International Journal of Biological Macromolecules 163 (2020) 2097–2112

Contents lists available at ScienceDirect

International Journal of Biological Macromolecules

journal homepage: http://www.elsevier.com/locate/ijbiomac

Review

A review on the synthesis of graft copolymers of chitosan and their

potential applications
Deepak Kumar a,c,⁎, Sachin Gihar a, Manoj Kumar Shrivash b, Pramendra Kumar a, Patit Paban Kundu c
a
Department of Applied Chemistry, M J P Rohilkhand University, Bareilly 243006, UP, India
b
Department of Applied Scieneses, Indian Institute of Information Technology, Road Devghat, Jhalwa, Prayagraj, UP 2110151, India
c
Department of Chemical Engineering, Indian Institute of Technology, Roorkee 247667, India

a r t i c l e i n f o a b s t r a c t

Article history: Chitosan is an antimicrobial, biodegradable and biocompatible natural polymer, commercially derived from the
Received 9 June 2020 partial deacetylation of chitin. Currently modified chitosan has occupied a major part of scientific research. Mod-
Received in revised form 25 August 2020 ified chitosan has excellent biotic characteristics like biodegradation, antibacterial, immunological, metal-
Accepted 10 September 2020
binding and metal adsorption capacity and wound-healing ability. Chitosan is an excellent candidate for drug de-
Available online 17 September 2020
livery, food packaging and wastewater treatment and is also used as a supporting object for cell culture, gene de-
Keywords:
livery and tissue engineering. Modification of pure chitosan via grafting improves the native properties of
Chitosan chitosan. Chitosan grafted copolymers exhibit high significance and are extensively used in numerous fields. In
Grafting this review, modifications of chitosan through several graft copolymerization techniques such as free radical, ra-
Drug delivery diation, and enzymatic were reported and the properties of grafted chitosan were discussed. This review also
Food packaging discussed the applications of grafted chitosan in the fields of drug delivery, food packaging, antimicrobial, and
Antimicrobial applications metal adsorption as well as dye removal.
© 2020 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2097
2. Methods of graft copolymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2098
2.1. Grafting initiated by free radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2099
2.2. Grafting by using radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2101
2.3. Enzymatic grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2102
3. Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2103
3.1. Drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2103
3.2. Wastewater treatment/water purification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2105
3.2.1. Adsorption of metal ions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2105
3.2.2. Dyes removal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2105
3.3. Food industries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2107
3.4. As antimicrobial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2108
4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2109
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2109
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2110

1. Introduction

⁎ Corresponding author at: Department of Chemical Engineering, Indian Institute of

Chitosan is a non-toxic, non-carcinogenic, non-immunogenic [1]
Technology, Roorkee 247667, India. versatile hydrophilic [2] and cationic natural polysaccharide. It consists
E-mail address: dpk.4470@yahoo.in (D. Kumar). of β-(1–4) linked D-glucosamine and N- acetyl-D-glucosamine units

https://doi.org/10.1016/j.ijbiomac.2020.09.060
0141-8130/© 2020 Published by Elsevier B.V.
D. Kumar, S. Gihar, M.K. Shrivash et al.
[3,4]. It is also known as soluble chitin and obtained from chitin via alka-
line deacetylation of the chitin as shown in Fig. 1 [5–7]. Chitin consists of
unbranched chains of β-(1–4)-2-acetamido-2-acetamido-2-deoxy-D-
glucose. Chitin is obtained from invertebrates [8], such as crustacean
shells [9] or insect cuticles [10], and also naturally present in mush-
rooms, and green algae and some microorganisms such as yeast and
fungi etc. The series of chitosan polymers exhibit the different viscosity
(<2000 mPa.s), degree of deacetylation (48%–98%) and molecular
weights (50 kDa–2000 kDa) [11].
Chitosan exhibits valuable characteristics such as non-poisonous,
biocompatibility [12], biodegradability [13] and non-carcinogenic [14].
Therefore, chitosan has potential utilities in various fields like biomedi-
cine [15], as antimicrobial agent [16], wastewater treatment [17,18],
food packaging [19–21] functional membranes [17,22] and flocculation
[23,24].
However, chitosan has less solubility due to its molecular weight of
chitosan and short shelf life, which limits its wide applications. Since
last few years, the attention of researchers has attracted toward the
preparation of low molecular weight chitosan, to improve the solubility
of chitosan and to expand its potential applications in more extensive
fields, especially polymeric surfactants [25,26] and the chemical modifi-
cation of chitosan [27,28]. Among several techniques, graft copolymeri-
zation is the most significant and useful technique for modifying the
native characteristics of polysaccharide especially natural polymer
[29]. Graft copolymerization is a significant and common way to en-
hance the compatibility of the polysaccharide with synthetic polymers.
Chitosan has two kinds of reactive functional groups [30]. The first one is
the amino group and the second one is the hydroxyl group, which is the
point of initiation of the graft copolymerization as shown in Fig. 2. In the
graft copolymerization, small molecules form functional derivatives by
joining the covalent bond on the spine of chitosan [31]. Several re-
searchers found that the graft-modified chitosan exhibited much-
improved stability, water solubility, and bioactivities [32] such as anti-
oxidant [33], antibacterial and antifungal properties [34,35]. Graft copo-
lymerization is a simple method [36] to improve native properties of
chitosan [37,38] such as enhancing complexation or chelating proper-
ties [29], antimicrobial [19], bacteriostatic effect and also increase the
adsorption capacity [39]; Although the graft copolymerization of chito-
san improves its native properties and also add the new properties
without disturbing its natural properties, such as biodegradability
[13], mucoadhesivity [40,41] and biocompatibility [12]. So far, many
Fig. 1. Showing the chitosan extracted from biosources.
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International Journal of Biological Macromolecules 163 (2020) 2097–2112
Fig. 2. Showing the repetitive unit of chitosan.
investigations have been carried out on the graft copolymerization of
chitosan to prepare polysaccharide-based advanced materials with
unique bioactivities [34] and thus to widen their applications in bio-
medicine and environmental fields [42]. A lot of literature has already
been reported by several authors on chitosan and its different applica-
tions. However, no review article seems available concerning the syn-
thesis of grafted chitosan copolymers, its properties, and applications.
This communication deals with the synthesis of various methods of
grafted chitosan with single monomer and binary monomers; the influ-
ence of reaction parameters on the grafting percentage; the properties
and the potential applications of grafted chitosan in the various fields
such as drug delivery [6], biomedical [15], tissue engineering [43],
food packaging [19], and wastewater treatment [34].
2. Methods of graft copolymerization
Chemically modifications will open paths to several applications of
natural polysaccharides of potential modifications, Graft copolymeriza-
tion method is considered very promising for developing highly sophis-
ticated functions; it would allow an extensive variety of molecular
designs to afford new types of tailored hybrid substances consists of
synthetic polymers and natural polysaccharides. Grafting of synthetic
monomers onto natural chitosan can add the desired properties and ex-
tend the area of applications of them by selecting several kinds of side
chains. Currently, various redox initiators such as CAN (ceric ammo-
nium nitrate) [36,37,44], APS (ammonium persulfate) [45], PPS (potas-
sium persulfate) [46], TCPB (thiocarbonate‑potassium bromate) [47],
PDC (potassium diperiodatocuprate) [48], and FAS (ferrous ammonium
D. Kumar, S. Gihar, M.K. Shrivash et al.
sulfate) [49] have been established to initiate graft copolymerization.
The graft copolymerization is also initiated through enzymes, gamma-
irradiation [38] and microwave irradiation [50]. The various grafting pa-
rameters such as the percentage of grafting and efficiency of grafting are
highly affected through the initiator, concentration and kind, concentra-
tion of monomer, reaction time and temperature. The characteristics of
the graft copolymers are controlled by the nature of grafted chains, in-
cluding number, length and molecular structure of grafted chain. So
far, many researches have been conducted to explore the influences of
these parameters on grafting percentage and the characteristics of
grafted materials [51].
2.1. Grafting initiated by free radicals
In the last few decades, grafting of vinyl monomers with chitosan
in the presence of free-radical initiators have attracted the attention
of various researchers. This technique allows the preparation of new
polymeric materials with desired properties. Bahramzadeh et al.
(2019) reported the article on grafted chitosan in which they pre-
pared the chitosan-graft-poly (N-hydroxy ethyl acrylamide) by
using the potassium persulphate initiator in an aqueous solution
for potential biomedical applications [52]. Hasan et al. (2019) syn-
thesized the graft copolymer of chitosan with poly[2-(acryloyloxy)
ethyl trimethylammonium chloride] in the presence of potassium
persulphate initiator via redox polymerization for antimicrobial
activity. It was found that the antimicrobial activities and water
Scheme 1. Schematic representation of the synthesis of chitosan -g- (acrylic acid-co-acrylamide).
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solubility were enhanced after the grafting [53]. Said et al. synthe-
sized the grafted chitosan [chitosan-g-(acrylic acid-co-acrylamide)]
through the grafting of chitosan in the presence of potassium persul-
fate free radical initiator and acryl acid and acrylamide monomers
and the mechanism of synthesis is presented in Scheme 1 [54].
Sabaa et al. (2018) prepared the chitosan-graft-poly(acrylonitrile)
by using PPS initiator by free radical polymerization for antimicro-
bial activities. The effects of potassium persulfate, acrylonitrile, reac-
tion temperature and time on graft copolymerization were studied
by determining the grafting percentage and grafting efficiency. The
reaction mechanism is shown in Scheme 2 [55].
In 2015, Khalil et al. prepared the water-soluble grafted chitosan
through the grafting of DCDA (dicyandiamide) onto chitosan. The
DCDA-grafted chitosan has shown antibacterial activity against E. coli
and S. aureus at pH of 7 and 4 respectively [56]. They proposed that
-NH2 and -CN groups of DCDA in grafted chitosan react with the micro-
bial membrane and prevent the rate of bacteria growth. Klaykruayat
et al. reported that grafting of cationic hyperbranched dendritic
polyamidoamine with terminal methyl ester on chitosan resulted in
an increase in water solubility of grafted derivative and displayed anti-
microbial property against S. aureus [57].
Kohsari at el. synthesized the antimicrobial chitosan-polyethylene
oxide and also evaluated the antimicrobial activities of chitosan-
polyethylene oxide against Staphylococcus aureus and Escherichia coli
bacteria through viable cell-counting method [58]. Yang et al. investi-
gated the antibacterial activities of cinnamic acids grafted chitosan
D. Kumar, S. Gihar, M.K. Shrivash et al.
Scheme 2. Representing the scheme of synthesis of chitosan-graft-polyacrylonitrile.
Scheme 3. Schematic representation of the mechanism of the synthesis of Ch-g-PANI.
against R. solanacearum, particularly RS-5, and plant pathogenic bacteria
[59].
Furthermore, so many workers have synthesized various types of
grafted chitosan for various applications. Khairkar et al. synthesized
the chitosan-g-polyaniline in the presence of APS in acidic medium by
a conventional method. Ch-g-PANI was used for the development of
electronic devices especially sensor devices [60]. The mechanism of
the synthesis of Ch-g-PANI was given in Scheme 3.
Aguilar et al. synthesized the polyacrylonitrile-g-chitosan (PAN-g-
CS) in the presence of an initiator ceric ammonium nitrate (CAN) via
the conventional method for the removal of Pb2+, Zn2+ and Cd2+ ions
in aqueous solutions as shown in Scheme 4 [61].
Wang et al. synthesized the binary grafted chitosan with two mono-
mers [acrylamide and (2-methacryloyloxyethyl) trimethyl ammonium
chloride] via γ-radiation method and used it as a cationic flocculant.
The reaction process is illustrated in Scheme 5 [62]. Soliman et al. syn-
thesized the chitosan-based flocculants by grafting of acrylamide onto
carboxymethyl chitosan in the presence of potassium persulphate
(PPS) initiator via the conventional method. The reaction process is il-
lustrated in Scheme 6 [63].
Sadeghi et al. have synthesized the chitosan-g-poly (acrylic acid-co-
acrylonitrile) hydrogel in the presence of APS initiator and MBA cross-
linker in an inert atmosphere. The mechanism of synthesis of grafted
chitosan hydrogel has been shown in Scheme 7 [64].
Mahdavinia et al. synthesized the hydrogel based on chitosan-g-poly
(acrylic acid-co-acrylamide) in the presence of APS initiator and MBA
Scheme 4. Schematic representation of the mechanism of the synthesis of PAN-g-CS.
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cross-linker under an inert atmosphere. The mechanism of synthesis
of hydrogel has been shown in Scheme 8 [65].
Hassan et al. have prepared the films of chitosan graft copolymerized
with poly (acryloyloxy) cetyltrimethylammonium chloride. Firstly they
synthesized the graft copolymer of chitosan with poly (acryloyloxy)
ethyl trimethylammonium chloride via the redox polymerization
(Scheme 9); after that, they prepared the film through a solution casting
method. Antimicrobial activity of this film was investigated against two
fungi and bacteria They found that the antibacterial activities of grafted
chitosan film were higher than pure chitosan [66].
Liu et al. improved the solubility and antioxidant activity of
carboxymethyl chitosan via grafting of three phenolic acids such as gal-
lic acid, caffeic acid, and ferulic acid on to carboxymethyl chitosan. They
reported that all the synthesized graft copolymers were water-soluble
and effective antioxidant agents [67]. Liu et al. synthesized the phenolic
acid (hydroxybenzoic and hydroxycinnamic acid) grafted chitosan by
using ascorbic acid and hydrogen peroxide (H2O2) redox pair under
an inert atmosphere for enhanced adsorption properties for Fe (II). It
was observed that the surface morphology of grafted chitosan was sig-
nificantly changed after the grafting of phenolic acids [68]. Wang et al.
studied the synthesis of grafted-chitosan with different phenolic acids
such as gallic acid, caffeic acid, gentisate acid and sinapic acid via the
grafting process. It was found that grafted-chitosan exhibits excellent
antimicrobial activities against Pseudomonas aeruginosa, Escherichia
coli, bacillus subtilis and Staphylococcus aureus [69] Curcio et al. have
prepared the water-soluble grafted chitosan with gallic acid-grafted-
D. Kumar, S. Gihar, M.K. Shrivash et al.
Scheme 5. Schematic representation of graft-copolymerization of chitosan.
Scheme 6. Schematic representation of grafted chitosan.
chitosan in the presence of ascorbic acid and hydrogen peroxide (H2O2)
redox initiator via free radical- grafting copolymerization [70]. Fan Qi
et al. synthesized some polymeric cationic surfactants based on chitosan
and 3-chloro-2-hydroxypropyl dimethyl dehydroabietyl ammonium
chloride by using the graft copolymerization technique [71].
Scheme 7. Schematic representation of chitosan-g-poly (acrylic acid-co-acrylonitrile).
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2.2. Grafting by using radiation
Compared to the conventional chemical routes, the radiation tech-
nique, in which neither initiators nor cross-linkers are required, has
many advantages. For example, the products are free of toxic additives.
The radiation-induced modification of chitosan through grafting with
either vinyl or acrylate monomers has been investigated. Considering
that chitosan is already rich in amino groups, it is interesting to incorpo-
rate carboxyl groups into chitosan.
Zhuang et al. prepared the chitosan-g-maleic acid by gamma radia-
tion for the adsorption of Co ions from aqueous solutions and the ad-
sorption capacity of chitosan modification was 2.78 mg/g [72]. Kumar
et al. studied the synthesis and characterization of the antimicrobial
grafted chitosan as a drug delivery device through microwave proce-
dure for the controlled release of curcumin drug [6].
Kumar et al. studied the synthesis a new antimicrobial and biode-
gradable binary grafted chitosan film by grafting of acrylamide and ac-
rylonitrile on to chitosan via microwave method and the reaction
mechanism is the suggested as Scheme 10 [19]. Sokker et al. synthesized
the chitosan grafted polyacrylamide through the gamma radiation for
adsorption of crude oil from aqueous solution. The results exhibited
that the optimized hydrogel has great elimination efficiency (2.3 g/g)
of crude oil at pH-3 [73].
Kumar et al. synthesized the novel antibacterial grafted and
crosslinked copolymer of chitosan by using the acrylic acid and
D. Kumar, S. Gihar, M.K. Shrivash et al. International Journal of Biological Macromolecules 163 (2020) 2097–2112

Scheme 8. Schematic representation of chitosan-g-poly (acrylic acid-co-acrylamide).

Scheme 9. Schematic representation of grafted chitosan.

acrylonitrile as monomers through the microwave route. Authors re-
ported that graft and crosslink copolymers of chitosan have excellent
antimicrobial properties [16].
Singh et al. synthesized the Chitosan-graft-polyacrylamide (Ch-g-
PAM) by using a microwave irradiation initiator in an aqueous solution.
They investigated the various grafting conditions, and 169% grafting was
achieved at 80% MW power in 1.16 min. They observed that the adsorp-
tion ability of chitosan was improved after grafting and also found that
microwave synthesized Ch-g-PAM has high adsorption ability for Ca2+,
Zn2+ cations in aqueous solution as compared to prepared by conven-
tional methods. Singh et al. also explained the mechanism for the synthe-
sis of grafted chitosan by microwave route as shown in Scheme 11 [74].
Singh et al. synthesized the grafted chitosan Ch-g-PAN by micro-
waves irradiation method without using any reagents and 170% grafting
yield in very short reaction time and found the while the same could be
synthesized only in 105% yield using K2S2O8/ascorbic acid as redox ini-
tiator in a thermostatic water bath in 1 h and the reaction mechanism is
the following Scheme 12 [75].
2.3. Enzymatic grafting
The synthesis and modification of polymer through enzymes are
very beneficial to the purpose of health and safety because it eliminates
the hazardous materials linked with reactive monomers. Enzymes are

Scheme 10. Showing the scheme of synthesis of chit-g-Poly (An-co-Am).

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Scheme 11. Scheme for synthesis of grafted chitosan [62].

also used for the environmental benefit because they decomposed the
waste into simple elements and also eliminate the hazardous material.
Finally, enzyme specificity may provide the possibility to accurately
modify the polymer structure without loss of any polymer function.
Many chitosan derivatives have been synthesized through enzymatic
modification which improves some unique properties of chitosan like
water-solubility, thermal stability, pH-sensitive and adhesive [76] prop-
erties. Enzymatic modification of natural chitosan with synthetic phe-
nolic compounds to increase water solubility in the basic environment
is reported as Scheme 13 [77]. Kaneko et al. studied the influence of en-
zymatic catalysts on the preparation of amylose-grafted chitosan.
Amylose-grafted chitosan was synthesized by graft copolymerization
reaction of chitosan and α-D-glucose 1-phosphate in presence of phos-
phorylase enzymatic catalyst in sodium acetate buffer solution [78].
3. Applications
shown considerable applications in drug delivery, due to its poor sol-
ubility in water [83]. To resolve this problem, grafting is the greatest
option to modify the native characteristics of neat chitosan for drug
delivery applications. Grafted/cross-linked derivatives of chitosan
have been extremely useful as a drug delivery carrier for the con-
trolled release of oral drugs.
Recently, several advanced chitosan-based drug delivery devices
have been established for drug delivery applications [84], to boost the
technological advancement in biomedical applications [4]. Although,
several researchers and pharmaceutical industries developed a more so-
phisticated and effective drug carrier that discharges the drug at the
right time and in the desired amount [85]. Therefore, the drug mole-
cules reach their target in the right way with considerable concentration
[83]. The great demand for effective and low-cost therapies [86,87], re-
search and developments have been formulated a novel and progressive
drug delivery systems for years [83].

Modified chitosan has so many applications in food packaging,

nanomaterial, wastewater treatment, tissue engineering and pharmaceu-
tical field as well as in mucoadhesive excipient, diluents in tablets and
capsules manufacturing, wound healing property and this is shown in
Fig. 3.

3.1. Drug delivery systems

Chitosan is more comfortable and safe with drugs as a carrier in drug

delivery systems due to their pulsated release of drug at the desired
temperature and pH for targeting site. Considering these impressive
polymeric properties for polysaccharides, which is a biologically active
natural polymer [25] and possess very interesting biological proper-
ties, namely nontoxicity [26], biodegradability [71], biocompatibil-
ity, cytocompatibility [78], antimicrobial [44,79], antioxidant, anti-
cholesterolemic [80], anti-inflammatory, analgesic [81], hemostatic,
mucoadhesion [82], these, polysaccharides have been used in a vari-
ety of applications, most relevant in the medical as well as in phar-
maceutical fields [44]. On the other hand, polysaccharides were not

Scheme 12. Showing the scheme of synthesis of grafted chitosan. Scheme 13. Showing the enzymatic grafting of chitosan with phenol and tyrosinase.

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D. Kumar, S. Gihar, M.K. Shrivash et al.
Fig. 3. Creative representation of the application of grafted chitosan.
Chitosan is extensively used as an active agent in drugs and biologics
due to their physicochemical [88] and biological properties. In the acidic
medium, chitosan is hydrophilic and positively charged polysaccharide
and this property allows it to interact with the negatively charged
materials, polyanions, and polymer [89]. Chitosan has significant bio-
pharmaceutical properties such as biocompatibility, low toxicity, and
pH sensitivity; because of these favorable characteristics, interest in chi-
tosan and its copolymers as excipients in drug delivery has enhanced in
the present time. Parsian et al. investigated that the targeted delivery of
anticancer agents increases efficacy while reducing harmful effects.
Among several drug delivery devices, nanoparticles of iron oxide coated
by chitosan (CsMNP) attracted attention due to their biodegradability,
low toxicity, biocompatibility, and target orientation under the mag-
netic area [90]. Alam et al. prepared the mucoadhesive based micropar-
ticles of furazolidone (antimicrobial agent) for the stomach target drug
delivery system by using the chitosan as mucin adsorptive polysaccha-
rides via spray drying method [91]. Balan et al. synthesized the nano-
Fig. 4. Showing the impact of time on drug release (%) at pH-5 (reproduced from Kumar
et al. [6], with permission from Elsevier).
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drug carrier (biotinylated N-palmitoyl chitosan) for the treatment of
breast cancer. They found that nanoparticles demonstrated a better
drug loading capability and susceptible to hemocompatibility, biode-
gradability and pH-dependent drug release behavior properties [92].
Huo et al. prepared the chitosan-microcapsules/starch blend film-
based drug delivery device for controlled antofloxacin (antibacterial)
drug release and the drug-releasing mechanism was pH-sensitive [93].
El-kharrag et al. synthesized the low coast chitosan-based nanoparticles
for drug delivery applications via modified wet technique [94].
Wang et al. synthesized the antioxidant active graft copolymer of
chitosan with tryptophan and phenylalanine via free radical grafting
method in the presence of ascorbic acid and hydrogen peroxide redox
initiator for drug delivery system [95]. Muddineti et al. synthesized
the cholesterol-grafted chitosan and the synthesized grafted chitosan
was used to prepare the nano-drug delivery system for the siRNA
drug for the treatment of lung cancer [96]. Evangelista et al. synthesized
the cyclodextrin-grafted chitosan for the controlled release of the carra-
geenan drug [97]. Almeida et al. synthesized the chitosan-grafted-
polycaprolactone via carbodiimide reaction for controlled release of
paclitaxel drug. It was found that the grafted chitosan-based micelles
were capable to increase the intestinal permeability of paclitaxel in
through intestine cells. Therefore, CS-g-PCL may be an effective
drug delivery system as a vehicle of paclitaxel intestinal delivery
[98].
Kumar et al. synthesized the chitosan-based antibacterial binary
grafted chitosan [chit-g-Poly (AA-co-Am)] for constant release of
curcumin (drug delivery) via microwave technique method. The poten-
tial drug delivery application of grafted chitosan was investigated at dif-
ferent time intervals and different pH. They found that the curcumin
release from binary grafted copolymer [chit-g-Poly (AA-co-Am)] was
increased with an increase in time and they achieved the maximum
percentage release of different formulation of curcumin from grafted
chitosan at 10 h and pH-5.4 as shown in (Fig. 4) [6]. The summary of
the current studies of the chitosan-based graft copolymer for drug deliv-
ery applications are given in Table 1.
D. Kumar, S. Gihar, M.K. Shrivash et al. International Journal of Biological Macromolecules 163 (2020) 2097–2112

Table 1
Various grafted species of chitosan for in vitro drug delivery applications.

Polysaccharide Graft chain Drug Drug loaded form Drug releasing Ref.
potential

Chitosan Polyethylene glycol Doxorubicin (DOX) Core-shell-corona DOX/PEG-g-CS-g-PDPA micelles 68.3%, pH 5.0, 60 h [99]
Chitosan SS-T-mSiO2 5-Fluorouracil (5-FU) SS-T-mSiO2 grafted chitosan capsules 48.72%, pH 7.4, 5 h [100]
Chitosan Dihydrocaffeic acid Doxorubicin (DOX) Doxorubicin loaded CS-DA/OP hydrogels 80%. pH 7.4, 24 h [101]
Chitosan Oligo(lactic acid) Lidocaine Lidocaine loaded CSWK-OLA NPs 100%, pH-7, 6 h [102]
N-maleoyl Chitosan β-Cyclodextrin Ketoprofen (KTP) KTP loaded CD-g-NMCS NPs 80%, pH 7.4, 24 h. [103]
Chitosan β-Cyclodextrin Etoposide (VP16) Encapsulation of VP16 into the CS-g-β-CD 90%, pH 7.4, 10 h. [104]
Carboxymethyl chitosan Carboxymethyl β-cyclodextrin Insulin Insulin-loaded hydrogels 70%, pH-7.4, 2 h [105]
Chitosan/polyurethane Acrylic acid Temozolomide (tmz) and Pa-g-cs/pu) core-shell nano fibers 80%, pH 5.0 [106]
paclitaxel (ptx)
N-trimethyl chitosan Aliphatic acid Kaempferol Kaempferol loaded NPs (DA-TMC-KNLC) 80%, pH-6. [107]
Chitosan O-methyl-O′-succinylpolyethylene Camptothecin Polymeric micelles 75%, pH 5.0 [108]
glycol and oleic acid

3.2. Wastewater treatment/water purification
Continuously increasing water pollution is a very serious concern for
the entire animal kingdom. All the animal and plant beings are directly or
indirectly affected by the discharge of industrial, domestic and medical
wastes along with agricultural effluents into the rivers and groundwater,
thus disturbing the biological balance of the aquatic system. A huge pop-
ulation is not able to get safe, clean and pure drinking water [109,110].
Water pollution became a serious issue in industrialized regions. Textile,
paper, pharmaceuticals, tannery and bleaching industries and other
metal processing industries have a major role to pollute the water re-
sources. These poisonous metals ions and dyes are not only probable
human health hazards but also hazardous for plants as well as for aquatic
life; this is especially true for dyes as these remain unaltered in the envi-
ronment for long period [111]. Many chitosan adsorbent derivatives
have been prepared for adsorbing metal ions and dyes by grafting
novel functional groups on the chitosan chain and these functional
groups are combined with chitosan to enhance the sorption capability
and change the pH value for the metal and dye sorption via transforming
the sorption surface to enhance sorption selectivity for the toxic metal.
3.2.1. Adsorption of metal ions
Toxic metals, like lead, tin, mercury, selenium, arsenic and cadmium
are introduced to the water/soil by various human activities and get de-
posited gradually in the ecosystem. The drainage of polluted water into
rivers and lakes is very common [112]. Reaching the toxic metals into
freshwater resources are the major cause for the poisoning of freshwa-
ter resources, influencing the entire eco-system due to uncontrolled
human activities [113].
Removal of toxic metal from the aqueous solution is one of the great
challenges and tasks for the scientific community in the last few years.
Several natural polysaccharides especially chitosan and their products
have been used as an adsorbent for adsorbing metal ions. Vafakish
et al. reported that the surface of the adsorbent is modified using various
cationic surfactants, thereby increasing the adsorbent's adsorption ca-
pacity several times [114]. Modification of pure chitosan and chitosan
succinate through surfactants for adsorption application was studied
by Harutyunyan [115]. Pal et al., modify the beads of chitosan by using
the sodium dodecyl sulfate as a surfactant for effective adsorption cad-
mium ion [116]. Chatterjee et al., impregnated the three different sur-
factants such as TX-100, SDS, and CTAB on to chitosan beads for
sorption of NAP from its solutions [117].
The beads of chitosan gel usually showed high water absorption ca-
pacity but they had the poor volumetric density of sorbent sites. The
grafting of amine groups on chitosan with other polar polymers can off-
set this disadvantage [118]. Lalita et al. synthesized the low cost and
eco-friendly hydrogel for the sorption of heavy metal ions via grafting
and crosslinking of acrylic acid alone and with other molecules of acry-
lonitrile, glycidyl methacrylate and acrylamide onto chitosan. They also
observed that modified chitosan showed good results compare to pure
chitosan and showed favored sorption of Fe(II) ions over Cr(VI) and
Cu(II) ions [119]. The summary of the current studies of the grafted chi-
tosan as an adsorbent for metal ions adsorption applications are given in
Table 2.
3.2.2. Dyes removal
Dyes are one of the great threats to the aquatic system and our envi-
ronment because low concentrations of dyes are extremely visible (aes-
thetic pollution) and disturb the aquatic life and food chain (chemical
pollution). Dyes are anionic, cationic, and non-ionic colored stable com-
pounds which could be obtained from the natural product without
treatment [130] such as plants, beetles, animals [131] and minerals,
and widely used in textiles, cosmetics, printing, rubber, plastics, leather

Table 2
Various grafted chitosan species for heavy metal removal applications.

Polysaccharide Graft chain Metal Adsorbent species Metal removal performance Ref.

Chitosan 2-Hydroxyethyl methacrylate Cr CS-g-P 96%, pH-5.3 [120]

(HEMA) and acrylic acid (AA) (HEMA-co-AA)
Chitosan 4-Aminobenzoic acid Pb, Cu, Ni, Zn, G/ECH-CS 92% Pb, 88% Cu at pH-5, 90% Zn, and Cd at pH-6 and 93% Ni at pH-7. [121]
and Cd
Chitosan EDTA and PVA Cu PVA-CS-EDTA 87.97%, pH-6. [122]
beads
Chitosan Methyl methacrylate Cu M-CTS 70%, pH-6. [123]
Chitosan Acrylic acid and lignosulfonate Cu and Co CSL adsorbent 386 mg/ g(Co) and 283 mg/ g (Cu) [124]
Chitosan Montmorillonite Fe CS/MMT/Mel 80%, pH-3.9 [125]
composite
Chitosan-cellulose Acrylic acid Ca and Mg CTS/cell)-g-PAA 90%, pH-6.5 [126]
Chitosan Acrylic acid Pb CS-g-PAA 204.89 mg/g [127]
Chitosan Acrylic acid Cu, Zn, Ni, Pb, Cd, CTS-g-PAA Zn- 114.94 mg/g, Cu-111.11 mg/g, Ni-99.01 mg/g, Cd-370.37 mg/g, [128]
Mn, Co, and Cr Pb-476.19 mg/g, Mn-138.89 mg/g, Cr-312 mg/g, and Co-135.14 mg /g
Chitosan N-vinylcaprolactam Cr and As Chitosan-g-PNVCL As-258.5 mg/g and Cr-269.2, mg/g [129]

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D. Kumar, S. Gihar, M.K. Shrivash et al. International Journal of Biological Macromolecules 163 (2020) 2097–2112

Fig. 5. (a) Effect of adsorbent dose on the MO dye adsorption (b) effect of pH on the MO dye adsorption (c) effect of time on the MO dye adsorption (d) effect of temperature on the MO dye
adsorption (reproduced from Kumar et al. [138], with permission from Elsevier).

industries [132] to color their products. Therefore, a large number of
dyes (color compounds) reached in water sources with industrial efflu-
ent and become a great cause of water pollution. Dyes are highly toxic,
carcinogenic, stable, non-biological degradable colored compounds and
very dangerous for human health, animals and aquatic life and remain
unchanged for a long time; therefore, there is an urgent need to remove
dyes from dye affected water bodies. Polysaccharide-based adsorbent
were extensively used for the removal of dye from their solution [133].
Chitosan has found wide applications in water treatment. The func-
tional side group of chitosan makes it a promising adsorbent for con-
taminants (e.g. synthetic dyes) by electrostatic force and hydrogen
bonding [134]. Chitosan has potential as an effective adsorbent for al-
most all kinds of dyes other than the basic pigment, which can be di-
rectly related to its natural cationic properties. There are several
reports on chemical modification of chitosan to remove simple dyes
from colored fiber [135]. The chemical modification of chitosan via
grafting of poly (acrylic acid) and poly (acrylamide) in presence of per-
sulfate redox initiator through grafting and covalent cross-linking
processes for removal of simple dyes and the maximum adsorption ca-
pability was reported by Lazaridis [136,137].
Abbasian et al. synthesized a series of grafted chitosan derivatives
such as chitosan-g-polyaniline, chitosan-g-poly(N-ethylaniline) and
chitosan-g-poly(N-methyl aniline) by chemical oxidation process for
adsorption of acid red 3 and direct red 23 dyes from aqueous solution
[134]. Kiakhani et al. prepared the biopolymer adsorbent by grafting
of chitosan with ethyl acrylate (Ea) for the adsorption of Basic Blue 41
(BB41) as well as Basic Red 18 (BR18) from their solutions. The Chit-
g-Ea has a higher adsorption ability toward simple dyes such as
217.39 ppm and 158.73 ppm for BB41 and BR18, respectively [135].
Kumar et al. synthesized the crosslinked material [chit-g-Poly (AA-co-
Am)] based on chitosan in the presence of CAN initiator for the elimina-
tion of methyl orange dye. The effect of several influencing parameters
such as adsorbent dose, pH, time and temperature on the removal of
methyl orange dye was investigated (Fig. 5) [138]. The summary of
the current studies of the grafted chitosan as an adsorbent for dye ad-
sorption applications are given in Table 3.

Table 3
Various grafted chitosan for dye adsorption applications.

Polysaccharide Graft chain Dye Adsorbent species Dye removal performance Ref.

Chitosan Acrylamide and sodium methacrylate Fuchsin basic dye CTS-g-(AAm-co-SMA) hydrogel 97%, pH 7, 180 min [139]
Chitosan Ethylenediamine (EDA) and methyl Congo red dye EDA-g-CS 1607 mg/g [140]
acrylate (MA) MA-g-CS a143 mg/g
Chitosan 2-Acrylamido-2-methylpropane Methylene blue PMCMs 1428 mg/g [141]
sulfonic acid
Chitosan Carbon clay material Methyl Blue CSCC Biohybrid adsorbent 95.31 mg/g [142]
Chitosan Methyl methacrylate, Orange-G, Congo Red, Remazol Brill ChgPMMA 80% [143]
Ethyl methacrylate, Blue R and Methyl Blue ChgPEMA 75%
Butyl methacrylate, ChgPBMA 60%
Hexyl methacrylate ChgPHMA 55%
Chitosan Acrylamide Acid Blue 113 PAM-Ch 96.38% [144]
Chitosan Acrylamide Reactive Red 195, Brill Red, Reactive chitosan-g-acrylamide RR195-7 mg/g [145]
Black 5 and Black B RB5 -15 mg/g
BR-20 mg/g
BB-25 mg/g
Chitosan Gallic acid Evan blue, Acid red 94 and Alcian blue 8GX GA-g-CS Evan blue-97.3% [146]
Acid red - 94%
Alcian blue 8GX −98%

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D. Kumar, S. Gihar, M.K. Shrivash et al.
3.3. Food industries
Food packaging is commonly used to maintain the quality and in-
crease the shelf life of food products and to keep them safe and edible
for a long time [147]. Various types of plastic, glass, cardboard, metal,
and paper are used for food packaging. These materials provide
physical protection to food products, as well as create appropriate
physicochemical conditions for food products that are essential for
the safety [148] and quality of foods [149]. Although the use of pack-
aging materials increases the life of food products, packaging mate-
rials pose a serious environmental problem as they are not easily
biodegraded. Biopolymers specifically polysaccharides are used to
solve this environmental problem. Applications of polysaccharide-
based films in food product packaging may provide new prospects
to develop new food packaging systems. In addition, biodegradable
films can reduce environmental problems associated with food pack-
aging [149].
Fig. 6. Food preservation application of antimicrobial binary grafted chitosan film to apple and guava (fruit 1 covered by film and 2 without any film as control) (A) 0 day (B) after 6 days
(C) after 12 day (D) after 18 days with film (E) after 24 days without film (F) after 24 days pieces fruit (reproduced from Kumar et al. [19], with permission from Elsevier).
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International Journal of Biological Macromolecules 163 (2020) 2097–2112
Kumar et al. prepared the antimicrobial film of grafted chitosan
[chit-g-Poly (An-co-Am)] for food packaging by grafting of acryloni-
trile and acrylamide on to chitosan via microwave initiated tech-
nique. They selected apple and guava to evaluate the potential
applications of chitosan film in the food packaging industry. They
studied the process by the wrapping of chitosan film for the preser-
vation of apples and guava and a pair was left without film (as con-
trol). They found that apple and guava packed with grafted chitosan
film were still edible without rottenness and the surfaces were
smooth without defect and microbial infection even after 24 days
of storage at 40–45 °C. In addition, the pair of apples and guava
that had been left as a control turned dark reddish-brown, with
many fungal spots with foul smell as evident in Fig. 6 [19].
Regarding the food preservation field, there is a possibility of using
chitosan film/or string for the preservation of meat during storage, to im-
prove the quality of fresh broccoli, to prevent spoilage of cold pork prod-
ucts and to control bacterial contamination during brewing [150–153].
D. Kumar, S. Gihar, M.K. Shrivash et al.
Many examples are available in literature in which edible chitosan coat-
ing increases the shelf life and maintains the nutrition and quality of veg-
etables and fresh fruits [154,155].
3.4. As antimicrobial agents
Microbial infections are one of the serious concerns because it is one
of the leading cause of death worldwide, especially in medical institu-
tions, where the public are mostly more vulnerable [156]; this due to
the persistence of the presence of pathogenic microbes (bacteria, vi-
ruses and fungi) in various places, such as healthcare products, textiles,
medical equipment, sanitary facilities and water purification equip-
ment. So, the prevention of microbial infections is very difficult [157].
Chitosan represents significant types of materials with interesting char-
acteristics that make them proper candidates in various utilities ranging
from the bacteriological to biomedical fields. Chitosan with antibacterial
activity are applicable for the direct removal of bacteria and can serve
antibiotics. Regarding these issues, the scientific community prepared
the antimicrobial macromolecules for combating the multi-drug resis-
tant microorganisms. The use of polysaccharide as antimicrobial candi-
dates generally shows various benefits since it has low long-term
activity and low residual toxicity, chemically stable, non-volatile and
does not penetrate via skin [158].
Chitosan with intrinsic antibacterial activity is generally based on
polycations, that are capable to kill the microorganisms through the
act on their negative cell membrane [9]. Generally, cationic groups pres-
ent in these polysaccharides are quaternary phosphonium, quaternary
ammonium, tertiary sulfonium, or guanidinium [159,160]. According
to the previously reported literature, many natural polysaccharides,
gums and mucilage exhibit the antimicrobial properties. Among those,
chitosan showed good antimicrobial properties [161].
Chitosan has a broad antimicrobial range to which fungi [162], gram-
positive [2], gram-negative bacteria [163] are greatly susceptible. Chito-
san and chitin have been examined as antimicrobial natural polysaccha-
rides against bacteria, algae, fungi and yeasts in tests involving in vitro
and in vivo interactions with chitosan in various forms (films, compos-
ites, and solution) [16]. Usually, in these investigations, the chitosan is
considered as a bactericidal or bacteriostatic. Goy et al. tested the anti-
microbial property of chitosan and trimethyl chitosan, against Gram-
positive and Gram-negative bacteria via turbidity and well inhibition
zone methods and found that chitosan was more active against the
S. aureus (Gram-positive) than E. coli (Gram-negative) [163].
Fig. 7. Representing antibacterial activity of grafted chitosan copolymer against E. coli, P. aeruginosa and S. aureus bacteria (reproduced from Kumar et al. [16], with permission from
Elsevier).
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International Journal of Biological Macromolecules 163 (2020) 2097–2112
The grafting of ethylene diamine tetraacetic acid onto chitosan in-
creased the antibacterial activity of chitosan against the gram-negative
bacteria through magnesium complexation [164]. The grafted copoly-
mer of dicyandiamide and chitosan displayed excellent antibacterial ac-
tivity against E. coli and S. aureus at pH of 7 and 4 due to the interaction
of bacterial membrane -NH2 and cyano groups [56]. The grafting of cat-
ionic hyperbranched dendritic polyamidoamine-containing terminal
methyl ester end groups onto chitosan increased its antimicrobial activ-
ity against S. aureus [57].
Many articles explain the antimicrobial property of chitosan-based
nanoparticles against E. coli, S. aureus. For S. aureus; nanoparticles of chi-
tosan proved to have a minimum concentration of bactericidal (MBC =
4 g/ml) compared to pure chitosan (MBC = 32 g/ml). The antimicrobial
activity was again improved when prepared nanoparticles of chitosan
are loaded with Cu (MBC = 2 g/ml) [165]. Nanoparticles of chitosan
on grafted with carvacrol or eugenol exhibited antibacterial activity
against S. aureus (MBC = 1 mg/ml) and (MBC = 2 mg/ml) respectively.
The grafted samples were slightly more effective to the chitosan nano-
particles but less effective to the phenolic compounds [166]. Pei et al.,
synthesized the dehydroabietylamine-chitosan cationic surfactants
with the reaction of chitosan and dehydroabietylamine. It was found
that the cationic surfactants exhibit excellent antibacterial activities
against Escherichia coli and Pseudomonas aeroginosa [167].
In previously published work, Kumar et al. synthesized some anti-
bacterial graft and crosslink of chitosan such as Chit-g-Poly (AA-co-
An), crosslinked Chit-cl-Poly (AA-co-An) [16], chit-g-Poly (An-co-Am)
[19], chit-g-Poly (AA-co-Am) [6] and crosslinked chit-cl-Poly (AA-co-
Am) [138]. Studies of antimicrobial activities of grafted and crosslinked
samples were investigated against gram-positive (S. aureus) and gram-
negative (E. coli and P. aeroginosa) bacteria (Fig. 7). It was observed that
grafting and crosslinking enhanced the antimicrobial activities of chito-
san due to the presence of a long alkyl chain in the monomeric unit of
the polymer [6,168]. Kumar et al. also studied the binding affinity of
grafted chitosan with three recognized bacterial molecular targets,
such as P. aeruginosa, E. coli and S. aureus, respectively through Autodoc
4.1 along with LGA algorithm parameters for automated flexible ligand
docking. They have also studied the binding affinity concerning to pi
bonding as well as H-bonding, and interacting amino acids, and found
that grafted chitosan has an excellent binding affinity with three bacte-
rial proteins (targets). Kumar and his coworker reported that the
grafted chitosan exhibited the binding affinity of −6.75 kcal/mol, with
P. aeruginosa, −7.72 kcal/mol with E. coli and −7.83 kcal/mol with
D. Kumar, S. Gihar, M.K. Shrivash et al.
S. aureus, respectively along with π-bond and Hydrogen bonds. Docking
image along with bonds and distances of grafted chitosan were shown
in Fig. 8.
4. Conclusion
Chitosan has the desired properties for safe use in biomedicine,
pharmacology and wastewater treatment. However, due to its insol-
ubility in neutral and basic aqueous media, its application is limited.
Grafting is a highly attractive method to improve chitosan's solubil-
ity and enhances its applications. Moreover, the grafting method is
applied to attach several new functional groups and side-chain
onto the chitosan backbone to control the cationic hydrophobic
and anionic properties of a graft copolymer of chitosan. In this re-
view, we have described the various methods of grafting and the po-
tential applications of grafted chitosan. The characteristic properties
of grafted chitosan have been controlled by the properties of the
grafted side chains. The published literature demonstrates that the
grafted chitosan has great antimicrobial activities, biocompatible
Fig. 8. Showing molecular docking and binding affinity of grafted chitosan with contracted amino acid of pathogens [(A) with E. coli, (B) with S. aureus, (C) with P. aeruginosa] (reproduced
from Kumar et al. [6], with permission from Elsevier).
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International Journal of Biological Macromolecules 163 (2020) 2097–2112
properties and cell growth efficiency. Therefore, grafted chitosan
has the potential to be used in cardiovascular applications, in
wound-healing management and targeting drug release studies.
The great sorption capabilities of grafted chitosan for metal ions
and dye molecules can be of great use for wastewater treatment
and the recovery of metals and also the treatment of polluted efflu-
ents. The published literature also shows that grafted chitosan is a
promising substance for biomedical applications. In the future, the
production and clinical use of new graft copolymers of chitosan
will provide a new approach in biomaterial scientific research of
commercial importance.
Acknowledgements
The authors acknowledge specially to Dr. Jyoti Pandey, Assistant
professor, Chemistry department, BBAU Lucknow for her kind co-
operation and help during this research. The authors are also very
thankful to University Grants Commission, New Delhi for the financial
support to carry out this work.
D. Kumar, S. Gihar, M.K. Shrivash et al.
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