H2O. During the synthesis, so-
dium alginate has found to play a dual role in stabilizing and reducing
the material. The two major functional groups carboxylate (COO–) and
hydroxyl (–OH) are found to provide coordination sites to Fe3+ forming
complexes. A recent study describes the fabrication of a pH-sensitive
alginate/ maghemite magnetic nanoparticles (~7.7 nm) by a Green
synthesis method and its adsorption properties on the cationic dye
methylene blue [65]. Maghemite obtained by oxidation of magnetite is
dispersed in water, obtaining a stable magnetic fluid (ferrofluid). Next,
alginate solution is gradually introduced to it obtaining alginate-bound
maghemite nanoparticles. The use of maghemite instead of magnetite is
of particular interest as the magnetic core is much stable in this phase.
Alginate nanomaterials with magnetic properties have revolutionized
the methods of drug delivery due to the magnet induced drug release
capabilities. Moreover, they are known to create a localized heat effect
upon exposure to an altering magnetic field that could be used in hy-
perthermia treatment. In water remediation, they can be easily re-
moved from treated wastewater [66].
4. Techniques used in the characterization of polymer-based
nanomaterials
With the increasing developments in analytical technologies, a
number of different novel techniques are utilized in the characteriza-
tion of polymer-based nanomaterials. The molecular structures are
mainly characterized by FTIR, additionally, NMR and X-ray techniques
are also used. The size of the nanomaterial is analyzed mainly by SEM
and Photon correlation spectroscopy (dynamic light scattering). Zeta
potential is an important parameter that indicates the nanoparticle
stability in a colloidal dispersion [67]. It measures the electrostatic
I.P.S. Fernando, et al. Chemical Engineering Journal 391 (2020) 123823

Table 1
Commonly used characterization techniques for polymer-based nanomaterials.
Technique Significance Reference

Photon correlation spectroscopy
Scanning electron microscopy
Transmission electron microscopy
Atomic force microscopy
X-ray photoelectron spectroscopy (XPS)
Scanning electron microscope with energy-dispersive X-
ray spectroscopy (EDAX)
Fourier transform infrared spectroscopy
Nuclear magnetic resonance spectroscopy
Raman spectroscopy
Superconducting quantum interference device (SQUID)
magnetometer
Differential scanning calorimetry
Liquid displacement test
Determine the average size distribution (granulometry) of the nanoparticles based on dynamic light [31]
scattering.
Widely used to study the shape, size, texture, and aggregation of nanoparticles. [68]
Used to study particle shapes, size, and morphology [55]
Can be used to study the surface morphology and the size distribution of the nanoparticles [68]
Use to analyze the chemical and elemental composition of a surface through measuring the binding [69]
energy of electrons associated with atoms.
Used for the elemental analysis of a selected part of the material while observing through the SEM. The [70]
principle relies on the emission spectrum of elements excited with x-rays.
Extensively used for the identification of alginic acid (and many other organic molecules) and [31,68]
characterization of the molecular structures based on functional groups in polymers.
Used for molecular level characterization of compounds. [71]
Molecular structures characterization based on functional groups. [72]
Used to determine the magnetic behavior of magnetic nanoparticles. [64]
Used in the characterization of the thermal behavior (heat capacity as a function of temperature) of [31,73]
polymers and nanoparticles based on their structure, hydrophilic properties, and state of association.
A method used for measuring the porosity of the scaffolds. [9]

potential at the interfacial double layer surrounding a colloidal particle
in solution. Particles are considered neutral if the zeta potential is be-
tween −10 and + 10 mV, whereas less than −30 mV or greater
than +30 mV are respectively considered strongly anionic or cationic.
Zeta potential of a particle can affect its tendency to permeate cell
membranes. Hence it is an essential parameter for nano encapsulated.
Dynamic light scattering and zeta potential are two of the indispensable
methods for proper characterization of nanoparticles. Table 1 sum-
marizes some of the major nanoparticle characterization techniques
used.
5. Potential applications of alginate-based nanomaterials
The number of applications is now countless with nanotechnology.
Alginate is one of the biocompatible, and biodegradable polymers are
widely studied for fabricating numerous nanomaterials. Fig. 4 sum-
maries a few of the major applications of alginate-based nanomaterials,
which are broadly described in upcoming sub-sections.
5.1. Nanotherapeutics
5.1.1. Drug encapsulation and targeted delivery
Nanoencapsulation is a developing field of research in drug de-
livery. Nanoencapsulation is proven to increase the bioavailability of
drugs and deliver them to the right place, with the right dosage [31].
Studies regarding alginate nanomaterials initiated during the past few
years. At present, an increasing demand is placed towards the use of
alginate-based nanoencapsulation for controlled delivery of drugs.
Table 2 highlights a few examples of alginate nanomaterial-based drug
delivery methods. Compared with other particulate carrier systems such
as liposomes, microparticles, and some nanoparticles, which are rapidly
taken up and degraded by mononuclear phagocytes such as the Kupffer
cells, alginate nanomaterials have shown better ability to withstand.
They are desirable for encapsulating proteins, enzymes, and some other
drugs while enhancing their stability and oral bioavailability [10]. A
matrix with an aqueous environment, a higher gel porosity, and bio-
compatibility are some of the major properties in the majority of algi-
nate nanoparticles [74]. Oral administration of drugs, such as proteins,
remains challenging due to their gastric digestibility. Encapsulation in
alginate-based nanoparticles could offer a solution to this problem due
to their indigestible nature and sustained drug release rate (nano-ob-
struction effect).
Delivering a higher drug concentration to a targeted site with
minimal toxicity on normal cells is a desirable strategy in cancer che-
motherapy. Some examples of clinical applications are albumin
conjugated paclitaxel and liposomal doxorubicin [75,76]. The sig-
nificance of targeted drug delivery relies on the use of targeting ligands
conjugated with nanoparticles, thereby increasing the nanoparticle
accumulation at the site of tumors [37,77]. Glycyrrhetinic acid and
glycyrrizin are common ligands used in targeted drug delivery systems
[69].
Drug entrapped magnetic nanoparticles, allows the rapid release of
drugs following the application of a magnetic force. Magnetic nano-
particles integrated with targeting ligands are presently used to deliver
radionuclide atoms and anticancer drugs to targeted tumors [78]. The
heat generated due to oscillations induced by a high-frequency mag-
netic field could be used to destroy malignant tumors (hyperthermia
treatment). It is a bi-modal approach against cancer achieving com-
bined chemotherapy and hyperthermia effects [66]. Inter-particle in-
teraction in nanoparticles resulting from magnetic field limits magneto-
assisted drug delivery and controlled release. Tetra-layered biopolymer
(chitosan/alginate) nanoparticles fabricated around MnFe2O4 nano-
particles via ionotropic gelation has indicated greater thermal stability,
without shielding the magnetization while having a decreased inter-
particle interactions ideal for magneto-assisted drug delivery [34].
Near-infrared laser photothermal therapy is another minimally invasive
approach for treating localized cancer. Calcium alginate nanohydrogel
encapsulated drug-loaded porous silicon nanoparticles conjugated with
gold nanorods (cytocompatible and approved by FDA) found to be
sensitive to localized photothermal degradation. These particles, too
could be utilized in combination therapy [30].
5.1.2. Gene therapy
Gene therapy is seen as a promising approach for the treatment of
cancer and genetic disorders. Alginate/CaCO3 hybrid nanoparticles
(145.0 ± 7.8 nm) have shown higher encapsulation efficiency and
delivery capabilities for tumor suppressor gene (p53) expression
plasmid and doxorubicin hydrochloride (an anticancer drug). Apart
from effective delivery into targeted cells, they have shown advantages
concerning the biocompatibility and cost over the conventional
methods of using viral vectors [79]. Surface-modified alginate nano-
particles have been used as a method of gene transfer to targeted
macrophages, a potential approach for anti-inflammatory therapy.
Tuftsin (a peptide sequence) has been used as targeting ligands that
bind with specific receptors on polymorphonuclear leukocytes and
macrophages [80].
5.2. Regenerative engineering
Fabrication of temporary scaffolds that are capable of providing a

7
I.P.S. Fernando, et al.
Fig. 4. Potential applications of alginate-based nanomaterials.
biocompatible extracellular matrix is one of the primary necessities in
regenerative tissue engineering. Natural polymers possess advanta-
geous characteristics such as hydrophilicity, less-immune resistance,
non-toxicity, enhanced cell adhesion, and proliferation, those which are
preferable for tissue engineering [88]. With recent advancements in the
fabrication of nanocomposite fibrous scaffolds, alginate has received
much attention due to its biocompatible properties. Alginate-containing
nanofibers are widely investigated as tissue engineering scaffolds for
bone, cartilage, and skin [51]. Alginates bears structural resemblance to
glycosaminoglycans, a major component of the extracellular matrix in
human tissues [88]. Especially for the engineering of bone scaffolds, the
controlled release of Ca2+ over a long period is desirable for enhancing
osteoblastic activity to stimulate in-situ bone regeneration [61]. Based
on several studies, hydroxyapatite/alginate nanocomposite fibrous
scaffolds are seen ideal for the adhesion, growth, proliferation, and
differentiation of osteoblasts followed by in situ mineralization
[9,51,89,90] indicating promising ability to be used in bone tissue
engineering. 3D printing in this regard is increasingly studied for fab-
ricating tissue scaffolds, especially bone tissues with greater control
over the size of filaments and pores, complex shapes, and porosity en-
hancing desirable mechanical properties [91,92]. Herein alginate does
not participate in the nanoparticle formation, rather it stabilizes hy-
droxyapatite nanoparticles and provides the hydrogel matrix for cells
and initial mechanical strength to the mineralizing tissue.
Ca-alginate hydrogel wound dressings are renowned for regulating
8
Chemical Engineering Journal 391 (2020) 123823
moisture, anti-inflammatory properties, and promoting collagen
synthesis resulting in reduced coagulation time, rapid granulation, re-
epithelization, and promote the differentiation of keratinocyte and in-
crease proliferation of fibroblasts mainly due to the controlled release
of Ca2+ [93]. A cohesive, biodegradable, colloidal gel prepared by
using a blend of PLGA-chitosan/PLGA-alginate nanoparticles is re-
ported desirable for seeding human umbilical cord mesenchymal stem
cells [94]. This gel could have potential applications in hematopoietic
stem cell transplantation in reconstituted bone tissues.
5.3. Nanoremediation
Contamination of water bodies with industrial effluents including
selenium, chromium, lead, fluoride, nitrate, pesticides, herbicides, and
organic dyes is a recent concern requiring an immediate response. In
recent literature, hydrogels composites and nanoparticles have out-
competed conventional adsorbents, particularly in terms of their ad-
sorption capacity and larger effective surface area [5]. Alginates are
extensively investigated biopolymers capable of removing metal ions
from aqueous solutions. The negatively charged carboxylate groups
have a greater affinity/chelating ability towards cations [95]. En-
capsulation reduces the agglomeration of nanoparticles by embedding
them in the alginate matrix, while increasing the effective surface area,
thus increasing their adsorption and catalytic performance [96]. Con-
struction of porous alginate-based beads has shown enhanced
 I.P.S. Fernando, et al.

Table 2
Use of alginate nanomaterial in nanotherapeutics.
Fabrication method Products encapsulated Properties Potential applications Particle size References
(nm)

Through controlled gelification using Ca2+ and poly-L-lysine Doxorubicin A higher drug-loading capacity. Biocompatible Drug encapsulation 250–850 [7]
By Ca2+ induced controlled gelification followed by the addition of Isoniazid, pyrazinamide, and Inhalable alginate nanoparticles Tuberculosis treatment N/A [74]
chitosan. rifampicin.
Nanoparticles by drug-loaded calcium alginate pre-gel complexed Pirfenidone Higher loading capacity and efficiency for transdermal Treatment for idiopathic pulmonary 80 [81]
with chitosan. delivery. fibrosis
Gelatin nanoparticles in calcium alginate microspheres Dexamethasone Possibility to use as drug release vehicles. Drug delivery and tissue 60 ± 5 [11]
engineering.
Nanospheres and vesicles fabricated through self-assembly of 5-Fluorouracil Encapsulation and sustainable release. Cancer chemotherapy 50 [82]
alginate.
Alginate-chitosan-pluronic composite nanoparticles. Curcumin Encapsulation and delivery. Cancer chemotherapy 100 ± 20 [68]
Glycyrrhetinic acid-modified alginate nanoparticles fabricated Doxorubicin Encapsulation of for Liver cancer chemotherapy 219.2 [69]
through CaCl2 crosslinking.
Calcium alginate/poly-L-lysine nanocapsules Antisense oligonucleotide Encapsulation and protect from serum degradation Lung, liver, and spleen disorders 210–610 [83]

9
Double and triple-layered nanoemulsions fabricated with alginate Capsaicin Higher loading capacity for lipophilic substance, increase Topical treatment for pain, 50–150 [63]
and chitosan the bioavailability and distribution gastrointestinal disorders
Nanosized calcium alginate beads DNA A higher encapsulation ability. Can release the content Carriers for sensitive biomolecules 200 [84]
using Ca2+ cheater.
Hydroxyapatite containing core–shell nanostructure-covered with an Modeled compound Rhodamine Enhanced drug loading, high biocompatibility, and pH- Cancer chemotherapy 160–650 [85]
alginate shell synthesized by a pre-gelation method 6G (for fluorescence detection) sensitive drug delivery under acidic conditions.
Alginate and chitosan containing hybrid nanoparticles Captopril, amlodipine, and Ability to load hydrophobic drugs Hypertension treatment 197–341 [86]
valsartan
Pluronic nanocarrier loaded with alginate and cross-linked by Positively charged proteins Higher loading capacity, serum stability, good Protein delivery systems 50 [87]
calcium. biocompatibility, and prolonged release.
Nanoencapsulates of pre gelling alginate by spray drying Protein (subtilisin) Intestinal release of drugs, Oral delivery of peptides for 2200 to 4500 [45]
intestinal absorption.
Alginate-Ca2+/egg white nanoparticles fabricated by electronic spray Paclitaxel Better drug loading encapsulation and sustainable release. Cancer chemotherapy 200 ± 18 [55]
technique. Stable and biocompatible
Alginate-cellulose nanocrystal hybrid nanoparticles fabricated by Rifampicin Biocompatible, weak swelling at pH 1.2 with low drug Drug delivery to the intestine via 55 ± 20 [39]
ionotropic gelation. release, rapid swelling at pH 6.8 and 7.4 and collapse with passaging through the gastric juice
rapid drug release.
Alginate-C18 conjugate nanoparticles in calcium alginate beads Insulin Biocompatible Higher loading capacity, reduced drug Insulin carrier 522.50 ± 66.47 [35]
encapsulated within a tripolyphosphate-crosslinked chitosan- release under gastric pH, and increased sustainable release
oleic acid conjugate coat under intestinal pH.
Chemical Engineering Journal 391 (2020) 123823
I.P.S. Fernando, et al. Chemical Engineering Journal 391 (2020) 123823

adsorption [56].

[100]

[101]

[102]
[96]

[56]
[97]

[98]

[99]

[65]
Ref.
Organic dyes from industrial effluents cause several complications,
including cancer, allergy, skin irritation, dermatitis, and mutations

Improved reactivity due to decreased FeS

Increased swelling capacity and thermal

Effective adsorption at acidic pH (pH 2)

Easy abstraction using a magnetic field

agglomeration of Nano zerovalent iron [97]. Nanocomposite adsorbents designed by impregnating nanoscale

Higher absorptivity due to increased

metallic or bimetallic particles into alginate (or another polymer) based
Effective reactivity due to reduced

lower nitrate reduction but higher

Increase the effective surface area

nanoparticles are applied as redox reagents or catalysts for the de-

Enzymes degrade organic dyes

gradation of environmental contaminants, such as azo dyes, PCBs
(polychlorinated biphenyls), organochlorine pesticides, halogenated
aliphatics, nitroaromatics and halogenated herbicides [98]. Further,
these nanoparticles could be integrated with a magnetic core allowing
their recovery using a magnetic field. Immobilization of nanoparticles
surface area
Properties

with certain enzymes such as glucose oxidase, laccase, that could de-
oxidation

capacity

stability
grade organic dyes is proven to be an effective strategy in wastewater
treatment [99]. Other than absorption, enzyme immobilization could
offer simultaneous adsorption and degradation of the organic pollutants
heteropolycyclic and azodyes removal; copper phthalocyanine- Fe2O3 for malachite

allowing continuous or multiple usage times per application. Table 3

confer some specific applications of alginate in nanoremediation. Cost-
MnO–Fe2O3 for acid red B removal; Charcoal-Fe2O3 for triphenylmethane,

effective and attractive environmental remediation approaches, as

above, may gain increased attention for their easy implementation and
effective clean-up procedures as these could be developed at an in-
dustrial scale.

5.4. Applications of alginate in nanobiotechnology

A developing trend in biotechnology is the development of minia-

turized biosensing devices with improved stability, selectivity, and
sensitivity [103]. Chaudhari et al. [104] describe the development of
fluorescence-mediated glucose detecting biosensors using glucose oxi-
Fe(0) and magnetite nanoparticles

green and crystal violet removal.

dase loaded alginate nano-microspheres. The operation basics are based

Organophilic montmorillonite

on the use of fluorescence quenching near-infrared radiation (NIR) of

Glucose oxidase and laccase
Iron sulfide nanoparticles

the oxygen-sensitive dye, RUDPP. Aggregation-induced emission (AIE)

is a unique fluorescence phenomenon that has gained great interest in
Nano zerovalent iron

Calcite or xonotlite

biological imaging applications. Oxidized sodium alginate conjugated

PhE-NH2 polymeric nanoparticles are described to possess such char-
Encapsulate

acteristics with desirable properties such as high water dispersibility,

good photostability, intense fluorescence, low critical micelle con-
N/A

N/A

centrations, desirable cell uptake, and ultrahigh biocompatibility

making them promising candidates for biological imaging applications
[42]. Alginate from marine seaweeds is described to be resourceful in
comparison with other synthetic or commercial polymers used in the
synthesis of AIE-active polymeric nanoparticles.
γ-ray polymerized Alginate/Ca2+-organophilic

Gene therapy is a hopeful approach for treating acquired and in-

MnFe2O4/ alginate/Ca2+ nanocomposites
Alginate composite nanoscale adsorbents

herited diseases based on modifying the gene expression. Genetic ma-

Alginate / acrylic acid nanocomposites
Biofilm coated alginate/Ca2+ beads

terial is introduced into the cells to compensate abnormal genes or to

Alginate/maghemite nanoparticles
montmorillonite nanocomposites
Porous zirconium alginate beads

synthesize beneficial proteins. Presently there is a high demand for

Magnetic alginate nanoparticles

research centered on developing biocompatible gene carriers using non-

toxic biopolymeric nanoparticles. Since therapeutic genes are in-
Encapsulation system

beads

troduced as naked DNA, the majority undergo degradation by nu-

cleases, which lower the transfection efficiency. Additionally, the ab-
2+

sence of a specific cellular targeting mechanism lowers their

Alginate/Ca

transfection efficiency. DNA-loaded chitosan-alginate-dextran sulfate

nanoparticles are described to have a higher DNA encapsulation effi-
Applications of alginate in nanoremediation.

ciency that makes them ideal as gene transfection vectors [105].

Organic dyes (methylene blue, indigo and
Malachite green, polycyclic dyes, crystal

5.5. Nano-antimicrobials
Anionic textile dyes, direct pink 3B and

Removal of toxic industrial dyes, water

Nitrate remediation from ground water

white, and other organic dyes

Nano-antimicrobials is a broad topic receiving increased attention

Enhanced fluoride adsorption

in both biomedical and environmental sciences. Various anti-tubercu-

Selenium (IV) remediation

losis drugs loaded nanoparticle-based drug delivery systems are studied

to reduce the frequency, quantity, and duration of drug administration
Potential applications

Methomyl (pesticide)

and to avoid first-pass effects while reducing the side effects. A broad
acid green B

description of alginate-based drug delivery systems for tuberculosis are

pollutants
Cr6+ removal

acid red)

presented by [106]. The preparation of a nanocarrier system for in-

halation delivery of antimycobacterial compound rifampicin is de-
Table 3

scribed by Scolari et al. [107]. Herein the nanocapsules are synthesized

by coating Tween 80 dissolved rifampicin loaded sodium alginate

10
I.P.S. Fernando, et al.
emulsion (pH 5.5) with chitosan in an aqueous solution containing
acetic acid (pH 4.5) under rapid mixing following ionic gelation
method. The nanoparticles are then separated by centrifugation. In
another similar study, rifampicin is encapsulated in alginate-chitosan
nanoparticles with an entrapment efficiency by ionotropic gelation by
loading the drug to a pre-gel state of alginate and chitosan. Aqueous
honey has been used as a surfactant and a stabilizer. Nanoparticles are
formed following the drop-wise addition of 1% calcium chloride solu-
tion with continuous stirring while maintaining the pH at 5.5. Fol-
lowing ultra-sonication for 5 min, nanoparticles have been collected by
centrifugation [108].
Water remediation by polymer nanocomposites is an emerging area
of research for disinfecting bacteria-contaminated water. Zinc oxide
nanoparticles encapsulated sodium alginate nanocomposites have
shown efficiency in inactivating bacteria in synthetic and surface water
contaminated with Staphylococcus aureus, Escherichia coli, and
Pseudomonas aeruginosa [29,109]. The inactivation could be improved
with dose-dependent nanocomposite supplementation and increasing
contact time. Moreover, the leached Zn2+ in water was within the re-
commended limits, which are desirable for its application. These na-
noparticles possess potential applications for water treatment.
The use of electrospun mats of polymer nanofibers incorporated
with metal nanoparticles is widely investigated for wound dressing
applications due to their antibacterial activities. Shalumon et al. [110]
describe the fabrication of sodium alginate, polyvinyl alcohol, nano
ZnO composite nanofibers by electrospinning. These have shown ade-
quate antibacterial activity, reduced cytotoxicity, and cell adhesion
properties providing the potential to be used in wound dressing appli-
cations. Propolis is known to contain numerous polyphenols with a
wide range of bioactivities, including strong antimicrobial activity,
antioxidant, anti-inflammatory, and antitumor activities. Encapsulation
of Propolis within zein/caseinate/alginate nanoparticles has allowed
improving its bioavailability in intestinal fluid surpassing the corrosive
gastric juice, which reduces its bioavailability [41]. These zein/case-
inate/alginate-based vehicles may broaden the application of propolis
and other similar acid-sensitive bioactive compounds in the cosmetic,
food, and pharmaceutical industries. Cinnamaldehyde is a natural
preservative with good antibacterial and antifungal properties. How-
ever, it’s poor water solubility, volatility, and instability limit its in-
dustrial applications. Cinnamaldehyde loaded sodium alginate-chitosan
nanoparticles, which indicate a slow release of the compound, would
allow overcoming above limitations expanding its wide applications as
a food preservative [111]. Nisin-loaded alginate-poly-l-lysine-chitosan
nanoparticles are reported as effective against bacteria and fungus. It
could inhibit Listeria monocytogenes growth at 4°C over 21 days due to
the sustainable release of the drug. These could have desirable appli-
cations in the food industry as bio-preservatives to increase the shelf life
of refrigerated, vacuum-packed meat products [38]. ε-Polylysine is
commercially used as a food preservative in Korea, Japan, and in some
other countries. Compared to ε-polylysine alone, ε-polylysine loaded
chitosan-sodium alginate nanoparticles have shown promising anti-
microbial activity with an initial burst in drug release followed by a
sustained release of the ε-polylysine desirable for food preservative
applications [112].
5.6. Other applications
In addition to the aforementioned applications in drug delivery,
tissue regenerative engineering, and sewage purification, alginate na-
nomaterial is extensively used in a variety of applications. Shang et al.
[113] describe the synthesis of nonflammable alginate nanocomposites
by incorporating ammonium alginate and magnesium hydroxide using
lyophilization and post-crosslinking method. The aerogels have shown
high thermal stability, low thermal conductivity, and appropriate me-
chanical strength to be used in producing foam-like materials. Nano-
spheres of chitosan/alginate with magnetic properties (65 nm) have
11
Chemical Engineering Journal 391 (2020) 123823
shown to be ideal carriers for immobilizing α-amylase, which increases
its catalytic activity, recycling time, pH, and thermal stability [16].
These immobilized enzymes are used in a wide variety of industrial
applications.
6. Remarks and future outlook
Investigation of alginate for the development of nanomaterial is
beneficial considering its biocompatibility, mucoadhesive properties,
non-toxicity, hydrophilicity, bioavailability, and in particular due to the
relatively low cost of mass production. The nanostructures of alginates
range from nanoparticles to nanocomposite scaffolds, nano-colloids,
nanofibers, and nanoaggregates. Within the past few years’ alginate
nanomaterials ranging from 25.0 nm have been fabricated using dif-
ferent methodologies such as controlled gelification using Ca2+ ions,
polyionic complex formation through ionic gelation, self-assembly into
nanoaggregates, nanocomposite fibrous scaffolds by electrospinning or
thermally induced phase separation and nanoparticles by using mi-
crofluidics-aided polyelectrolyte complexation methods. Alginate-based
nanomaterial possesses the ability to be integrated into a variety of
applications, including drug delivery, regenerative engineering, en-
vironmental remediation, wound dressing, for developing probes and
biosensors, transfection of genetic material, and a variety of other
biofunctional materials.
Based on present literature regarding alginate-based nanoencapsu-
lates, advancements have been made to overcome limited control of
drug release, increasing stability and drug-loading capacity, reduce
pseudoallergy responses upon in vivo applications. However, more in-
vestigations are required to increase the purity of industrially prepared
alginate and to overcome issues on the potential accumulation in the
body. Developing analytical techniques to study the heterogeneous
structure of alginate, which depend on seaweed source and environ-
mental conditions is a major prerequisite. Further studies are required
for increasing current understanding of how the monomer composition
of alginate, monomer attachment sequence and alginate molecular
weight would affect the physicochemical properties of nanomaterials
and biocompatibility. In this manor studying structural properties of
alginate in major seaweeds, which is used for industrial alginate pro-
duction, is an immense requirement. Further verification of functional
properties in proper animal models would endure the future advance-
ments of this research area in clinical trials. The continuing advance-
ments in exploring alginate-based nanomaterials will revolutionize the
future progresses in nanotechnology, biotechnology, medicine, and
numerous scientific disciplines.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgments
This work (Grants No. M01201820150306) was supported by Korea
Institute of Marine Science & Technology Promotion (KIMST).
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