Materials Science and Engineering C 68 (2016) 929–938

Contents lists available at ScienceDirect

Materials Science and Engineering C

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

Review

Modification of polysaccharides: Pharmaceutical and tissue engineering

applications with commercial utility (patents)
Rishabha Malviya a,b,⁎, Pramod Kumar Sharma a, Susheel Kumar Dubey c
a
Polymer Science Laboratory, Department of Pharmacy, School of Medical & Allied Sciences, Galgotias University, Greator Noida, UP, India
b
Department of Pharmacy, Uttarkhand Technical University, Dehradun, Uttarkhand, India
c
Siddarth Institute of Pharmacy, Dehradun, Uttarkhand, India

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

Article history: Polymer modifications open new era for the development of polymers with requisite properties. Use of modified
Received 12 May 2016 polymers is practically boundless. Different studies focus on biomedical applications of chemically modified poly-
Received in revised form 8 June 2016 saccharides. Development and utilization of modified polysaccharides get attention to be used as carrier for phar-
Accepted 29 June 2016
maceutical drug delivery as well as tissue engineering scaffolds. Grafted polymer shows better cellular
Available online 30 June 2016
regeneration, signal transmission, diagnostic and imaging material than putative form. This review article aims
Keywords:
to discuss various approaches to modify naturally derived polymer and their applications as pharmaceutical
Modified polymer drug carrier and as a material for wound dressing and artificial cartilage due to better biophysical cues. Manu-
Co-polymer script included various patents based on the applications of modified polymers and techniques used to modify
Grafting polymers.
Drug delivery © 2016 Elsevier B.V. All rights reserved.
Tissue engineering
Scaffolds
Patent

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929
2. Classical methods for grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
3. Microwave based grafting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
4. Pharmaceutical applications of polymer modifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931
5. Applications depend upon ionic nature of modified polymer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
6. Tissue engineering applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
7. Use of synthetic copolymers in tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
8. Use of thermosensitive grafted polymers in tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
9. Induction of pharmacological activities and use in tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
10. Use of grafted polymers in targeted cellular delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934
11. Other applications of grafted polymers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 936

1. Introduction

⁎ Corresponding author: Department of Pharmacy, School of Medical & Allied Sciences,
Galgotias University, Plot No 2, Sector 17-A, Yamuna Expressway, Greator Noida, Gautam
Buddh Nagar, UP, India.
E-mail addresses: rishabhamalviya19@gmail.com,
rishabha.malviya@galgotiasuniversity.edu.in (R. Malviya).
Polymer is made up of two words; polus (means many) and meros
(means parts). So polymer by its name shows a structure which is
made of repeating units (Fig. 1). Term polymer was coined by Jacob Ber-
zelius in 1883 [1].

http://dx.doi.org/10.1016/j.msec.2016.06.093
0928-4931/© 2016 Elsevier B.V. All rights reserved.
930 R. Malviya et al. / Materials Science and Engineering C 68 (2016) 929–938
Fig. 1. Schematic diagram of polymerization.
Polysaccharides such as gum and mucilages are abundant, plentiful,
cheap and widely used in pharmaceutical confectionary and food indus-
try. Natural polysaccharide (gums and mucilages) have been explored
for their uses in food industry, paper and textile, cosmetics and pharma-
ceutical industry. Increasing demands of polymer for different purposes
open the door for the search of new polymers from renewable re-
sources. Contents of any natural polymer depend upon environmental
conditions of growth, fermentation process and culture media. Proper-
ties of polymer are depends upon their content. Basic properties such
as swelling, solubility, mucoadhesion etc. are varying from polymers ob-
tained from plants grown in different conditions [2].
In the formation of gel, linear gums and mucilages occupy more vol-
ume of water as compared to branched polysaccharides. That's why lin-
ear homogenous polysaccharide show less viscosity than branched
polysaccharide for same concentration. Some polymer also shows
change in viscosity during storage and viscosity of polymer may be
maintained by the modification of polymer [2,3].
As for we know it is the first kind of report deals with various
grafting techniques with pharmaceutical and tissue engineering appli-
cations together in a single manuscript.
Modified polymers show superior properties to the source crude
material in terms of solubility, swellibility, mucoadhesion, sorbency,
coagulancy and floccolancy i.e. transformation into customizable mate-
rial. pH sensitivity of polymer attributed due to presence of free –COOH,
–OH,–CH2OH, −NH2 etc. groups. Swellibility and solubility of polymer
characterized in terms of hydrophilicity, hydrogen binding and ioniza-
tion. Modifications of these groups entirely changes their properties
hence responsiveness towards pH.
Derivatization of natural gums, pectins and mucilages result in de-
velopment of high performance biological macromolecules. Polymer
modification may be required to target drug at required site, to change
solubility of polymer, to improve thermal stability of polymer, to make
biodegradable polymer, to reduce toxic effect of drug, to make polymer
moisture resistant, to make controlled hydration, to make polymer
more microbial resistant, to improve transparency of polymer and to
improve moisture sensitivity. Modified polymer has been found as sta-
bilizing agent in nano-composite system. Most of the gums are hydro-
philic in nature and so soluble in aqueous medium. Due to this reason
they become irresponsive in organic solvents. Controlled introduction
of small or long hydrocarbon chain on the polymer backbone results
in the formation of new derivatives having both hydrophilic and hydro-
phobic region in their molecular structure. They may act as surfactant
and can form micelle in solution. This property of gum may affect sol-
gel transition in aqueous solvent.
Characteristics of these polymers can be altered by formation of
cacervates and polyelectrolytic complex, grafting of polysaccharide
backbone with other synthetic or natural polymers and derivatization
of groups by another chemical moieties [3]. In new era of civilization
naturally derived polymers are replaced by their modified form. Poly-
mers can be modified by using following three methods:
1. Blending: In blending physical mixture of two or more than two
polymers are prepared to induce required characters (Fig. 2).
2. Grafting: In grafting method different monomers are covalently
linked to the polymer and degree of binding and chain length of
monomer defined the properties of polymer. Grafted polymer con-
sists of macromolecular chain with one or more monomers attached
to the main chain as side chain. Grafting is a way to add desired
Fig. 2. Schematic diagram of blending.
properties in polymer without significant loss of initial characteris-
tics of polymer (Fig. 3).
3. Curing: In this method oligomer mixture is used to adhere over sub-
strate to form a coating. Binding of oligomer mixture is due to phys-
ical forces (Fig. 4).
Natural polysaccharide (gums and mucilages) generally contain –
OH groups. In alkaline medium these –OH groups, donates it hydrogen
to generate –ve ion on the backbone of gum. This ionic gum can attack
carbon atom of epoxy or ester group to form vinyl derivatives of gum.
Vinyl derivatives are prepared either by esterification reaction or nucle-
ophilic substitution reaction. Maleic anhydride, acryloyl chloride, acrylic
acid, glycidyl methacrylate has been successfully used to form vinyl
functionalized gum. Extent of degree of substitution/ modifications
also depends upon stearic hindrance caused by –OH group present in
gums/mucilages. Free –CH2OH groups present at side chain and ex-
treme are more susceptible to modification. Schematic diagram of reac-
tion is shown in Fig. 5.
Grafting of another synthetic monomer units over natural polymers
alleviate limitations of natural polysaccharides. Grafting lead to comb or
brush type graft copolymers. Linear backbone with high grafting density
of side chain is the characteristics of brush type graft copolymers while
comb type graft copolymers are characterized by a polymer backbone
covalently bonded with one or more side chain [4].
Schematic diagram of techniques of grafting are shown in Fig. 6.
In Free radical formation technique an external radical inducing
agent is used to produce free radical at main backbone of the polymer.
After formation of free radical sites, monomer can get added up through
chain reaction and formation of grafted chain takes place. Generally no
initiators are used in microwave initiated technique of grafting. In mi-
crowave assisted initiators are used to produce free radicals. In both mi-
crowave initiated and microwave assisted techniques of grafting
microwave energy convert into heat energy due to dipolar relaxation
of water (solvent) or localized rotation of polar functional groups of
polysaccharides. In plasma radiation induced grafting excited electrons
transferred their energy from plasma to polysaccharides and leads to
cleavage of bonds, which further produces free radicals. Enzymes are
used in reaction mixture, which produces reactive moieties with sub-
strate in enzymatic grafting. These reactive moieties further react to
produce graft- co polymer. In photochemical grafting; polysaccharides
contain chromophore, absorb light and excited electron leads to forma-
tion of free radicals. Redox grafting method has less control for mono-
mer distribution over crude biopolymer. Free radical should not
rapture the original backbone of parent polymer. Grafting through liv-
ing polymerization (or living radical polymerization) shows better con-
trol over monomer distribution and less influenced by presence of
moisture [4].
Fig. 3. Schematic diagram of grafting.
 R. Malviya et al. / Materials Science and Engineering C 68 (2016) 929–938
Fig. 4. Schematic diagram of curing.
2. Classical methods for grafting
In classical methods of polymer derivatization, reaction are carried
out in closed vessel may create problem due to generation of high
pressure during reaction and also limit the maximum use of reactant
(40–50 g).
Free radical based reactions essentially involve specific concentra-
tion of radical/redox initiators (e.g. ferrous ammonium sulfate/potassi-
um persulphate, ethylene diamine tetraacetic acid/ceric ammonium
nitrate, ceric ammonium nitrate/nitric acid). It is a widely used tool for
functionalization of polysaccharides but require inert environment for
reaction to proceed. It is also a time consuming process.
In conventional methods reaction is carried out in inert environment
because presence of oxygen in air inhibits radical formation. Microwave
based polymer grafting have advantage as reaction can be carried out
under atmospheric environmental conditions. In conventional methods
of grafting oxygen is act as inhibitor hence should be expelled out before
reaction proceed but in microwave based methods it is not required to
expel oxygen. Use of free radicals initiator can be limited by using
other sources such as microwave radiation, Ƴ radiation and UV
radiation.
3. Microwave based grafting
In polymer synthesis, classical methods should be replaced by mi-
crowave technique. Microwave based synthesis is adopted for higher
yield, better selectivity, higher reaction rate, less solvent, minor energy
consumption and better compatibility with environment due to less
waste material. Use of microwave radiation reduces reaction time and
contact between crude material and toxic organic solvents. It also im-
proves yield of grafted polymer. Microwave technique is used to modify
biopolymer without using harsh conditions and high temperature [5].
Fig. 5. Nucleophilic substitution reactions of natural gum and mucilages.
931
Microwave radiation induces vibrational movement of molecules;
therefore heat generation takes place within molecules. Intensity of vi-
bration is function of quantity of heat generated within molecules.
Quantity of radiation absorb by sample molecule depends upon polariz-
ing power of molecule, intermolecular binding as well as shape and size
of molecules. Polarizing power of molecules depends upon dielectric
constant of vibrational movement [6]. Due to microwave radiation di-
poles formed and tend to align with the direction of electric field. In mi-
crowave direction of electric field changes simultaneously and
preformed dipoles do not change their direction as fast as changed by
electric field, resulting in generation of heat in the medium. Generation
of heat within the medium is function of ability of medium to convert
electromagnetic energy in to heat energy. The input energy in micro-
wave based synthesis should be optimized so that solvent system of re-
action does not approach its boiling point. In microwave based
synthesis sometimes solid base is used but reduces rate of reaction. It
has been studied by researchers that analysis of sugar molecules and
their linkages can be performed in less time as compared to convention-
al methods [7,8]. Schematic diagram of microwave based synthesis is
shown in Fig. 7.
In conventional methods of heating, heat transfer from source to ex-
ternal surface of reactants, but in microwave methods heat generates
with the reactant to promote more effective reaction with relatively
less time. Generally grafting are carried out in aqueous medium where
water molecules itself polymerize to form dipole resulting in bulk
heating. In the presence of inorganic salts water molecules easily con-
vert microwave energy into heat energy due to polarization of aqueous
medium and ionic conduction of heat due to ionization of added salts.
Microwave based grafting shows higher yields and rapid grafting
whereas use of free radical initiators is also not necessarily required.
So microwave initiated grafting is eco friendly. In some case radical ini-
tiation are also added which create ionic drift and resulting in better
heating [9,10].
4. Pharmaceutical applications of polymer modifications
Modified polysaccharides show complete drug release due to their
biodegradable nature in intestine while synthetic polymer may show
incomplete drug release. Grafted polymer has been used for targeted
drug delivery especially for colon targeting due to their neutral pH,
longer transit time and reduced enzymatic activity [11]. Konjak
932 R. Malviya et al. / Materials Science and Engineering C 68 (2016) 929–938
Fig. 6. Various methods of grafting.
glucomannan co-polymerized with acrylic acid and crosslinked by N,N
methylene-bis-(acrylamide) was used for colon targeting. Copolymers
may be used as active targeting carriers and controlled drug distribu-
tion, a key factor for effectiveness of drug delivery system [12]. Deriva-
tization of hydrophobic polymer extends drug release days to weeks
[13,14].
Cardia myxa polysaccharide was extracted in one study and modi-
fied into polysaccharide-g-poly (acrylonitrile) copolymer. Modified
polysaccharide was used to prepare mucoadhesive tablets for targeted
delivery of an antihypertensive drug captopril in to stomach. It was
also observed that modification of Cardia myxa polysaccharide also in-
creases mucoadhesive properties of polymer [15].
Water penetration hence swelling properties of gum also increases
with modification. It is a desired feature when water is required to
avoid dryness. Water holding capacity becomes very important to pro-
mote cell implantation and drug delivery [16]. Bacterial cellulose having
good mechanical strength has modified using acrylamide shows better
Fig. 7. Common procedure for microwave based grafting.
drug entrapment efficiency and more porosity as drug carrier. Hydrogel
shows pH sensitive swelling behavior and better release profile when
evaluated in vitro [17].
Gum Arabic a polysaccharide consists of glucuronic acid with galac-
tose, arabinose and rhamnose. Gum Arabic has been used as emulsify-
ing agents in food industry and pharmaceutical formulations in the
concentration of 15%. Chemical modification of gum increases its emul-
sifying properties [18]. Encapsulation efficacy of gum can be increased
by esterification using alkane or alkene substituted dicarboxylic acid an-
hydride (eg. octenyl succinic anhydride. Encapsulation property is de-
pends upon length as well as amount of alkyl chain attached to gum
[19–21]. Polysaccharide (gellan gum) has been undergone microwave
assisted free radical polymerization using acrylamide as copolymer.
Modified gellan gum based tablets show drug (metformin hydrochlo-
ride, an antidiabetic molecule) release up to 8 h when evaluated in
vitro [22]. pH responsive polymers has been prepared by controlled
graft polymerization of poly (acrylamide) over HPMC backbone under
microwave irradiation. Grafted polymer shows targeted delivery of
ornidazole in to intestine without showing any significant drug release
in to gastric ph of stomach [23]. Grafting of vinyl derivatives such as ac-
rylamide on to crude material improves flocculating properties of poly-
mer. Vinyl derivatization of polymer also improves adsorption
properties of polysaccharides towards metal ions and contaminants.
Vinyl derivatization of polymers shows stimuli dependent drug delivery
due to improved pH sensitivity of polymer [24]. Methacrylic acid
grafted guar gum has been successfully used for the colon targeted de-
livery of metronidazole [25]. Cynoethylation based gum shows
pseudoplastic flow, greater viscosity, and more solubility and formed
a clear solution than putative form [26]. Poly (acrylic acid) derivatives
shows high tendency towards water hence limit their uses as drug de-
livery carrier due to prior drug release before reaching to absorption
site. It becomes necessary to crosslink with appropriate linkers to
form interpenetrating network system. Use of cross linker also inhibits
their ability to respond towards stimuli [27]. Polysaccharides also
form linkage in the presence of metallic ions. Metallic ions form co-or-
dinate bonds with polysaccharides and this type of binding is stronger
than ionic binding of interpenetrating networks system [28].
It was found that poly (acrylamide) derivatization of guar gum also
improves sensitivity towards pH and ionic strength. Swelling behavior
of polyacrylamide guar gum microgels also increases with pH of external
phase. Also drug release pattern changes from super class II to non-Fickian
when pH changed 0.1 M HCl to phosphate buffer pH 7.4 [29,30]. Some of
the applications of modified polymers are tabulated (Table 1).
 R. Malviya et al. / Materials Science and Engineering C 68 (2016) 929–938 933

Table 1
Pharmaceutical applications of modified polymers.

S. no. Polymer details Application Reference

1 Carboxymethyl chitosan-graft-acrylamide Acrylamide grafted polymers were successfully used as flocculating agent to remove both cationic and [31]
anionic dyes from their aqueous solutions.
2 Vinyl modified guar gum Adsorbent material was prepared by the condensation of tetraethoxysilane in the presence of vinyl [32]
modified guar gum.
3 Poly(methylacrylate) functionalized guar gum Poly(methylacrylate) functionalized guar gum was used to remove chromium (VI) from aqueous [33]
solution and adsorption is dependent upon pH.
4 Partially carboxymethylated guar gum modified Modified polymers shown better water holding capacity and flocculating agent in aqueous solutions. [34]
with 4-vinyl pyridine
5 Xanthan gum-g-poly(ethylacrylate) Xanthan gum-g-poly(ethylacrylate) adsorb Pb2+ ions four times compare to the xanthan gum. [35]
Adsorption of Pb2+ ions followed Langmuir isotherm model
6 Acrylamide and methacrylic acid crosslinked Acrylamide and methacrylic grafted Gum ghatti was found to be cation exchange properties and act as [36]
Gum ghatti super absorbent.
7 Guar Gum-g-poly(sodium acrylate) / Guar gum-g-poly(sodium acrylate)/Na-montmorillonite uperabsorbent nanocomposites were [37]
Na-montmorillonite synthesized by grafted copolymerization of guar gum with acrylic acid and Na-montmorillonite and
was found to be better sorbent and exhibit pH resistant.
8 Acrylamide grafted Gum ghatti Electrical stimulus sensitive crosslinked network of gum ghati-acrylamide was prepared and it was [38]
observed that swelling and de-swelling of material depends upon electrical stimuli.
9 Guar gum- Synthesized guar gum-graft-poly-(acrylamide-co-diallyldimethylammonium chloride have wood pitch [39]
graft-poly-(acylamide-co-diallyldimethyl fixative properties.
ammonium chloride
10 Plasma enhanced modified xanthan gum Xanthan gum (XG) modified in a cold plasma environment was found to be improved gelling properties [40]
than native form.
11 H-partially corboxymethylated guar Partially hydrolyzed graft co-polymer (H-partially corboxymethylated guar gum-g-methacrylic acid) [41].
gum-g-methacrylic acid was found to be thermally more stable than partially corboxymethylated guar gum. So grafting with
methacrylic acid on –OH group of partially corboxymethylated guar gum increases thermal stability of
polymer.
12 Poly(acrylonitrile) grafted ipomoea seed gums Ipomoea seed gum was grafted with acrylonitrile and grafted polymer shown better water sorbent and [42]
viscosity enhancer specially where medium to low viscosity with good shelf life is required.
13 Acrylamide grafted xanthan gum Xanthan gum was grafted with acrylamide using microwave irradiation and successfully used for colon [43]
targeted drug delivery as grafted polymer was more succiptible to colonic microbial content.
14 C-glycosylated guar gum C-glycosylated guar gum was prepared have grafted polymer shown significant anti-inflammatory and [44]
anti-cancerous properties.
15 Acrylic acid grafted guar gum-nanosilica Guar gum was grated with acrylic acid and trasdermal drug delivery system was prepared using grafted [45]
membrane polymer and nanosilica membrane.
16 Grafted gum karaya and silica hybrid Grafted gum karaya and silica hybrid nanocomposite was prepared and nanocomposite was found to be [46]
effective adsorbent for the removal of methyl blue.
17 Gum Arabic grafted cyclodextrin Cyclodextrin-citrate-gum Arabic modified magnetic nanoparticles were prepared and successfully used [47]
as carrier for ketoprofen delivery.
18 Gum ghatti cross linked with poly(acrylic acid Nanaocomposite material was prepared using gum ghatti crosslinked with poly(acrylic [48]
-co-acrylamide) acid-co-acrylamide) and further reinforced with reinforced with iron oxide magnetic nanoparticles and
successfully use fir the removal of rhodamine B.
19 Gum ghatti grafted Poly Gum ghatti grafted poly(acrylamide-co-methacrylic acid hydrogel shown better flocculating and [49]
(acrylamide-co-methacrylic acid adsorption properties as compared to native polymer.
20 Acrylamide grafted gum ghatti Acrylamide grafted Gum ghatti was found that swelling of grafted polymer responsive towards [50]
Temperature, pH and electric stimulus.
21 Poly(acrylamide-co-acrylonitrile) grafted Gum Poly(acrylamide-co-acrylonitrile) grafted Gum ghatti hydrogel was prepared and it was found that [51]
ghatti absorbent properties of hydrogel responsive towards salt, pH and temperature.
22 Gum ghatti-cl-poly(acrylamide-aniline) Gum ghatti-Cl-poly(acrylamide-aniline) interpenetrating network was used as novel electrically [52]
conductive biomaterials.
23 Modified gum Arabic with glycidyl Glycidyl methacrylate, acrylic acid, and acrylamide grafted Gum Arabic shown Better swelling ability [53]
methacrylate, acrylic acid, and acrylamide and improved mechanical strength.
24 Acrylamide grafted gum ghatti Improved biodegradability and flocculation properties were shown by acrylamide grafted gum [54]
hydrogel.
25 Gum ghatti-grafted Gum ghatti-grafted poly(acrylamide-co-acrylonitrile) Biodegradable Hydrogel was used to remove [55]
poly(acrylamide-co-acrylonitrile) Pb2+ and Cu2+ from aqueous solutions.
26 Gum ghatti- Cl-poly(acrylic acid-aniline) Gum ghatti-Cl-poly(acrylic acid-aniline) grafted polymer shown better water absorption properties so [56]
can be used to improve water retention capacity of soil.
27 Adipic dihydrazide grafted gum Arabic Nanoparticles were synthesized by coupling doxorubicin (DOX) to adipic dihydrazide-grafted gum [57]
Arabic simultaneous imaging, sensing and targeted intracellular delivery of doxorubicin.
28 Gum ghatti-g-poly(acrylic acid-aniline) Gum ghatti-g-poly(acrylic acid-aniline) based interpenetrating network system was used for the colon [58]
delivery of amoxicillin trihydrate and paracetamol.
29 Poly(acrylamide-aniline)-grafted gum ghatti Synthesized Poly(acrylamide-aniline)-grafted gum ghatti [Gg-cl-poly(AAm) shown better [59]
[Gg-cl-poly(AAm) biodegradability.
30 Polymethylmethacrylate grafted psyllium gum Polymethylmethacrylate grafted psyllium gum was synthesized and proved as better flocculent than [60]
native polymer.
31 2 hydroxyethyl methacrylate grafted Multi walled carbon nanotube composites were prepared using 2 hydroxyethyl methacrylate grafted [61]
carboxymethyl guar gum carboxymethyl guar gum for transdermal delivery of diclofenac sodium.
32 Polyacrylamide grafted Gum acacia Effects of O7+ and Ni9+ swift heavy ions irradiation on polyacrylamide grafted Gum acacia thin film [62]
was studied and it was observed grafted polymer can be used to adsorb methylene blue from solution.
33 Poly (sodium acrylate) guar gum Super sorbent for water. [63]
34 Methacrylate-guar gum Colon targeted delivery of metronidazole. [64]
35 Polyacrylamide-g-guar gum Colon targeted delivery of diltiazem. [65]
36 Polyacrylamide grafted pectin Film former for controlled drug delivery. [66]
934 R. Malviya et al. / Materials Science and Engineering C 68 (2016) 929–938
5. Applications depend upon ionic nature of modified polymer
Different amphoteric derivatives of gum are prepared recently. Am-
photeric derivatives has both cationic and anionic region at polymer
backbone. These amphoteric derivatives receive attention in chemical,
paper making, packaging and water treatment. They are prepared by si-
multaneous reaction with cationic and anionic monomers. Basic disad-
vantages of amphoteric derivatives are that concentration of both
cationic and anionic region difficult to control. Amphoteric modifier
can be used to modify gum with pre-specified ratio of cationic–anionic
ratio.
Introduction of some functional group such as imino, quaternary
ammonium, quaternary phosphonium and sulphonium over the back-
bone of gum and mucilages results in formation of cationic derivatives.
They become carrier for anionic drugs and dyes due to selective interac-
tion. They can be used for selective filtration and flocculent. These poly-
mers are also less responsive towards pH due to presence of cationic
regions that cannot be easily protanated.
In different experiment it has been observed that hydroxylethyl de-
rivatives of polysaccharide have better dispersibility, stability and solu-
bility than their parent's molecules. They also have better compatibility
towards ionic and non-ionic surface active agents, that's why they re-
ceive more attention in food and cosmetic industry.
Grafting of –COOH or –COONa groups into polymer backbone con-
vert a non-ionic gum into anionic form. Both –COOH and –COONa
groups improved hydrophilicity, aqueous solubility, swelling and hy-
dration characteristics of grafted polymer as compared to parent poly-
mer. Sensitivity of polymer also increases towards pH and electrolyte
open a new door to be used for stimuli sensitive biomedical purposes.
As they have negative charge so can be used to selectively carry cationic
molecules [67,68].
Some of the patents based of the applications of modified polymers
are shown in Table 2.
6. Tissue engineering applications
Grafted polymer have combined properties of both polysaccharide
backbone i.e. biodegradability and synthetic copolymer i.e. mechanical
strength, flexibility etc. Grafting also improves tendency of modified
polymer towards contaminants. It is observed that grafting shows pos-
itive impact on cell attachment and proliferation. Modified natural poly-
mers act as conductive materials for stimulation of cells, biosensing and
bioengineering applications. Modified polysaccharides have great water
holding capacity and consistency. They resemble cellular structure.
Grafting of polymers changed swelling behavior as well as enzymatic
degradation in the biological fluids. Grafted polymers are also less sus-
ceptible to microbial growth. Cell proliferation, growth, function and re-
generation depend upon mechanical input to the cells. Modified
polysaccharides mimic act as scaffolds and provide better pre and post
gel properties and flow behavior when introduce at the cell level.
Grafted polysaccharides have solvent properties and good miscibility
with cellular component and converted to gel when injected in vivo.
Scaffolds have good mechanical properties to bear loads of cells/tissues
and maintain their requisites. Biodegradability (hydrolysis, enzymatic
cleavage and dissolution) increase positivity towards used of natural
polymer based scaffolds. Scaffolds provide transport facilities for gases,
minerals, vitamins, proteins and waste materials of cells. Scaffolds
have ability to imbibe large amount of cellular fluid and water and
maintaining positive interactions with cells. Biocompatibility and bio-
degradability added positiveness to be used in tissue engineering.
They can be used as carrier for stem cells. Gelatin and collagen contains
receptor sites for fibronectin like proteins and hence promote tissue re-
generation and osteogenesis e.g. gelatin grafted gellan gum micro-
spheres were used to deliver living cells to damaged tissue for better
regeneration [109].
7. Use of synthetic copolymers in tissue engineering
Use of synthetic copolymers limit the applications of modified form
due to low hydrophilicity and lack of cell recognition sites, while poly-
saccharides easily interact with cell components because carbohydrates
are essential components of cells and present as adhesion molecules,
glycoprotein and glycosides [110]. Synthetic polymers have some disad-
vantages but they have been used for tissue engineering approaches e.g.
polyurethane and polycaprolactone were grafted by poly (acrylamide),
poly (methacrylic acid), or poly (N,N-dimethyl aminoethyl methacry-
late) and modified polymers showed better endothelial cell adhesion
[111], methyacrylate gellan gum acts as a barrier for angiogenesis and
enhances cell viability [112].
8. Use of thermosensitive grafted polymers in tissue engineering
Thermosensitive grafted copolymers are getting more attention be-
cause they are solution at storage temperature (low temp) but form
gel above lower critical solution temperature which is designed below
body temperature [113] e.g. poly (N-isopropylacrylamide is a
thermoresponsive polymer grafted over alginate backbone to form
thermoresponsive biodegradable polymer as an injectable scafoolds
and improved cell viability of human bone mesenchymal stem cells
[114]. Grafting of N-isopropyl acrylamide on to chitosan backbone im-
proved temperature responsiveness and mechanical properties of poly-
mer [115]. A temperature responsive copolymer was prepared by poly
(N-isopropylacrylamide) grafting over methyl cellulose. Grafted poly-
mers showed gel formation at body temperature and gelation proper-
ties vary with content of methyl cellulose. Researcher also concluded
that poly (N-isopropylacrylamide) grafting methyl cellulose can be
used as barrier for blood vessel [116].
9. Induction of pharmacological activities and use in tissue
engineering
Grafting on polymer backbone also induces pharmacological activity
in the polymer e.g. poly(n-vinyl imidazole) grafted carboxymethyl chi-
tosan showed antimicrobial activity [117], 2 hydroxyethyl methacrylate
and acrylic acid grafted chitosan have wound healing properties [118],
gellan gum grafted by cinnamate moieties have anti-inflammatory ac-
tivities [119].
10. Use of grafted polymers in targeted cellular delivery
Stearic acid grafted chitosan was used to prepare nanoparticles for
the targeted delivery of paclitaxel in cancerous cells [120]. Literature
also shows that carbohydrates grafted with amine terminated
poloxomer can be used to form slow release network system for cipro-
floxacin and growth harmone [121,122]. Chitosan grafted by polyethyl-
ene glycol releases bovine serum albumin over 70 h [123,124]. In one
study Poly-l-lactic acid grafted by vinyl monomers and modified poly-
mer showed better cell adhesion and viability when studied in cultured
media [125]. Grafted polymer of N-isopropylacrylamide and
methacrylic acid have been used as template to prepare magnetic nano-
particles. Tumor targeted delivery of doxorubicin loaded nanoparticles
are evaluated using A549 lung cancer cell line [126]. Poly (ethylene
imine)-graft –poly (ethylene glycol) block copolymer/Si RNA
polyplexes have been prepared and successfully used for the cytoplas-
mic delivery of Si RNA. Polyplexes also provide protection against
RNase degradation based on poly (ethylene glycol) chain length [127].
1 ethyl-3-(3 dimehtyl amono propyl) carbodiimide crosslinked gellan
gum film was used to prevent scar formation and possessed
antiplatelates properties [128]. Methacrylic acid copolymerized
polycaprolactone membrane linked gelatin was used to improve
cytocompatibility of polycaprolactone towards human endothelial
cells [129]. In a research blends of poly-(Ɛ-caprolactone) and starch,
 R. Malviya et al. / Materials Science and Engineering C 68 (2016) 929–938 935

Table 2
List of patents based on modified polymers.

S. No Patent No. Objective Reference

Patents based on the applications of modified polymer:

1 WO2015091160 A1 Polysaccharide was modified to prepare a derivative which can be used as cleansing agent and anti-graying agent in [69]
laundry.
2 US8932858 Hydroxyethyl cellulose was modified using lauryl acid chloride to from hydrophobic derivatives that was successfully [70]
used for cell culture and shown better adhesive properties than parent polymer.
3 US 20150010494A1 Polysaccharide was oxidized and further formed conjugates with protein which further increases half life of protein [71]
and thus activity for long time.
4 US8877216 Siloxane derivatives of polysaccharide were prepared that have better properties to be used in cosmetics and skin [72]
care products.
5 US8859724 Chitosan was grafted using heparin and chondroitin sulfate and derivatives act as carrier and shown better [73]
pharmacological activity.
6 WO2014152269 A1 Modified guar gum and further used for the preparation of soft gelatin capsules for pharmaceutical drug delivery. [74]
7 US20130034516 A1 Cationic derivatives of dextran and hydroxypropyl cellulose were prepared using glycidyltrimethylammonium [75]
chloride and N-acrylamidopropyl-N,N,N-trimethylammonium chloride that was potentially used for neutralization of
heparin present in blood and other biological fluids.
8 US 20120213725 A hydrophobically-modifed polymethacrylate (acrylates/beheneth-25 methacrylate – Novethix L10 polymer from [76]
Lubrizol) finds use in difficult-to-thicken zwitterionic surfactant systems.
9 9,211,424 Hydrophobically modified sugars have been brought forward as a way to impart durable semi-permanent shape to [77]
the hair by L'Oréal researchers.
10 US20120216823 For example N-propionylethyleneimine/dimethylsiloxane copolymer applied to the hair allows the hair to conform to [78]
a desired style that can be re-shaped by heating the hair to about 50 °C with a hair dryer.
11 US20120237465 The hydrolytic character of polymers is reported to be improved by the use of dimethylaminopropyl methacrylate [79]
and substantially improved by the use dimethylaminodimethylpropylmethacrylate.
12 US 20120230934 Cationic hydroxypropylcellulose confers both good feel and good manageability to the hair. [80]
13 US 20120201774, US 20120207695 In a continuation of the trend towards sustainable materials, hydroxypropyl starch has been shown to be an effective [81,82]
fixative for temporary styling of hair even in a high humidity environment.
14 US 20120237462 Hydroxypropyl starch phosphate (Structure XL from Akzo Nobel) enhances the viscosity and stability of formulations [83]
thickened with conventional associative thickeners.
15 EP2241579 A1 Gum Arabic was modified by change in temperature and further evaluated for emulsifying properties. Thermally [84]
modified gum shown better emulsification properties.
16 US20040228826 Silicone derivatives of resin were prepared that have antimicrobical properties, [85]
17 WO2004064777 A3 Pectin was modified further used with improved anticancer activity. [86]
18 WO2003080134 A1 Chitosan and cellulose were corboxylated and used as wound dressing material because of antioxidant activity of [87]
polysaccharide derivatives.
19 WO 1999064468A1 Gellan gum was modified to form acetylated guar gum in the presence of base. [88].
20 US5273767 A Prepared rapidly hydrating xanthan gum and guar gum having better gelling properties as compared to native [89]
polymer.
21 WO1984003053 A1 Modifications of cellulose to prepare various hydrophilic and hydrophobic derivatives. [90]
22 US4298729 A Inventors modified starches with xanthan gum. It was concluded after study that xanthan gum modified starches [91].
shows properties as chemically-modified pregelatinized starches.
23 US2995513 Starch was modified to prepare ether derivates that have better flocculation properties. [92]
24 232,922 Cassia tora gum was modified by treatment of ammonia gas and modified gum shown better properties as flocculent [93]
in paper industry, for mud settling in sugar industry and as thickener in textile industry.

Patents based on modification technique:

25 US6846882 B2 Developed a method to modify acid group containing polymer with sulphor. [94]
26 213,493 Craboxymethyl guar gum was prepared and films were formulated using modified gum. Prepared film shown better [95]
clarity and controlled drug release pattern.
27 US6833491 B2 Starch and cellulose were modified naturally using glucosyl transferase enzymes and sugar group donor; without [96]
using any chemical. Modified polymers shown better applicability in food and non-food industry.
28 WO2003093324 A1 Gum Arabic was modified by the treatment of heat at specified humidity level to improve emulsifying properties of [97]
gum
29 US 6280515 Starch, dextrin, cellulose and guar gum were modified using alkyl succinic anhydride as graft monomer to prepare [98]
foamable adhesive system
30 US6398911 B1 Polysachcharide was modified to form polysiloxane derivatives that can be used as softeners, debonders, opacifiers [99]
and strength agent in paper for better applicability.
31 EP0893451 A3 Esterified starch in densified supercritical carbon dioxide without using any solvent. [100]
32 US3438970 Starch was modified to form cynamide derivatives that have better stability than native starch. [101]
33 US3380799 Anionic derivative of cellulose was prepared after reaction of cellulose and cynamide. [102]
34 US3415927 A GUAR gum was modified by heat and modified guar gum shows better dispersible properties. [103].
35 US3228928 A Developed a method to oxidized Locust bean gum and Guar gum using periodate. [104]
36 US2644763 A Modified locust bean gum and after study it was concluded that modified locust bean gum has better dispersibility in [105]
aqueous solutions.
37 US2644765 A In this study locust bean gum was modified and modified polymers have better dispersing properties. [106]
38 US1942544 A Developed a new process for modification of starches, dextrines, and British gums by chlorination and oxidation [107]
process.
39 WO 1995006069A1 Developed a method of modification of gum by direct fluorination. [108]

dextran and gellan gum were prepared and showed receptor mediated
adhesion in fibroblasts culture [130]. In one study gelatin-chondroitin-
hyaluronan tri copolymer scaffold was synthesized to mimic animal car-
tilage. These copolymers are biodegradable and mimic extra cellular se-
cretions. Due to biodegradable nature this grafted polymer better suits
over synthetic derivatives for cartilage tissue engineering [131].
Collagen-glycosaminoglycon copolymer bsed scaffols has been used as
artificial skin substitute [132]. Sulfobetain-grafted poly (vinylidene fluo-
ride) membrane showed better blood compatibility, controlled protein
absorption on the cell membrane, platelet activation and controlled
plasma clotting with less blood cell hemolysis [133]. Nanoparticles
entrapped in polypropylene-G-poly (ethylene glycol) graft copolymers
936 R. Malviya et al. / Materials Science and Engineering C 68 (2016) 929–938
incorporated showed less inflammatory reaction as compared to pure
nanoparticles when implanted in skin. It was also observed by SEM
study that high branched peg create less inflammation as compared to
low molecule weight peg. Poly (propylene fumurate-co-ethylene gly-
col) has synthesized as an injection carrier for bone transplant and tis-
sue engineering [134]. Guar gum methacrylate hydrogels were
prepared and shown significant cell viability and proliferation when
evaluated with human endothelial cell line. It was also observed that en-
zymatic biodegradation of hydrogel decreases with increasing degree of
methacrylation [135]. Modification of gum with protein and selective
chemical moiety improves cell adhesion properties of gum and has
been successfully used as biomaterial. Peptide modified gum enhance
neural stem progenitor cell survival and proliferation as compared to
non-modified gellan gum. So peptide modified gum can be used as ve-
hicle for cell transplantation to enhance survival rates of cells [136].
Corboxymethylated (kappa-carrageenan) have been used as wound
healing matrix possessing anticougalant and anti microbial properties.
11. Other applications of grafted polymers
Modified polymers have good water holding capacity. This property
of modified polymer has been successfully used in drought. Modified hy-
drogel improves water retention capacity of soil as it releases moisture
very slowly to soil. Acrylic acid-aniline derivatives of gum ghatti can be
used for agriculture purpose. These modified polymers are also biode-
gradable and added positivity to be used as biomaterials [56]. Graft co-
polymers of (kappa-carrageenan) with N,N-dimethylacrylamide and N-
venyl formamide can be used for the treatment of coal mine waste
water [137,138]. Corboxymethylation of gum and mucilages shows
greater solubility, hydrophilicity and makes solution more clear.
Carboxymethyl derivatives of polymers show pseudoplastic behavior
when studied. These modified polymers show improved sensitivity to-
wards metal ions (divalent and trivalent). It was also observed that triva-
lent ions show better crosslinking than divalent ions [139].
12. Conclusion
Literature survey and discussion above shows that polymers can be
easily modified using microwave irradiation as compared to conven-
tional closed vessel modification. Among various modification tech-
niques, grafting has been widely used to induce desired features in
polysaccharides. There are limitless numbers of areas where modified
polymers may find use. In current scenario, environmental responsibil-
ity should be key for the development of sustained and controlled drug
delivery system. Biodegradability added positiveness towards their use
in pharmaceutical drug delivery. Biodegradable modified polymers may
be pH or thermal sensitive hence deliver drug entities in to target site.
Studies show strong support that biodegradable polymers have ability
to modulate cell signaling, cellular attachment, migration, proliferation
and differentiation. Manuscript reveals the fact that various commercial
patents have been granted for the use of modified polymer. Researches
are going on but great space for research is still now vacant. To maintain
pollution free environment manufacturing business should be make
clear vision towards use of modified biodegradable polymers in phar-
maceutical, medical, cosmetic and mine industry.
Conflict of interest
Authors have no conflict of interest.
Acknowledgement
Authors are highly thanksful to Department of Pharmacy, School of
Medical and Allied Sciences, Galgotias University, Greater Noida, for
providing library facilities.
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