Farida MoultiMati
c
Philippe Michaud
a
and Guillaume Pierre
a*
a
Université Blaise Pascal Institut Pascal UMR CNRS 6602 F63000 ClermontFerrand France
b
Université Clermont Auvergne
SIGMA Clermont Institut Pascal BP 10448 F63000 ClermontFerrand France
c
Laboratoire de Biochimie Analytique et Biotech
nologies Université M Mammeri BP N°17 RP 15000 Tizi Ouzou Algeria
A R T I C L E H I S T O R YReceived September 30 2016 Revised February 07 2017 Accepted July 22 2017 DOI 1021741385272821666170811114145
Abstract
Background
Regarded as biofunctional poly and oligomers having much
higher potential than cellulose in many fields chitosan and its derivatives have become of great interest thanks to the recent progress in chitin chemistry Chitosan which is a naturalbased polymer obtained by alkaline deacetylation of chitin is an interesting bioactive polysaccharide composed of many reactive groups Objectives
This gives huge possibilities of chemical modifications to create new deriva
tives with a broad range of physicochemical and biological activ
ities
Method and Results
Special emphasis is given here to quaternized
Nalkyl
Nacyl oxy
chitosan derivatives but also depolymerized chitosan The present review also provides insights into chitosan derivatives and their biological activities Numerous studies led for twenty years until now have put on track antimicrobial and antioxidant activities of chitosan derivatives Biomedical applications have also been addressed such as bioadhesive properties antitumor activities adsorption or chelation Recent progresses of chitosan derivatives chemistry opened the way to new developments in medical and pharmaceutical fields for example in tissue engineering or drug delivery system Finally biodegradability and environmental assessment concepts are reported Conclusion
This work highlights the need for integral and comprehensive approach to comprehend all the
biological potential of chitosan and its derivatives
Keywords
Chitosan polysaccharide bioactivity chitosan derivative chemical modification biodegradability
1 INTRODUCTION
Since two decades chitin chitosan and their derivatives re
ceived increasing attention for their use as bioactive agents and can be classified in the toprank list of the more studied polysaccharides Often considered as cellulose derivative chitin is the second most ubiquitous natural polysaccharide and is composed of
(14)
2acetamido2deoxy
D
glucose repeating units Ordered in crystal
line microfibers chitin is a highly insoluble hard inelastic white and nitrogenous polysaccharide [1] Nature has done a good piece of working and has kept both cellulose and chitin for their mechanical resistance and the possibility to isolate organisms Thus the first one is dedicated to plants and allows some interaction with water during their growth whereas the second is used for creating strong and impermeable exosqueleton of marine organisms (crustacean shells and mollusks) and insects (insect cuticles) [2] Note also that both cellulose and chitin are found in cellwalls of fungi [3] The last ones are today considered as alternative sources to overcome problems involved by using biowastes from aquatic organisms and in particular seasonal and variable supply [4 5] Today the produc
*Address correspondence to this author at the Université Blaise Pascal Institut Pascal UMR CNRS 6602 Université Blaise Pascal 2 avenue Blaise Pascal 63178 AUBIERE France Tel +33 (0) 4 73 40 74 22 Fax +33 (0) 4 73 40 78 29 Email guillaumepierre@ucafr
tion of chitosan from crustacean shells is only economically viable if the recovery of carotenoids (astaxanthin …) is included [6] Overall approximately 10 billion t of chitin are produced each year by mollusks crustaceans insects fungus and related organisms [7] Chitosan is a biopolymer of the aminoglucopyran family obtained by alkaline deacetylation of chitin and is still the only cationic polysaccharide in nature Soluble in acidic aqueous solutions (acetic acid formic acid
etc
) it is composed of a randomly distributed
(14)linked
D
glucosamine and
N
acetyl
D
glucosamine The poor
solubility of chitosan in alkaline pH solutions is due to intra andor intermolecular hydrogen bonding which form crystalline domains Its degree of crystallinity depends on the DD and it varies for commercial chitosans between 60 to 100 Chitosan has primary amine groups at the C2 position primary alcoholic groups at the C6 position and also secondary hydroxyl groups For a breakthrough in very high valued fields such as medicine and niche markets chemical modifications will be a key point to enhance the field of the
potential applications of chitosan Thanks to its reactive sites many grafting andor modifications such as hydroxyalkylation carboxyalkylation sulfation thiolation phosphorylation alkylation acylation acidic or enzymatic depolymerizations can be performed under mild reaction conditions to create new functionalized derivatives [8 9] As reported in Fig (
1
) various promising activities have been
reported during the last few years in medicine pharmaceutics membranes paper industry cosmetics biotechnology agriculture
Guillaume Pierre
Send Orders for Reprints to reprints@benthamscienceae
Current Organic Chemistry
2018
22 641667
641
REVIEW ARTICLE
Bioactivity of Chitosan and its Derivatives 642 Current Organic Chemistry 2018 Vol 22 No 7 Laroche et al
textile food and feed additives [10] Biocompatibility which is the
ability of the biopolymer to perform with an appropriate host re
sponse in the specific application [11] and bioactivity of these de
rivatives are function of a wide range of parameters such as deace
tylation degree average molecular weight distribution of N
acetylglucosamine and glucosamine global charge character po
rosity solubility The increase of commercial availability of chito
sans opens the way for developing new uses especially for non
biomedical fields [2] Extensively chitosan and derivatives can be
used in a broad range of biological applications eg wound heal
ing biomaterial biomedical adhesive drug and genedelivery sys
tem tissue engineering chelation antioxidant antimicrobial anti
tumoral and antiparasitic This overview provides recent insights
into chitosan chitosan derivatives and their biological activity
Biodegradability and environmental assessment of these derivatives
are also discussed
2 WHAT ABOUT CHITOSAN
We cannot talk about chitosan without talking about chitin Chi
tin is generally described in literature as a cellulose analog with
which it shares some structural and functional characteristics The
main differences between these two (14)Dglucans forming
crystalline nanofibrills or whiskers are the presence of acetamido or
amino groups on C2 of Glcp of chitin instead of hydroxyl (Fig 2)
Cellulose the most abundant organic compound in nature is the
main component of tough cell wall that surrounds the plant cells
Chitin is also a supporting polysaccharide isolated from fungi
arthropods and insects even if chitin or chitooligosaccharides have
been isolated from bacteria diatoms and marine microalgae [12
15] The annual worldwide production of chitin is estimated to 1011
tons per year [10] Chitin occurs in three polymorphic forms called
and chitins The crystalline structure of chitin is composed
of antiparallel arrangements of polysaccharidic chains with intra
and interchains hydrogen bonds (NHOC) This form of chitin is
mainly extracted from fungi and arthropods The chitin isolated
from squid pen is composed of parallel chains whereas the rarest
chitins from notably cocoon fibers of some insect or stomach of
common squid possesses two parallel chains in association with
one antiparallel [14 16] On contrary to chitin the presence of chi
tosan is very limited in nature except in some mushrooms such as
Mucor rouxii [17 18] Chitosan is obtained after alkali deacetyla
tion of chitins and is the corresponding polymer of glucosamine
(GlcN) Neither chitin nor chitosan are homopolymers as both con
tain varying fractions of 2acetamido2deoxyDglucopyranose
(GlcNAc) and GlcN (Fig 2) Native chitins are highly acetylated
including up to 90 of GlcpNAc in their structure When the
deacetylation degree (DD) of chitin is over 60 the term chitosan
is used [19] Contrary to the major part of polysaccharides chitosan
(and also chitin) is an alkaline polysaccharide where amino groups
Fig (1) Main fields of applications for chitosan and its derivatives
Fig (2) Chemical structure of (A) cellulose and (B) chitosan with R H andor COCH3Bioactivity of Chitosan and its Derivatives Current Organic Chemistry 2018 Vol 22 No 7 643
are more accessible to reagents due to less crystalline structure
compared to that of chitin This basic character of chitosan enables
its dissolution in nearly all aqueous solutions of inorganic or or
ganic acids such as acetic or formic acids to form water soluble
salts Crystalline chitosan has an extended twofold helical structure
with intrachain hydrogen bonding between OH of C3 and O(5’)
varying in several polymorphs (packing density and water content)
[20] Depending on conditions used during chitosan salt preparation
(nature of acids concentrations of acids temperature and others)
the polymer conformations have been classified in 4 groups type I
(anhydrous salt and extended twofold helix) type II (hydrated salt
and relaxed twofold helix) type IIa (hydrated salt and 41 helix)
and type III (anhydrous salt and 53 helix) [21]
Nowadays the primary source of commercial chitosan is waste
of marine organisms from marine capture fisheries such as crabs
lobsters squid krill and freshwater crayfish [22] Processes for
isolation of chitin and its transformation in chitosan from different
shellfich consist of four steps with some variations (temperature
concentration of reagents and time) depending on the starting mate
rial [23] Firstly proteins are removed (deproteinization) by an
alkaline treatment (with NaOH or KOH at concentrations between 1
and 10) under temperature between 25 and 100°C during several
hours (05 to 10 h or more) After that minerals and notably
CaCO3 abundant in biowastes from crustaceans were extracted
with dilute acids (HCl between 25 and 8 ) at room temperature
during 2 or 3 hours The colored chitin obtained is then bleached by
washing with ethanol sodium hypochlorite hydrogen peroxide
ether acetone or a combination of them at room temperature Fi
nally the chitin is deacetylated at room temperature with high con
centrations (4050) of NaOH or KOH during 05140 hours [20]
This deacetylation was achieved dissolving the resulting chitosan in
acetic acid (2) With this method the obtained chitosan is low
degraded and nearly 100 deacetylated [20] Generally speaking
there is an inverse correlation between molecular weights and
deacetylation degrees versus time of reaction and concentration of
reagents Molecular weights of chitosans from shellfish are between
104 – 106 Da for a deacetylation degree generally above 65 and
up to nearly 100 [20 24] The second industrial source of chito
san is represented by mushrooms wastes from mushrooms farms
Exploited species are numerous and include Agaricus bisporus
Lentinula edodes Pleurotus species and others [25 26] The main
components of mushroom cell walls being chitin chitosan and
(13)(16)Dglucans the chitosan collected from this source is
polluted by glucans Shortly the extraction process is quite similar
to that applied to crustaceans but generally not include the step of
demineralization and decolorization [25 26] Chitosans obtained
from mushrooms have molecular weights of 12 x 106 Da and DDs
between 70 and 90 [2527]
Other exotic andor emergent sources of chitosan and new
technologies for chitosan manufacturing from traditional raw mate
rials have been abundantly published these last years Therefore
insect cuticules composed of proteins melanin and chitin have
been processed to produce chitosan [28 29] In a world context
where new sources of proteins are actively researched for human
food and feed the development of insect production to supplement
animal protein could lead to the emergence of large quantities of
insect byproducts available for chitosan production In the same
way the composition of cuticles from terrestrial crustaceans
showed a rich amount of chitinproteins fibers associated with cal
cium carbonate [30] Another emergent source of chitosan could be
in a next future the fermentative production of fungal microorgan
isms As explained above chitin is a major component of the fungal
cell wall and can be obtained as industrial byproducts from fungi
molds (mainly Zygomycetes) or yeasts [31] Considering the devel
opments of alternative processes to chemical ones the main innova
tions are probably the biotechnological processes using enzymes or
microorganisms to remove proteins from shellfish wastes (prote
ases) and deacetylases to avoid high alkaline treatments [24]
3 PREPARATION OF CHITOSAN DERIVATIVES
As mainly described in the last two decades chitosan and de
rivatives have drown more and more attention due their properties
and biological activities in diverse niche markets such as food ma
terial environmental cosmetic and pharmaceutical fields Nonethe
less due to its reduced solubility in (organic) solvent and water the
specific use of chitosan appeared very limited One of the best ways
to improve or develop new applications to chitosan is the depolym
erization andor the modification of the backbone chain structure by
functional group grafting Generally speaking the most common
functionalization are performed on the hydroxyl group (OH) and
the primary amine group (NH2) Lot of studies has proposed the
modification of chitosan in order to modulate and improve the in
trinsic biological and physicochemical properties
31 Chemical Modification of Chitosan
Many papers have been published in the last years on the spe
cific chemical modification of chitosan Till now the structure of
chitosan continues to be chemically modified to lead to a variety of
polysaccharide derivatives with enhanced properties and applica
tions In this chapter we emphasized in a nonexhaustive manner
the main chemical modifications reported in literature such as qua
ternization Nalkylation Nacylation C6carboxylation and de
polymerization
311 Quaternized Chitosan Derivatives
In order to increase the putative applications of chitosan lot of
chemical modification have been investigated to adjust the positive
charge of chitosan (NH3
+) to allow its solubilization over a large
pH range and more especially for neutral and weakly alkaline pH
In this case the quaternization of the primary amine group from
chitosan was largely described [3234] In this way this specific
functionalization considerably enhances the water solubility of
chitosan by controlling the cationic character without pH depend
ence [35] In fact with the protonation of amino groups at
pH below than 65 chitosan is cationic but quaternized derivatives
of chitosan are permanently cationic for a very large pH range [36]
Therefore the quaternized chitosan derivatives are very attractive
for pharmaceutical field and can be used to improve different ionic
complexes stability for biological systems [37 38] In general the
quaternizing process carried out with reaction between alkyl iodide
and chitosan under basic condition system [39] NNNtrimethyl
chitosan chloride (TMC) is certainly the most quaternized chitosan
derivatives described for a broad spectrum of applications [33 39
40] Classically as presented in Fig (3) TMC is produced in two
steps (i) by reacting at 5060°C chitosan and CH3I in Nmethyl2
pyrrolidinone solution with NaOH as alkaline reagent and (ii) by
substituting iodide ion with chloride ion by using ion exchange gel
[39] In a general way the reaction can be summarized by a nu
cleophilic substitution of the tertiary amine from chitosan with alkyl
halides in order to generate various Nalkylammonium groups By
this easy process Avadi et al [41] and Bayat et al [42] produced 644 Current Organic Chemistry 2018 Vol 22 No 7 Laroche et al
quaternized chitosan derivatives such as triethylchitosan (TEC) and
dimethylethylchitosan (DMEC) in order to develop nanoparticules
carried for insulin delivery in colon
In the same chemical approach authors have proposed the syn
thesis of highly cationic chitosan derivatives As for example Xu et
al [43] generated a quaternized chitosan such as the N(2hydroxy)
propyl3trimethylammonium chitosan chloride (HTCC) by using
glycidyltrimethylammonium chloride in order to build new
nanoparticles as biomaterial carrier for the protein drug administra
tion In other hand Curtis et al [36] used Nmethyl2pyrrolidone
to synthesize highly cationic NNNtrimethylchitosan with io
domethane in sodium hydroxidewatersodium iodide at room tem
perature Authors evaluated influence of reaction conditions (tem
perature reaction time reagent ratio) in order to avoid non specific
Omethylation to generate highly free Omethylated NNN
trimethylchitosan with high quaternization level More Verheul et
al [35] proposed a twostep synthetic way in order to prepare free
Omethylated NNNTMC derivatives with various degree of qua
ternization In their chemical process authors developed a dimethy
lation step by using formaldehydeformic acid medium following
by adding excess quantity of iodomethane to perform the quaterni
zation step Currently work is still in progress to develop response
surface methodology (RSM) and mathematical models for the pur
pose of finding the best quaternization experimental condition to
generate a large range of biological active TMCs [4446] As re
ported by authors all these novel classes of TMC and other quater
nized chitosan derivatives have potential biological interest in sev
eral delivery systems such as in vaccine gene and mucosal drug
delivery
312 Nalkyl Chitosan Derivatives
The production of various Nalkylated chitosan derivatives can
be performed by chemical treatment using ketones andor aldehydes
compounds For the most part these chemical reactions performed
efficiently in a methanolaqueous acetic acid binary solvent to solu
bilize both liposoluble alkyl compound and hydrosoluble chitosan
Therefore the specific chemical condensation of chitosan with
ketonesaldehydes groups induces gelation system with the forma
tion of poor soluble Schiffbase reactive intermediates [47] From a
chemical point of view as related by Kumar et al [48] this Schiff
reaction occurred between chitosan amine group and ke
tonesaldehydes leading to the formation of ketiminesaldimines
residue Then there is the conversion to Nalkylated derivatives due
to borohydride hydrogenation with sodium borohydridecyanoboro
hydride which allows imine linkage reduction (Fig 3) In this way
Kurita [49] used phthalaldehydic acid to produced Northo
carboxybenzyl chitosan derivative with good solubility at neutral
pH solution
Furthermore the synthesis of various alkyl chain lengths from
C3 to C12 has been proposed in literature In their study Desbrieres
et al [50] developed Nalkylation approach in order to synthesize
different hydrophobic chitosan derivatives with a range of rheologi
cal behavior depending to the alkyl chains used Authors clearly
established that a Nalkyl chain with a minimum of six carbons onto
chitosan derivatives was essential to exhibit hydrophobic interac
tions in aqueous media In addition others authors has revealed the
importance of both Nalkylated substitution degree and alkyl chain
lengths into the specific interaction of modified chitosan in aqueous
Fig (3) The main strategies to synthesize chitosan derivatives by (A) quaternization process with example of NNNtrimethyl chitosan chloride (B) N
alkylation process and (C) Nacylation process using (i) acyle chloride and (ii) acid anhydride
N
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ii
7
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)
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8C8C vu 11
Srqpvt th pu h yhprpryyivrhyr 9 virryvivrhy vr 9typr Gspr
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S28C8C vu 11 #Bioactivity of Chitosan and its Derivatives Current Organic Chemistry 2018 Vol 22 No 7 645
media [51 52] As a consequence it was confirmed the physical
gelation of the aqueous system due to the creation of hydrophobic
domains with an optimum alkyl chain length of C12 and a degree of
chitosan grafting of 5 (in mole of the glycosidic units) [51] More
it was evidently mentioned that grafting with five carbon alkyl
chain increased the rigidity of chitosan macrostructure and then was
not efficiency to promote aggregation [52] It is important to men
tion that in other study Zhang et al [53] synthesized several am
phiphilic NalkylNtrimethyl chitosan derivatives for polymeric
micelle systems It was particularly demonstrated the promising use
of NoctylNtrimethyl chitosan (OTMCS) for the solubilization and
the controlled release of a hydrophobic anticancer drug such as
hydroxycamptothecin derivatives In some studies authors pro
posed to enhance the amphiphilic properties of Nalkylated chitosan
derivatives by using multiple grafting of both hydrophilic and hy
drophobic chemical functional groups Thus for example the high
yield preparations of diverse molecules have been related such as
the NoctylOsulfate chitosan the NoctylOglycolchitosan and
the Npoly(ethylene glycol)NoctylOsulfate chitosan [5458]
Finally as an alternative synthesis some authors reported the
use of sugars moieties to generate highly water soluble N
glycosylated chitosan derivatives [5961] As an example N
alkylation reaction was successfully investigated by using various
reducing sugar such as lactose cellobiose maltose Dribose meli
biose maltotriose Dglucose Lfucose Lrhamnose Dgalactose N
acetylglucosamine Dglucosamine Dxylose and Dgalactosamine
As related by authors the specific grafting of carbohydrates moie
ties to amine groups from chitosan is a very promising synthetic
way allowing to considerably modify this waterinsoluble polysac
charide into graftedchain watersoluble chitosan derivatives com
patible with various salted aqueous solution waterethanol mixture
media and organic solvent Recently by using this Nglycosylated
chitosan strategy Alupei et al [62] have synthesized a new chito
sanmaltose derivative with very interesting antitumor drug delivery
properties As a result of the chitosan functionalization authors
reported the easiest convenience of nanomagnetic particle prepara
tion due to the improving polymer hydrophilicity which constitutes
a key factor in retention time rinsing of nanoparticles in blood
313 Nacyl Chitosan Derivatives
In the aim of providing hydrophobic chitosan derivatives with
fatty acids have been grafted in several studies with acylation As
largely related by Kumar et al [48] from the last years hydropho
bic polysaccharides derivatives are considered as innovative cate
gory of technologically significant macromolecules Moreover
based on the results from Naberezhnykh et al [63] it was sug
gested that these classes of molecules could be proposed in thera
peutical application as endotoxins mimetic From a chemical point
of view the Nacylation synthesis occurred with additionelimi
nation process by specific amidation reaction between the terminal
carboxylic acid group from fatty acid moieties and the amine group
from chitosan (Fig 3) In general way the chitosan Nacylation is
investigated using acyl halide or acid anhydride As outlined by
Mourya and Inamdar [61] chemical media regularly used to per
form the acylation reaction are pyridine chloroformpyridine
methanolwateracetic acid NNdimethylacetamidelithium chlo
ride formamidemethanol methanolethanolwater and di
chloroethanetrichloroacetic acid Generally speaking according to
experimentation condition Oacylation could be generated because
of the reactivity of the two hydroxyl group present in the repeating
unit of chitosan [61 64 65] That is why methanolwateracetic
acid media is mostly used in order to solvate acid anhydride for N
acylation selectivity [60 66] To avoid Oacylation authors used
protection of primary hydroxyl group of chitosan with trityl group
and then increase the Nacylation by preparing for example N
chloroacyl 6Otriphenylmethyl chitosan [67] Therefore the last
years lot of examples of Nacylated chitosan derivatives has been
occurred with diverse acid anhydride such as propionic butyric
pentanoic hexanoic octanoic decanoic lauric myristic palmitic
and stearic anhydride [60 64 66 68] Some cyclic acid compound
as phthalic cis1236tetrahydrophthalic trimellitic 5norbornyl
endo 23dicarboxylic itaconic cis12cyclohexyl dicarboxylic
maleic pyromellitic succinic 2octen1ylsuccinic citraconic and
glutaric acid anhydrides have also been used for the preparation of
partially Nacylated chitosan [60 6973] By this way the N
succinyl chitosan family was largely studied for therapeutic and
cosmetic field due to the presence of several carboxyl groups which
could modulate in vivo and in vitro physicochemical characteristics
[7375]
Alternatively other strategy using fatty acid chlorides (gener
ally C6 to C16) was performed to generate Nacylated chitosan
derivatives [76] As an example in their study Zhang et al [77]
converted the carboxylic acid of oleic acid into acid chloride de
rivative before Nacylation reaction step with chitosan in pyri
dinechloroform mixture Then oleoylchitosan derivatives (OCH)
were prepared with degree of substitution (DS) of 1011 and with
different molecular weights such as 5 kDa (OCH5) 38 kDa (OCH
38) and 300 kDa (OCH300) in order to generate selfassembling
nanoparticles as efficient carriers for antitumor agents In the same
way Xing et al [78] have recently prepared efficient antifungal
oleoyl chitosan derivatives against Alternaria tenuissima Botryos
phaeria dothidea Nigrospora sphaerica and Nigrospora oryzae
Some authors have reported that according to DS and the fatty
acid chain length the physicochemical properties of chitosan
(solubility rheological behavior etc) could be impacted [61] As a
consequence for low DS and for the shorter fatty acid chains of N
acylated chitosan derivatives (acetyl to octanoyl moieties) it was
established high solubility in acetic acidwater media Nevertheless
when both DS and fatty acyl residues (decanoyl to stearoyl) in
creased the hydrophobicity increased [60 61] In their publication
Kumar et al [48] revealed that different kind of Nacylated chitosan
derivatives gelhydrogel could be modulated with acetyl propionyl
and butyryl groups Authors confirmed that even if some O
acylated residues are found in chitosan derivative the gelation was
due to selective Nacylation by using ethylene glycol formamide or
methanol as specific organic solvent Till now in literature lots of
applications using Nacylated chitosan derivatives hydrogels are
proposed Then in their review Bashir et al [79] gave a very inter
esting current state of the art concerning Nsuccinyl chitosan de
rivatives (NSC) Authors have among other things given all the
important application in life sciences using NSC in different areas
such as in tissue engineering wound dressing drug delivery and
others potential biomedical applications In the same way other
recent studies reported the synthesis of Nsuccinyl chitosan based
hydrogel for anticancer drug delivery application and tissue engi
neering [74 75 80 81]
314 Oxychitosan Derivatives
Many studies investigated the production of new water soluble
carboxylated chitinchitosan called chitouronic acid sodium salt
(Fig 4) by using the nitroxy radical 2266tetramethylpiperidine
1oxyl (TEMPO) to catalyze oxidation processes in sodium hypo646 Current Organic Chemistry 2018 Vol 22 No 7 Laroche et al
chlorite and sodium bromide medium [8285] The radical TEMPO
was mainly described in literature for the regioselective oxidation
of primary hydroxyl group from many polysaccharides [8691]
Then in 1999 Muzzarelli et al [82] develop regionselective oxi
dation process using TEMPO to synthesized 6oxychitinchitosan
derivatives as new hyaluronan like polysaccharides In general
authors produced (14)polyNacetylglucosaminuronic sodium
salt (chitouronic acids sodium salt) from regenerated chitin ob
tained after chemical andor enzymatic pretreatment of fungal and
crustacean chitins In their study Muzarelli et al [88] used indus
trial fungal biomass from Trichoderma reesei and Aspergillus niger
to manufacture new family of oxychitinchitosan derivatives It
was shown that these carboxylated polysaccharides have biocom
patibility toward human keratinocytes and could be used in drug
delivery [92] In fact authors demonstrated that oxychitinchitosan
derivatives could reduce the hydrolytic action of lysozyme toward
chitosan structure allowing to delay considerably the miconazole
drug release As depicted in lot of publications these chitouronic
acids are soluble in a large range of pH (3 to 12) due to the anionic
characters from carboxylated group and have remarkable gelling
sequestering thickening and biological properties appropriate for
industrial applications in cosmetic pharmaceutic and agriculture
areas [85 88 90] Recently a new C6 oxidized chitosan derivative
was produced and evaluated as bioactive agent [85] It was demon
strated that this zwitterionic polysaccharide could be an efficient
antiparasitic drug In fact in this study authors have shown that
100 of promastigotes of Leishmania infantum LIPA 137 were
suppressed after treatment with oxychitosan Finally among the
many putative applications these anionic carboxylated chitosan
derivatives from TEMPO oxidation might be used as biomaterial
[93]
32 Chitosan Depolymerization
Oligosaccharides have been described as bioactive regulatory
and signal molecules in various biological properties As related by
Delattre and Vijayalakshmi [94] lot of processes including enzy
matic and physicochemical depolymerization have been published
to specifically produce bioactive low molecular weight chitosan and
chitosan oligosaccharides (Fig 5)
In various biological applications reduction of molecular
weight is one of the most important factors to improve the efficient
solubilization and properties of chitosan in acetic acid andor water
media Therefore chitosan can be depolymerized by chitosanolysis
processes in order to generate water soluble monomers oligosac
charides and low molecular weight chitosan (LMWC) with low
viscosity [61 95] In the major depolymerization way we could
mention the chitosanolysis by (i) chemical processes using H2O2
HCl HNO2 [9698] (ii) enzymatic processes using chito
sanasechitinase or nonspecific enzymes such as protease pepsin
lipase papain hemicellulase pectinase pronase cellulase endo
glucanase and lyzozyme [99104] and finally (iii) physical proc
esses using as for example thermal electromagnetic radiation
gamma irradiation sonication and microwave treatments [61 95
105107]
As related by studies the non specific depolymerization of chi
tosan using physicochemical and enzymatic treatment have the
advantage of generating high LMWC yields [95 99] Furthermore
in most cases the main drawbacks of enzymatic depolymerization
of biopolymers are the expensive enzyme cost the low oligosac
charides and LMWC yield during slow reaction [94] Regarding the
chemical depolymerizations the main drawback is that these proc
esses are not environmentally friendly [94] Consequently the im
provement of new methods for the efficient depolymerization of
chitosan is of growing interest Recently new interesting strategies
were proposed to efficiently prepare chitooligosaccharides It was
mentioned the use of different types of zeolites adsorbents to adsorb
and purify oligosaccharides during acid hydrolysis [108] In another
study electrochemical process was developed to depolymerize
chitosan by using IrO2 electrodes [109] It was observed that the
efficient depolymerization of chitosan could be effectively de
graded using TiTiO2IrOxIrO2 anode Moreover the solution
plasma method was proposed for the high yield depolymerization of
Fig (4) Synthesis of C6oxychitosan by oxidation process using TEMPONaBrNaOCl system
+&
)
Bioactivity of Chitosan and its Derivatives Current Organic Chemistry 2018 Vol 22 No 7 647
chitosan [110] This technique using metal chitosan complexation
allowed producing both chitosan oligosaccharides and LMWC oli
gomers in largescale up Authors mentioned that the solution
plasma treatment is more efficient by comparison to conventional
enzymatic andor acid depolymerization
Finally we could point out that all this depolymerization proc
esses could be performed onto the functionalized chitosan (see Sec
tion 31) in order to generate novel classes of oligochitosan deriva
tives On this basis Pierre et al [85] obtained bioactive chitosan
oligosaccharides derivatives by enzymatic depolymerization of C6
oxidized chitosan using commercial enzymes such as macerozyme
glucanex celluclast endocellulase and chitinase
4 BIOLOGICAL ACTIVITIES
41 Antimicrobial Activities
The growing antibiotic resistance of some pathogens is a major
problem throughout the world and the emergence of antibiotic
resistant microorganisms has reduced the treatment options There
fore there has been an amplified interest in the development of
antimicrobial substances from natural products Owing to their
excellent properties exhibited in antimicrobial activities chitosan is
approved as a biopesticide (insecticide fungicide and rodenticide)
by the US Environmental Protection Agency (EPA registration
number 916642) and as a food additive (use in foods generally
including meat and poultry for multiple technical effects) approved
by the US Food and Drug Administration (FDA GRAS Notice N°
443) [111 112] Obviously many physicochemical factors can
influence the antimicrobial activity of chitosan and its derivatives
The electrostatic interactions between the positively charged
chitosan and the negatively charged bacterium surface explain gen
erally the antimicrobial activity of chitosan In relation with the
degree of deacetylation the pH determines the positively charge
density of chitosan and thus its antimicrobial activity At pH below
its pKa (pH < 65) the amino groups of chitosan become ionized
(positively charged) allowing an antimicrobial effect [113 114]
However at pH greater than or equal to its pKa (pH 65) depro
tonation of amino groups makes chitosan inactive and insoluble
For that many efforts have been carried out to prepare derivatives
of chitosan solubles in water with antimicrobial activity at neutral
or basic pH [113] Although there is a large variety of chitosan
derivatives reported in literature some of them are described below
For example quaternary ammonium chitosan has positive
charges independently of the pH of the aqueous media Moreover it
exhibited stronger antibacterial activity relative to chitosan [115]
Also by carboxyalkylation carbomethylation sulfonation or
complexation chitosan derivatives exhibited an improved solubility
and antimicrobial properties [116121]
The antimicrobial effect of chitosan and derivatives differs with
types genera and species of microorganisms These differences
may result from various factors ie (i) chitosanase production by
microorganisms [122] (ii) chemical composition of the microbial
cell envelope [123 124] (iii) nutrient components in the growth
medium which can affect the interaction with chitosan and deriva
tives [125]
411 Antimicrobial Potential on Bacteria
Though as a polymeric macromolecule chitosan and some de
rivatives are unable to cross the outer membrane of Gramnegative
bacteria Therefore chitosan and derivatives must create a polyca
tionic structure which can interact with the predominantly anionic
components (lipopolysaccharides and proteins) of the outer mem
brane [126 127] In fact using electron microscopy some studies
demonstrated that chitosan can bind to the outer membrane and
causes extensive cell surface alterations causing the formation of
vesicular structures on the outer membrane Electrophoretic and
chemical analyses of cellfree supernatants of chitosantreated cell
suspensions showed that interaction of chitosan with Gramnegative
bacteria involved no release of lipopolysaccharide or other mem
brane lipids [124] However it seems that some Gramnegative
bacteria such as Erwinia spp Klebsiella pneumoniae and Salmo
nella enteritidis PT4 are unaffected by chitosan at 5000 ppm [128
129]
In Grampositive bacteria chitosan and derivatives can interact
with teichoic acids of bacterial cell wall that results in a sequence of
Fig (5) The main strategies to produce oligosaccharides and low molecular weight chitosan by using depolymerization processes (with R H andor COCH3)
#
( ( ) 0100 2
i
＇
* 13
ii 4
＇
5 10
6
7
#
( ＇
(
4
＇
5 10
8
#
8
( #( ##
( #
(
#( ##
( 88
＇
* 13
6
7
N 7
6648 Current Organic Chemistry 2018 Vol 22 No 7 Laroche et al
events that eventually lead to the leakage of intracellular
compounds such as proteins glucose nucleids acids or potassium
ions [130 131] Chitosan and derivatives can precipitate and stack
on the microbial cell surface In that way it can form an impervious
layer (film) around the cell Such an impermeable layer can be ex
pected to prevent the transport of essential nutrients (ie mass trans
fer limitation) and may also destabilize the cell wall beyond repair
thereby causing severe leakage of cell constituents [132] The cati
onic nature of chitosan and derivatives causes them to bind with
sialic acid in phospholipids of bacterial andor fungal cell mem
brane consequently restraining the movement of the membrane
constituents [133] Some chitosan derivatives such as quaternized
chitosan can also interact with the hydrophobic interior of the bac
terial cell by hydrophobic–hydrophobic interactions between the
aryl substituent and the hydrophobic component of the bacterial cell
wall [134 135] Some chitosan derivatives such as watersoluble
LMWC derivatives or nanoparticles could penetrate the cell walls
of bacteria incorporate with deoxyribonucleic acid (DNA) and
inhibit the DNA transcription [136 137] Beside chitosang
poly(acrylamide)CuS nanocomposite may inhibit the growth of
Escherichia coli bacteria through the inhibition of dehydrogenase
enzyme periplasmic enzyme activity and active transport [127
138] Finally chitosan can chelate metals causing inhibition of the
microbial growth and the toxin production [139]
412 Virus and Fungi are not Spared
Chitosan and derivatives can induce plant resistance to viral in
fection Antiviral chitosan and derivatives activity depends on the
molecular weight In bean plants high molecular chitosan displays
higher antiviral activity [140] However in potato plants the reverse
effect is observed [141] Chitosan enhance ribonuclease activity
Evidently ribonucleases can depolymerize viral ribonucleic acid
(RNA) and inhibit its replication and translation resulting in the
chitosaninduced resistance to viral infection However it was
shown that chitosan failed to eradicate viral infection and evi
dently it cannot be used for obtaining virusfree material [140] As
in bacteria chitosan and derivatives reacts with the fungal cell sur
face alter fungal cell permeability causing the leakage of material
[142] LMWC derivatives incorporate with DNA and inhibit the
synthesis of mRNA [136 137] Pyridinechitosans damage and
deform fungal hyphae structure causing growth inhibition [143]
Iminoboronatechitosan hydrogels inhibit the metabolic activity
with strong antifungal activity against Candida yeasts [144]
As nanobiocide chitosan nanoparticle application stimulates
some defense mechanism in leaves which control the growth of
fungal pathogen Pyricularia grisea in leaves [145]
413 Algicide Properties of Chitosan and Derivatives
Chitosan and derivatives exerts potent algicidal activity against
harmful algal cells caused by an efflux of intracellular components
and an increased super oxide dismutase activity [146] Also chito
san and derivatives can interact with thylakoid membranes and
chloroplast envelope composed of phosphatidylglycerol and sulfo
quinovosyldiacylglycerol negatively charged lipids [147 148]
Overall and based on literature review some mechanisms of an
timicrobial action of chitosan and derivatives can be proposed A
brief summarization of Minimum Inhibitory Concentrations (MIC)
of chitosan and derivatives against some microorganisms is pre
sented in Table 1
414 Chitosan and Derivatives as Antiparasitic Drugs
The constant outbreak of some emerging or reemerging para
sitic diseases has caused serious harm to human health Also the
appearance of drug resistant organisms and toxic side effects of
current agents are attracting increasing interest in development of
new natural agents for parasitic diseases treatment Chitosan and
derivatives are promising natural agents which proved some anti
protozoal activities
In leishmaniasis chemotherapy chitin chitosan and C6 oxi
dized chitosan showed an antileishmanial activity against Leishma
nia infantum LIPA 137 [85 156] However chitin microparticles
(but not chitosan microparticules) induced cell proliferation and
increased TNF and IL10 production as it was reported for
Leishmania major infection [157]
As drug delivery system 4sulfated Nacetyl galactosamine an
chored chitosan nanoparticles permit to deliver amphotericin B
efficiently to infected vacuoles in leishmaniasis via specific recep
tors of 4SO4GalNAc present on the macrophage surface and via
charge based chitosan mediated preferential engulfment which
causes enhanced internalization of bioactive in cells [158] Also
rifampicin loaded mannoseconjugated chitosan nanoparticulate
system was evaluated as selective rifampicin delivery to the macro
phages in the management of visceral leishmaniasis in albino rats
The results indicated a higher accumulation of rifampicin in the
macrophage rich organs (liver and spleen) [159] Also bis4
aminophenyldiselenide formulated in chitosan hydrogels exhibited
antiparasitic activity against Leishmania major [160] Furthermore
to cure with unsightly scars caused by the body＇s inflammatory
response to cutaneous leishmaniasis lapachone loaded in leci
thinchitosan nanoparticles promoted wound healing [161]
To treat malaria chitosan–tripolyphosphate conjugated chloro
quine nanoparticles were studied for attenuation of Plasmodium
berghei infection in Swiss mice [162] Chitosan conjugated chloro
quine was proposed to inhibit caspase activation and apoptosis in
liver during Plasmodium berghei NK65 infection [163] Also to
restore the tissue damage in malaria infection chitosantrypoly
phosphate conjugated nanochloroquine showed decrease of the
stress markers and proinflammatory cytokines as well as increase
of antioxidants level in liver and spleen of mice infected by Plas
modium berghei NK65 [164]
Chitin or chitosan supplementations in diets can enhance im
mune response and affords disease resistance of scuticociliatosis
caused by Philasterides dicentrarchi in Epinephelus bruneus (kelp
grouper) [165]
Chitosan and silver nanoparticles can be used in prophylaxis
and treatment of toxoplasma In fact chitosan combined with silver
nanoparticules increased gamma interferon level in mice infected
by Toxoplasma gondii [166] However Chitosan microparticles of
Toxoplasma gondii GRA1 protein vaccine and chitosan nanoparti
cles of Toxoplasma gondii GRA1 pDNA elicited GRA1specific
immune response [167] Antigens of Brugia malayi thioredoxin
encapsulating in chitosan was proposed as a potent vaccine of lym
phatic filariasis [168] As trichomoniasis treatment LMWC showed
a high antitrichomonial effect on Trichomonas gallinae [169] To
treat cryptosporidiosis enteritis caused by Cryptosporidium par
vum bioadhesive microsphere system of chitosanpoly (vinyl alco
hol) for the delivery of diloxanide furoate–cyclodextrin was pro
posed It can suppress by impairment the attachment of Crypto
sporidium parvum sporozoites to enterocytes [170] Overall phar
macokinetics (PK) in vivo have an important role on drug efficacy Bioactivity of Chitosan and its Derivatives Current Organic Chemistry 2018 Vol 22 No 7 649
and PK can also be associated with biodegradation Few papers deal
with PK studies using chitosan and derivatives as antiparasitic
drugs eg the use of albendazolechitosan microsphere to treat
alveolar Echinococcosis in mice [171] the potential of chitosan
microparticles as a delivery system of doxorubicin for the treatment
of visceral leishmaniasis [172] or the use of pentamidineloaded
nanobodychitosan nanoparticles in African trypanosomiasis treat
ment [173] Note also that Kean & Thanou (2010) also reported in
an extensive review chitosan biodegradation in vivo [112]
42 Antioxidant Properties
Reactive oxygen species (ROS) including superoxide anion
radicals (O2•) hydroxyl radicals (•OH) and hydrogen peroxide
(H2O2) are often generated as the oxidation products of biological
reactions or exogenous factors ROS can oxidize biomolecules
such as lipids proteins carbohydrates and DNA leading to cellular
oxidative stress For several years chitosan and derivatives have
been extensively studied for antioxidant properties both in vitro
and in vivo The antioxidant activity of compounds can be attributed
to various mechanisms such as the decomposition of peroxides a
reductive capacity a radical scavenging effect and the binding of
transition metal ion catalysts In order to evaluate the antioxidant
potential of compounds several in vitro tests exist corresponding
to these different mechanisms such as radical scavenging ability
chelating ability and reducing ability Free radical scavenging abil
ity can be tested using DPPH test (22diphenyl1picrylhydrazyl
[174]) whereas hydroxyl radical scavenging activity can be deter
mined using deoxyribose test [175] Reducing power can be evalu
ated following method described by Jung and Zhao in 2012 [176]
Chelating ability on ferrous ions can be determined by the method
of Dinis et al [177] Results are generally reported as IC50 defined
as the effective concentration at which the antioxidant activity was
50 and compared to well known antioxidant substances such as
vitamin C for example
The antioxidant properties of chitosan and derivatives (Table 2)
are reported to be related to the structural characteristics of chito
san including DD Molecular Weight (MW) or crystallinity
Moreover it seems that impact of these parameters on the antioxi
Table 1 Minimum Inhibitory Concentrations (MIC) of chitosan and derivatives against some microorganisms (concentrations normalized to
ppm) and their antimicrobial mechanisms developed
Microorganisms MIC Antimicrobial
Mechanisms References
[6253970] for chitosan A [114 130 131 135]
A B [134 135] Gram+ Staphylococcus aureus [1251000] for quaternized
chitosan C [115]
[6251300] for chitosan D [124 126 149]
Gram Escherichia coli [1251000] for quaternized
chitosan D [134 150] Bacteria
Mycobacteria Mycobacterium tuberculosis [801] for ampCSMNP(1)
nanocomposite
E [151]
Molds Aspergillus flavus
[4] for chitosan
[05] for chitosanpentyl
F [152]
Fungi
Yeasts Candida albicans [053125] for chitosan [11] for
ampCSMNP* nanocomposite
G
H
[153 154]
[151]
Virus
Bacteriophage
MS2
[5000] for chitosan
oligosaccharides
I [155]
Algae Hetrosigma akashiwo [01](2) for low molecular weight
water soluble chitosan J K [148]
(1) AmpicillinChitosan Magnetic NanoParticules
(2) Algicidal activity 90
A Chitosan causes extensive cell surface alteration and covers the outer membrane with vesicular structures
B The longer the chain length of the alkyl substituent the higher the antibacterial activity attained
C Hydrophobic interaction
D Chitosan and derivatives create a polycationic structure which can interact with the predominantly anionic components (lipopolysaccharides and proteins) of the outer membrane
E Mycobacteria species showed intrinsic resistance to amp Antimycobacterial activity might be explained by the presence of the other components of the AmpicillinChitosan
Magnetic Nano Particules that might have synergistic effects with amp
F Chitosan and chitosanpentyl can interact with negatively charged cell surface membrane preventing nutrients from entering the cell
G Chitosan forms a film which may inhibit nutrient adsorptions
H Ampicillin is an antibacterial antibiotic The antifungal activity of the nanocomposite might be attributed to chitosan and the magnetic nanoparticules components
I Chitosan derivatives can interact with viral surrogates leading to the shielding effect on these regions thus preventing the binding of viruses to the cell surface
J Chitosan and derivatives act upon to the chloroplast envelope and thylakoid membranes composed of negatively charged lipids
K Chitosan derivatives with hydrophobic and hydrophilic moieties can bind to and insert into the lipid bilayers 650 Current Organic Chemistry 2018 Vol 22 No 7 Laroche et al
Table 2 In vitro antioxidant activities of chitosan and some derivatives Mw Molecular weight DD Deacetylation degree HPCTgMAS maleic
acid sodium (MAS) grafted onto hydroxypropyl chitosan (HPCT) CMCTSgMAS maleic acid sodium (MAS) grafted onto car
boxymethylchitosan sodium (CMCTS)
Chitosan and Derivatives
|(Substitution Degree)
Mw DD Assays IC50 andor Efficiency References
Chitosan from crab 833933
DPPH 9131630 mgmL1 464523 at 10 mgmL1 reducing power 134620 mgmL1
hydroxyl radicals 006008 mgmL1 623766 at 01 mgmL1 chelating activity
057068 mgmL1 829965 at 1 mgmL1
[178]
Chitosan from larvae of Musca
domestica 426 kDa 90 Hydroxyl radicals 039 mgmL1 566 at 05 mgmL1 superoxide anion radicals 078 mgmL1
DPPH 0373 mgmL1 571 at 05 mgmL1 chelating ability 781 at 1 mgmL1 [231 232]
Chitosan 71
Hydroxyl radicals 507 mgmL1 2913 at 1 mgmL1 superoxide anion radicals 212 mgmL1
3518 at 1 mgmL1 H2O2 43292 mgmL1 544 at 1 mgmL1 lipid peroxidation
359 mgmL1 3588 at 1 mgmL1
[233]
Chitosan 76 kDa 97 Hydroxyl radicals 048 mgmL1 60 at 07 mgmL1 [215]
Half Nacetylated chitosan
281 kDa 535
972 kDa 511
175 kDa 498
17 kDa 479
Hydroxyl radicals 493 668 771 and 837 at 5 mgmL1 superoxide anion radicals
151 303 355 and 788 at 025 mgmL1 H2O2 137 191 198 and 286 at 1 mgmL1
chelating activity 145 173 262 and 418 at 1 mgmL1
[186]
Sulfated oligochitosan (145) 114 kDa 87 Hydroxyl radicals 132 mgmL1 superoxide anion radicals 0025 mgmL1 [234]
Ncarboxymethyl chitosan (28 41
and 54)
5 kDa DPPH 032 042 and 071 mgmL1 superoxide anion 348 264 and 318 mgmL1 [218]
Nsubstituted chitosan (8793) 76 kDa 97 Hydroxyl radicals 20 at 07 mgmL1 [215]
Quaternized chitosan (805907) 76 kDa 97 Hydroxyl radicals 846100 at 07 mgmL1 [215]
Schiff bases 20 kDa 97 hydroxyl radicals 62517 at 5 mgmL1 superoxide anion radicals 62517 at 5 mgmL1 [217]
Nacyl chitosan oligosaccharide
(49) maloyl and succinyl 73 kDa
Hydroxyl radicals 024 mgmL1 (maloyl) superoxide anion radicals 225 (maloyl) and
327 mgmL1 (succinyl)
[219]
N(2hydroxy3trimethylammonium)
propyl chitosan chloride
97 kDa 80 DPPH 319 at 5 mgmL1 [235]
2[phenylhydrazine (or hydrazine)
thiosemicarbazone]chitosan (612
746)
200 8 kDa 96 Hydroxyl radicals 02660531 mgmL1 superoxide anion radicals 43129809 at 04 mgmL
1 chelating activity 1278 at 1 mgmL1 [236]
Gallic acid grafted chitosan 500 kDa 100 DPPH 932 at 1 mgmL1 [237]
Gallic acid grafted chitosan 950 kDa 92 DPPH 014 mgmL1 87 at 024 mgmL1 carboncentered alkyl radicals 00019 mgmL1
hydroxyl radicals 0066 mgmL1 [238]
Gallic acid grafted chitosan 310 kDa 90 DPPH 000178 mgmL1 [226]
Table 2 contd… Bioactivity of Chitosan and its Derivatives Current Organic Chemistry 2018 Vol 22 No 7 651
Chitosan and Derivatives
|(Substitution Degree)
Mw DD Assays IC50 andor Efficiency References
Ferulic acid grafted chitosan 71
Hydroxyl radicals 075 mgmL1 5679 at 1 mgmL1 superoxide anion radicals 076 mgmL1
5658 at 1 mgmL1 H2O2 163 mgmL1 3575 at 1 mgmL1 lipid peroxidation 097 mgmL
1 51 at 1 mgmL1
[233]
Caffeic acid grafted chitosan 47 198 544 kDa DPPH 07 mgmL1 reducing power 1 mgmL1 [227]
Caffeic acid grafted chitosan 71
Hydroxyl radicals 05 mgmL1 636 at 1 mgmL1 superoxide anion radicals 03 mgmL1
6778 at 1 mgmL1 H2O2 074 mgmL1 557 at 1 mgmL1 lipid peroxidation 057 mgmL1
5789 at 1 mgmL1
[233]
HPCTgMAS 880 kDa 97 Hydroxyl radicals 0246 mgmL1 [230]
CMCTSgMAS 880 kDa 97 Hydroxyl radicals 0498 mgmL1 [230]
dant properties are crosslinked as some synergistic effects may
exist It is important to take into account antioxidant activities from
in vitro and in vivo experiments as it is reported in Table 2 and
Sections 421 and 422
421 Antioxidant Activity Depends on PhysicoChemical Pa
rameters
Numerous parameters can influence the potential antioxidant
activity of chitosan and its derivatives such as (i) the deacetylation
degree (ii) the molecular weight (MW) or the crystallinity First
Yen et al [178] studied the antioxidant properties of chitosan from
crab shells with different DD All of the chitosans showed relatively
high antioxidant activities from 583702 at 1 mgmL1and 799
852 at 10 mgmL1 The scavenging activities of the hydroxyl
radicals were in the range of 887941 At 1 mgmL1 the chelat
ing abilities of all chitosans on ferrous ion were 829965 Stud
ies pointed out that hydroxyl radical scavenging activity of chitosan
increased with DD [179180] Antioxidant activity seems to be
linked to the amount of amino groups in C2 positions which is
greater for longer Ndeacetylation time [178 181] Nevertheless
DPPH radical scavenging was not affected by DD highlighting a
different mechanism Increasing DD was shown to decrease chelat
ing ability leading to hypothesis that metalchitosan interactions are
mainly affected by the distribution of acetyl groups [182] Another
factor affecting antioxidant activity of chitosan is the molecular
weight of the polymer Je et al [179] indicated that 15 kDa chito
san with 90 degree of deacetylation (DD) has the highest radical
scavenging activity Sun et al [183] reported that chitosan oli
gomers with low MW (230 327 and 612 kDa) exhibit better anti
oxidant activity than that of higher MW oligosaccharides (1525
kDa) Authors determined the IC50 of their scavenging ability
against hydroxyl radicals and superoxide anion The best antioxi
dant activities were found for oligosaccharides with MW lower than
23 kDa Same conclusions were found by other authors [183] Sig
nificant scavenging of superoxide radicals (742) was shown by
LMWC (21 kDa) at 01 mgmL1 The scavenging percentages of
high molecular weight chitosan (HMWC) (210 kDa) and LMWC
against hydroxyl radicals were 166 and 638 respectively
[184] To explain these results differences in structure especially
differences in the intramolecular hydrogen bonding ability between
high and low MW chitosan are highlighted The less compact struc
ture of LMWC could better allow amino and hydroxyl groups to
react with free radicals and hence exhibit better scavenging activity
According to Chen et al [185] the number of amino groups in
chitooligosaccharides should be more than two for providing anti
oxidant activity in hydrolyzed chitosan Feng et al [186 187]
found that low MW chitosan has higher solubility due to the low van
der Waals forces Similarly Kim and Thomas [188] reported the
highest DPPH radical scavenging activity in 30 kDa chitosan due to
the increase in polymer mobility with lower MW
The same kind of conclusion and interpretation can be done
concerning the chelation of metal ions as the chelating ability of
chitosan is negatively correlated with MW A HMWC should have a
lower mobility than a LMWC which could increase the possibility
of intramolecular bonding between HMWC and metals [188190]
Other in vitro tests on murine melanoma cell line confirmed
suppression of intracellular radical species generation using LMWC
(1kDa) However intracellular glutathione level (GSH) was in
creased for all MW tested highlighting a different mechanism in
dependent of MW Human serum albumin (HSA) is a major target
of oxidative stress in several diseases Treatment with LMWC for
four weeks decreased the amount of oxidized albumin and in
creased the total plasma antioxidant activity [191] Same conclu
sions were found by Tomida et al [192] who showed that low MW
chitosan (28 170 and 335 kDa) were more efficient in inhibiting
the oxidation of serum albumin resulting in reduction of oxidative
stress This antioxidant activity of LMWC also have potential ap
plications in food industry as demonstrated on salmon as well as
apple juice [193] or navel oranges [194]
Apart from in vitro assays some in vivo studies have been also
conducted using various animal models as well as clinical trials
Chitosan has an in vivo stimulatory effect on nitric oxide pro
duction and decreases lipid peroxidation modulating hydrogen per
oxide level as demonstrated on human endothelial cells [195 196]
as well as pancreatic cells [197] or human embryonic hepatocytes
[198] A decrease in intracellular level of ROS has also been no
ticed in mouse neurons when treated with LMWC [199]
As discussed above LMWC is believed to possess greater anti
oxidant activities than HMWC as observed by in vitro assays
However the impact of MW during in vivo evaluations has not been
welldocumented so far Concerning HMWC significant effect has
been evidenced on oxidant stress and associated chronic renal fail
ure [200] but also on glutathionedependent antioxidant system in
rats with putative antiaging effect [201] The antioxidant effect of 652 Current Organic Chemistry 2018 Vol 22 No 7 Laroche et al
high MW chitosan has been also confirmed in a clinical trial [202]
For LMWC it has been shown to improve antioxidative enzymes’
levels and prevent redox imbalance [203 204] and to inhibit neu
trophile activation and oxidation of serum albumin [203]
Nevertheless beside multi evidences that LMWC exhibit en
hanced efficiency for antioxidant properties than HMWC this ac
tivity observed could be in some cases related to the concentrations
tested as significant interaction effect can be explained by different
C* (coiloverlap concentrations) depending on MW Jung et al
[176] have studied relationship between concentration and Mw on
antioxidant activities They demonstrated that to maximize the anti
oxidant ability of HMWC concentration has to be lower than C*
At concentration higher than C* antioxidant activity is reduced as
intermolecular interactions are less susceptible to occur For
LMWC no relationship between concentration and MW was ob
served in hydroxyl radical scavenging activity [176] Finally the
last parameter that may influence antioxidant activity of chitosan
deals with crystallinity Chitin can be found under 2 main forms (
and ) depending on the extraction source The chitin presents
less stability than chitin due to the absence of intersheets hydro
gen bonds [205 206] The initial crystallinity index (CI) of and
chitin are different (283 for chitin and 208 for chitin)
and chitin is less susceptible to deacetylation [207 208] with
slightly change in CI of chitosan derived from chitin whereas CI
of chitosan from chitin is significantly decreased [209] There
fore these differences may influence the antioxidant activity of
chitosan but results from different studies are contradictory Kumar
et al [210] reported decreased CI in lower MW whereas Ogawa
found increased CI in lower MW [211] Liu et al [212] reported
increased crystallinity in high DD and low MW Jung et al [176]
have studied influence of crystallinity of chitosan on antioxidant
properties and observed that chitosan had significantly higher
reducing ability and hydroxyl radical scavenging activity at high
MW At high MW chitosan could have more rigid structure due to
the covalent bonds or interactive force (Van der waals) [186] thus
resulting in highest IC50 in DPPH radical scavenging activity and
reducing ability The dissociation energy of O–H and N–H can be
increased along with higher crystallinity and MW thus chitosan
can be more difficult to be dissociated than chitosan Also
chitosan could have more available functional groups free from
crystalline polymeric structure with hydrogen bonds at high MW
422 Antioxidant Activity of Chitosan Derivatives
As described in Section 3 various modifications can be applied
on chitosan Some authors have also explored the antioxidant
properties of such derivatives
Among chitosan derivatives sulfated ones have shown en
hanced biological activities especially free radical scavenging [184
213] Zhong et al [214] reported an enhanced scavenging effect on
O2• (8090 at 04 mgmL1) and •OH (5575 at 07 mgmL1)
and also an enhanced reducing power of chitosan conjugated with
5chloro4hydroxybenzene13disulphonyl dichloride or 5chloro
2hydroxybenzene13disulphonyl dichloride Hypothesis is that
the hydroxyl and amino groups of the chitosan and the hydroxyl
group of the disulphonamides reacted with the hydroxyl radical to
form stable macromolecular radicals
Many other modifications have been reported to improve free
radical scavenging activities of chitosan such as quaternization
[215 216] Schiff bases reaction [217] carboxymethylation [217
218] and acylation [219]
For NCarboxymethyl chitosan Sun et al [218] prepared oligo
saccharides with different degrees of substitution and tested the
antioxidant properties With the increasing of substituting degree
(28 41 and 54) the scavenging activity against DPPH radical
decreased and reducing power increased probably related to the
content in substituting groups For superoxide anion scavenging
the order is 41 > 54 > 28 highlighting different mechanisms
and donating effect of substituting carboxymethyl groups Car
boxymethylated chitosan was also studied as an inhibitor of MMP2
and MMP9 expression (Matrix metalloproteinases involved in
tumor invasion and metastasis) in HT1080 human fibrosarcoma
cells Carboxymethylated chitosan showed a high level of inhibition
of membrane protein oxidation and membrane lipid oxidation
[184] Carboxylated chitooligosaccharides were also demonstrated
to have a potent inhibitory effect on the generation of ROS [220]
In another study quaternized carboxymethyl chitosan deriva
tives were prepared with a degree of quaternization in the range of
343595 All of the derivatives showed a better scavenging ac
tivity against the hydroxyl radicals than native chitosan The scav
enging activity increased with the increasing degree of quaterniza
tion which signified the influence of the positive charge on the
scavenging activity against •OH [221]
For chitosan derivatives impact of molecular weight has also
been noticed The antioxidant activities of high and low MW chito
sanN2hydroxyNNNtrimethylpropan1amonium chloride were
compared Scavenging rates were enhanced with increasing concen
trations of the chitosan conjugate The LMW form showed a
stronger scavenging effect of O2 • (87 at 08 mgmL1) and •OH
(45 at 30 mgmL1) and the reducing power was also more pro
nounced than for HMW quarternized chitosan The chelating effect
of both molecules for ferrous ion was not concentration dependent
[216] The same study found antioxidant activity of 2phenylhydra
zinecarbothioamide chitosan and hydrazinecarbothioamide chito
san Two different MWs were studied highlighting a better scaveng
ing effect on O2 • (8090 at 04 mgmL1) and •OH (7090 at
14 mgmL1) and also reducing power in the range of 1015
mgmL1 The –NH and CS groups were able to react with free
radicals and increased the antioxidant activity of chitosan [221]
In the study of Chen et al [185] two kinds of chitin oligosac
charides or Nacetyl chitooligosaccharides with different molecular
weights (13 kDa and < 1 kDa) were evaluated in live cells Both
exhibited an inhibitory effect against DNA and protein oxidation In
addition enhanced antioxidant activity (intracellular radical scav
enging effect and GSH level) were noticed in mouse macrophages
The most effective against protein oxidation and production of in
tracellular free radicals in live cells was found to be the 1–3 kDa In
addition their inhibitory effect on myeloperoxidase activity and
oxidation of DNA and protein were identified in mouse macro
phages [222]
Some natural compounds obtained from plants can exhibit anti
oxidant properties To improve antioxidant properties of chitosan
grafting of small antioxidant molecules has been tested by several
authors by chemical crosslinking as well as by enzymatic treat
ments These molecules could be essential oils [223 224] phenolic
compounds [224226] or flavonoids [227 228] The resulting
polymers exhibited significant DPPH radical scavenging chelating
activities and superoxide anion scavenging activity [229] This
grafting strategy can be also applied on chitosan derivatives as
demonstrated by the graft copolymerization of maleic acid sodium
onto hydroxypropyl chitosan and carboxymethyl chitosan sodium
These modified chitosan exhibited IC50 values ranged from 0246 to Bioactivity of Chitosan and its Derivatives Current Organic Chemistry 2018 Vol 22 No 7 653
0498 mgmL1 for hydroxyl radical scavenging with an increasing
effect with concentration [230]
43 Biomedical Applications of Chitosan and its Derivatives
431 Bioadhesive Properties
Adhesive is a substance capable of forming bonds to two parts
when the final object consists of two sections that are bonded to
gether in a relatively small quantity compared to the final object
[239] Bioadhesives are high molecular weight biocompatible and
biodegradable polymers used to join two surfaces where at least one
of them is a living tissue Chitosan is the unique polycationic poly
saccharide extracted from bioresources soluble only at acidic pH
This characteristic gives to it specific properties finding some ap
plications such as adhesive in several industrial fields Chitosan as
bioadhesive has been considered during last decades to be promis
ing due to the ability of being biodegradable biocompatible and
nontoxic Moreover chitosan and its derivatives have anti
microbial properties [240 241] and are simply modifiable (chemi
cally and enzymatically) for improving physicochemical properties
[242245] There are five adhesion theories proposed in the litera
ture ie mechanical theory adsorption theory diffusion theory
electrostatic attraction theory and thermodynamic theory [246254]
The characterization of the adhesion is obtained through the meas
urement of the maximum force that breaks the adhesion between
adhesive and adherent (causes a fracture) To do this there are sev
eral mechanical tests to apply a force on both adherent faces joined
by an adhesive (Fig 6) When the fracture is located on the adher
ent or on the adhesive it’s called cohesive failure This kind of
fracture means that the connection between the components is high
est The fracture can be also located at the interface meaning the
rupture of the adhesive Finally the fracture can be mixed meaning
an adhesivecohesive failure [2 243 244]
Nowadays chitosan is widely used as adhesive for several ap
plications in different fieldsOne of the first applications of chito
san in biomedical field is correlated to its natural hemocompatibil
ity properties (antithrombogenic) and low antigenicity [245] It is
possible to use chitosanbased material for emergency hemostasis
as well as for skin wound closure [2 255 256] Moreover chitosan
films and hydrogels have recently been used as very good biomate
rials to perform woundhealing sutureless and laseractivated tissue
repair [255257] CloSurPAD® ChitoSealTM pad HemCon® and
ChitoFlex® are commercial hemostatic agent based on chitosan
The mechanisms underlying the action of chitosan are not com
pletely understood but it has been suggested to involve vasocon
striction and the rapid mobilization of red blood cell clotting fac
tors and platelets to the site of the injury as a result of the positive
charge on the chitosan molecule [256]
In the literature there are many studies based on chitosan as
bioadhesive using both film and hydrogel forms for medical appli
cations For example Barton et al [257] have shown that chitosan
as bioadhesive films adhered to sheep intestine strongly without any
chemical modification In this study results showed that adhesives
based on chitosan with medium molecular weight achieved the
highest bonding strength [257] In another application Reis et al
[245] used mucoadhesive chitosanbased liposomes to improve
oral absorption of insulin whereas Ishihara et al [258] designed a
chitosan molecule (AzCHLA) that can be photocrosslinked by
ultraviolet light irradiation to form hydrogel as a safe adhesive with
surgical applications The results showed that the sealing ability of
chitosan hydrogel was found to be stronger than that of fibrin on in
vivo punctured carotid artery and lung rabbit’s cells Some other
examples of bioadhesive applications including medical and phar
maceutical applications are summarized in Table 3 Furthermore
chitosan was found to be the most fascinating polysaccharide in
biosourced adhesive development in different other areas such as
wood metallic agromaterial and glass bonding Some studies are
summarized in Table 4 to illustrate those applications
Table 3 Some bioadhesive applications of chitosan in medical and
pharmaceutical fields
Bioadhesive Applications References
Hemostatic agent [242 257 259]
Mucoadhesive agent [245 260266]
Tissue engineering [259 267 268]
Drug delivery [262 269272]
Antibacterial activity [273 274]
Fig (6) Different mechanical analysis to characterize the adhesive strength
Tension test Compression test Cleavage test
Peel test
Bioadhesive
Adherent
Single lap shear test Double lap shear test654 Current Organic Chemistry 2018 Vol 22 No 7 Laroche et al
432 Antitumor Activities
Cancer is the world’s second biggest killer after cardiovascular
disease It is an important cause of death group worldwide it is
projected to continue expanding with an estimated 115 million
deaths in 2030 Chitosan and derivatives may be effective and safe
agents for the chemoprevention or cancer chemotherapy In chemo
prevention microencapsulation of micronutrients with chitosan
increased blood circulation time to enhance drug delivery [283] In
chemotherapy chitosan and derivatives showed a highly specific
tumor activity chitosan and derivatives can be considered as anti
cancer agents exerting fewer side effects on normal cells [284
285]
The action of chitosan and its derivatives according to the tu
mor is reported as follows
Chitosan can induce apoptosis in osteotropic prostate and breast
cancer cells by caspase2 and caspase3 activation it diminishes
their formation in bone [286] Lowmolecularweight chitosan can
induct apoptosis G1S cell cycle arrest and a subtle intensification
of caspase activity in oral cancer cells Ca922 [287] Hyaluronic
acid chitosanpluronic F127 poly (DL lactidecoglycolide)
doxorubicin hydrochloride irinote nanoparticles can demonstrate
high efficacy against both the prostasphere and mammosphere cells
enriched with cancer stemlike cells in vitro and cancer stemlike
cells in human breast tumor in vivo by simultaneous inhibition of
topoisomerases II and I [288] Moreover biomoleculeloaded chito
san nanoparticles induce apoptosis and molecular changes (DNA
fragmentation lipid peroxidation caspase activation) in a human
cervical cancer cell line (SiHa) [289] In fact the interaction be
tween the positively charged chitosan (NH3
+) and negative charges
on the membranes of cancer cells and also the tight junctions in
crease the permeability of the cancer cells membrane [290] Chito
san induces apoptosis of bladder carcinoma cells (RT112 and
RT112cp) by the externalizing of phosphatidylserine [291] How
ever a potent anticancer effect of chitosansilver nanocomposite
against A549 lung cancer cell line results in the formation of reac
tive oxygen blocking electron transport chain via an unknown
mechanism [292]
To prevent colorectal cancer liver metastasis the use of chito
san nanoparticles as carriers of interluekin12 was suggested
Mechanistically nanoparticles block the toxicity of interluekin12
and induce infiltration of natural killer cells and some T cells [293]
As anticancer drugs delivery systems chitosan derivatives
(such as paclitaxelloaded chitosan oligosaccharidestabilized gold
nanoparticles polycarboxylic acids functionalized chitosan nano
carriers or cationic cyclodextrinalginate chitosan nanoflowers)
increase drugs’ efficacy and decrease adverse effects [294296]
Modified chitosan thermosensitive in situ hydrogel composite has
been exploited for a promising drug delivery system for solid tu
mors to achieve enhanced antitumoral efficacy [297] Also phos
pholipidchitosan hybrid nanoliposomes prepared with quaternized
NOoleoyl chitosan promote drugs’ entry in cervical cancer cells
[298]
In cancer gene therapy chitosan and PEGylated chitosan
nanoparticles with small interfering RNA (siRNA) molecules was
used to reduce catenin protein levels in human colon cancer cells
tumor progression [299] Moreover chitosan was used to STAT3
siRNA delivery to inhibit STAT3 (signal transducer and activator
of transcription 3 molecule implicated in the survival proliferation
angiogenesis metastasis and immune evasion of cancer cells) to
down regulates genes involved in angiogenesis and metastasis and
promotes apoptosis of cancer cells in melanoma [300] Also to
overcome multidrug resistance (MDR) cancertargeted MDR1
siRNA delivery using selfcrosslinked glycol chitosan nanoparti
cles [301] Besides quantum dotchitosantripeptide nanoconju
gates recognize v3 integrin receptors (cancerspecific receptors) at
the cellular level for diagnostic and therapeutic purposes [302]
Furthermore crosslinked folic acid–poly(ethylene glycol) chito
san oligosaccharidelactate nanoparticles were used for siRNA de
livery to ovarian cancer cells [303]
In immunotherapy chitosan thermogels permit to deliver CD8+
T in the tumor microenvironment to produce Th1 cytokine and
cytotoxic markers and subsequently kill their target cells [304] In
radiotherapy water soluble chitosan can reduce the negative effect
of radiotherapy on the immune function by increasing CD3 CD4
CD8 CD4CD8 ratio and also NK cells IL6 and TNF levels
Table 4 Some applications of chitosan as adhesive in other fields
Field of Applications References
Wood bonding
Developement of formulated chitosan as wood adhesives
[248 275277]
Agromaterial bonding
Conception of insulating agrocomposites based on sunflower stalk particles and chitosan as adhesive
[278279]
Metalic bonding
Use of formulated chitosan to bond aluminum adherents
[248]
Polyethylene bonding
Adhesion of chitosan solutions modified by tyrosinasecatalysed reaction with 34dihydroxyphenetylamine (dopamine)
to lowdensity polyethylene plates surfacegrafted with hydrophilic monomers
[280 281]
Glass bonding
Formulation of semidilute solution of chitosan with dopamine and tyrosinase to produce a waterresistant
adhesive that fastened glass slides
[282] Bioactivity of Chitosan and its Derivatives Current Organic Chemistry 2018 Vol 22 No 7 655
[305] In photodynamic therapy porphyrin dye into the chito
sanPEG film is a very good singlet oxygen quantum yield So
porphyrin dye is released by the film then internalized by cancer
cells and activated by light [306] In diagnosis methotrexate loaded
chitosan nanoparticles was proposed for breast cancer imaging
[307] and a bimodal molecular imaging probe based on chitosan
encapsulated magnetofluorescent nanocomposite was proposed for
specific cancer cells imaging in vitro [308]
433 Neurodegenerative Disease and drug Delivery System
Neurodegenerative diseases such as Alzheimer’s disease (AD)
and associated dementia are probably in the top three pathologies
that will affect more than 200 million people in 2050 [309]
Chronic inflammatory response through specific activation by
amyloid peptide and interleukin1 can be involved in AD Wa
tersoluble chitosan can decrease the production of pro
inflammatory cytokine in human astrocytoma cells and delay some
pathological events [310] Chitosan and some derivatives (mainly
chitosan oligosaccharides) can suppress iNOS expression in acti
vated microglial cells but also inhibit the lipopolysaccharides
induced phosphorilation of p38 MAPK and ERK12 or the activa
tion of both NFB and activator protein1 [311] Changes in pro
tein conformations eg oxidation or glycation have also been re
ported as structural modifications related to Alzheimer’s disease
and associated dementia [309] Water at the proteinlipid interface
of membrane proteins is involved in protein structures Reducing
this water content often lead to protein conformational diseases
especially during ageing process [312] Chitosan and its derivatives
can (i) decrease low density of lipoprotein cholesterol content [313
314] (ii) inhibit protein conformational changes [312 315] modify
water distribution hydration degree and binding energy at interface
[312 316] Other drugs such as growth factors have a great thera
peutic potential for treating AD but require a delivery system to
ensure protection and a sustainable delivery Strategies must be
found to correctly deliver drugs and siRNA to the brain [317] and
chitosan nanoparticles (and derivatives) have been reported as
promising delivery system for targeting the brain [318] and for
brain targeted nanoformulation [319] Wahba et al [320] used gal
antamine drug (GAL) in rat brain attaching GAL to a ceria
containing carboxymethyl chitosancoated hydroxyapatite
(GAL@CeHApCMC) nanocomposite and successfully upregu
lated oxidative stress inhibited Aplaques and healed specific
degenerative neurons Chitosan has been used for the nanoformula
tion of ThryrotropinReleasing Hormone (TRH) encapsulated
poly(lactidecoglycolide) PLGA nanoparticles in order to generate
new potential membrane penetrating neuropeptides [321] The size
of chitosan nanoparticlesbased therapeutic systems is a tunable
parameter that can also modify the delivery efficiency as it was
reported by Cho et al [322] who prepared different types of hyda
lazineloaded chitosan particles Chitosan drug delivery system can
also be used for imaging brain pathologies Immunenanovehicles
made of chitosancoated PLGA conjugated to an antiamyloid anti
body were thus developed to image cerebral in vivo amyloid an
giopathy deposits [323]
434 Tissue Engineering
Since the last decade innovative chitosanbased materials have
been developed for a broad range of applications in tissue engineer
ing [324] The use of 3D (gels and sponges) and 2Dscaffolds chi
tosans (films and fibers) have been extensively discussed in numer
ous papers and more recently in the feature article of Croisier and
Jérôme [325] The development of chitosan biobased material espe
cially for implantable scaffolds requires specific body compatibil
ity mechanical properties porosity morphology and heal
ingreplacement capacity [326] Obviously no acute or chronic
response is allowed as well as the scaffold must be biodegradable
and allow cell attachment and proliferation [327] Shape chitosan
hydrogels and foams have been widely studied since their high
water content makes them highly compatible To our knowledge
three main types of chitosan hydrogels have been studied ie (i)
noncovalent crosslinked chitosan hydrogels (ii) crosslinked chi
tosan by coordination complex (iii) crosslinked chitosan hydrogels
by chemicals [325] Beside chitosan sponges can soak up exudates
from wound and enhance tissue regeneration [325] Some authors
have used them in bone tissue engineering as a filling material
[328]Over the years carboxymethyl chitosans were highlighted as
a must for the development of new drug delivery systems and im
proved scaffolds [329] Yet numerous other derivatives showed
great potential Jaikumar et al [330] developed a hydrogel scaffold
composed of alginateOcarboxymethyl chitosannano fibrin dedi
cated to adipose tissue engineering Lacticglycolic acidchitosan
hydrogels have been synthetized by Qu et al [331] and could be of
great interest thanks to the polyester side chains which are biocom
patible and biodegradable Another bioactive hydrogel based on
quaternized chitosangraftpolyanilineoxidized dextran seemed
promising for tissue engineering in terms of antibacterial activity
against Escherichia coli and Staphylococcus aureus [332] Drugs
can be added to chitosan hydrogel to enhance its medical character
istics Khoshfetrat et al [333] proposed an enzymaticcalygellable
galactosylated chitosan for liver tissue engineering applications
However some derivatives chitosan scaffolds don’t always give
interesting results Toxicity and biocompatibility can occur depend
ing on the chitosan derivatives and the nanoformulation of the scaf
fold as it was reported by Kamarul et al [334] who prepared a
poly(vinyl alcohol)NOcarboxymethyl chitosan system On the
other hand chitosan based 2Dscaffolds can be used in particular
for wound dressing and are usually described as (i) chitosan films
or (ii) chitosan nanofiber membranes An overview of how improv
ing the properties of these films have been developed in the review
of Croisier and Jérôme [325] As a complementary review Pav
inatto et al [335] addressed the use of chitosan and some deriva
tives in nanostructured thin films Here again the functionnaliza
tion of chitosan and the nanoformulation have a great impact on the
scaffold properties As example composite crosslinked nanofibrous
membranes of chitosan by using ethylene glycol diglycidyl ether
(EGDE) and polyethylene oxide have been prepared by Agil et al
[336] As reported by the authors skin fibroblasts and endothelial
cells showed good attachment proliferation and viability on the
membranes Recently a novel hybrid membrane of chitosanpoly
(caprolactone) showed excellent mechanical properties and 5
days21 days culture assays showed the capacity for cells to prolif
erate on the scaffold [337] Song et al [338] developed a function
alized superhydrophobic biomimetic chitosanbased film through
the use of 36Oditertbutyldimethyl silyl chitosan The film
showed impressive topography and a controlledwettability leading
the way for the preparation of new hydrophobic surfaces which can
be used in antibacterial strategies Various biocompatible crosslink
ing agents such as genipin glycidoxypropyltrimethoxysilane
(GPTMS) or dibasic sodium phosphate (DSP) can be used to in
crease performance of chitosan and obtain interesting chitosan
membranes [339] The authors showed that the optimization of the
crosslinking mechanism can give specific chitosan membrane prop656 Current Organic Chemistry 2018 Vol 22 No 7 Laroche et al
erties which could be used in different medial fields Some authors
also designed artificial skin usable to longterm chronic use by
using chitosan as a primary matrix [340] As reported in chitosan
and some derivatives can mimic glycosaminoglycans and enhance
processes involved in skin replacement
435 Other Applications
Overall many other medical applications can be found in the
literature for chitosan and its derivatives Ravi Kumar et al [1] tried
to give an extended overview of potential uses for a large range of
chitosan derivatives Considering the high turnover about chitosan
studies the lifetime of a review about the medical properties of
chitosan and its derivatives is probably less than 2 years before
being outdated Yet some derivatives and dedicated applications
are also given in Table 5 Immunologic ophthalmologic or antico
agulant applications are probably the most interesting other medical
applications of chitosan and derivatives Thus inflammatory and
immunologic responses should take into account to understand the
potential of chitosan and its derivatives for healing wounds This
antiinflammatory activity of chitosan and its derivatives is usually
due to glucosamine hydrochloride sulfate phosphate alkylacyl
groups and from salts generated during salt conversion step [341]
Okamoto et al [342] highlighted the immune stimulating properties
of chitosan which involves the release of cytokines from macro
phages necessary for the healing process Chitosan oligosaccharides
can stimulated fibroblast production and then facilitate the forma
tion of connective tissues [343] Besides there is growing interest
in ophthalmic research by using mucoadhesive polysaccharides in
insert technology and tissue engineering since twenty years [344]
In order to treat the corneal diseases tissue engineering develop
ment was investigated by using new generation of biomaterial as
promoter of cornea cells growth Generally a perfect artificial cor
neal scaffold biomaterial must have (i) high biocompatibility and
(ii) mechanical and optical properties In this context the last years
chitosan derivatives have been largely used to generate corneal
surrogate biomaterials [345 346] In a very interesting study Chen
et al [346] used a chitosansodium hyaluronatecollagen triblock
polymer gels as artificial cornea It was particularly demonstrated
Table 5 Some medical applications of chitosan
Area of Applications Examples References
Tissue engineering
Articificial skin
Burn treatment
Wound healingdressing
Carbopolchitosan
Chitosan
Crosslinkedphotocrosslinked chitosan
Carboxymethyl chitosanbased
Lacticglycolic acidchitosan hydrogels
Glycidic methacrylatephosphorylcholinechitosan (PCCsGMA)
Sensitive chitosan and polyelectrolyte complexes
[347]
[348]
[349]
[329]
[331]
[350]
[349]
Drug release system
ThryrotropinReleasing Hormone encapsulated poly(lactidecoglycolide) PLGA nanoparticles
Galantamine drug@CeHApCMC) nanocomposite
Hydralazineloaded chitosan nanoparticles
N(2hydroxy)propyl3trimethyl ammonium chitosan chloride for use in gene deliveryGene delivery
Hydroxypropyl chitosan derivatives
Carboxymethyl chitosan for repressing tumor angionesis
[321]
[320]
[322]
[351]
[352]
[353]
Ophtalmology
Chitosancollagen crosslinked membranes
Corneal endothelial cells scaffold based on chitosan
Collagenchitosansodium hyaluronate
Chitosanbased hydrogel
Hybrid hydrogelbased contact lens with quaternized chitosan
[344]
[345]
[346]
[354]
[355]
Antiinflammatory
Chitinchitosan
Chitinchitosan
[342]
[343]
Medical sensordetectiontargeting
Cadmimum sulfide (CdS) quantum dots (QDs) chitosan derivatives
Carbohydratebranched chitosans
Chitosancoated PLGA conjugated to an antiA antibody
[356]
[357]
[323]
Anticoagulant ChitosanOsulfate derivative and Nsulfated chitosan [358 359] Bioactivity of Chitosan and its Derivatives Current Organic Chemistry 2018 Vol 22 No 7 657
that these chitosan derivatives could efficiently promote the rabbit
corneal endothelialstromalepithelial cells Recently a novel
biomimic corneal biomaterial made up of collagen and chitosan
crosslinked was generated by chemical process using 1ethyl3(3
dimethylaminopropyl) carbodiimide (EDC) [344] This chitosan
biomaterial was shown as very biocompatible with human corneal
epithelial cells
436 Adsorption and Chelation
Adsorption is a physicochemical process which is the result of
the specific interaction between an adsorbent (solid material) sur
face and molecules ions or atoms of an adsorbate Due to the
strong positive electrical charge highmolecular weight chitosan
strongly interacts with negatively charged molecules (ie polymers
components of the bacterial cell wall) and form electrostatic com
plexes or multilayer structures [360] The bond strength depends on
the environmental pH (low pH favour chitosan or chitosan deriva
tives binding) and on the chitosan molecular weight and acetylation
degree [361]
Among the chitosan characteristics biodegrability high binding
capacity high hydrophylicity good adsorption capacity large
number of adsorption sites and flexible structure of the polymer
chain make this natural polymer as a perfect candidate for cheaper
alternative adsorbent to the common activated carbons for water
purification [362 363] Therefore most articles that describe the
chitosan or chitosan derivatives utilisation as adsorbents are dedi
cated to metal (arsenic cooper mercury silver nickel lead chro
mium radionuclides as uranium and strontium) or dyes (azo an
thraquinone) removal in order to purify (waste)waters [364367]
Generally the metal adsorption on chitosan occurs through single
or mixed mechanisms like electrostatic interaction (ion exchange)
at low pH media or metal coordination (chelation) Among these
the chelation is a particular mechanism of metal ion binding on
different ions and molecules when two or more separate coordinate
bonds are created This particular adsorption mechanism is attrib
uted to the amino group functionality [368] and is dominant in the
majority of chitosanions systems [369]
In order to enhance the adsorptive properties of chitosan for
metals or dyes many composite with organic or inorganic fillers (or
matrix) were developed namely cyclodextrin modified clays and
zeolites magnetic particles carbon nanotubes glutaraldehyde eth
ylenediaminetetraacetic acid (EDTA) keto glutaric acid xanthate
carboxymethyl etc [369] Beside the environmental application
chitosan utilisation as a biocompatible adsorbent or metal chelating
agent turned interesting in other domains as pharmaceutical indus
try dentistry and medicine
Due to the capability of binding bioactive compound chitosan
is used as ingredient in food supplement formulations As chitosan
and chitosan derivative bind lipid cholesterol fatty acids and
triglycerides there are used in the treatment of overweight and
obesity as dietary supplements However the results of some clini
cal studies show that the efficiency of chitosan and chitosan deriva
tives in obesity treatment is contestable [370 371] Over and above
as ingredient in food supplements chitosan affects the bioavailabil
ity of some drugs (antiinflammatory antibiotics etc) due to his
adsorption capacity [372374]
In pharmaceutical industry chitosan and some chitosan deriva
tives are already used as a safe excipient in drug formulations but
many papers suggest that the applications of this polymer for bio
medical and pharmaceutical could be extended due to its special
adsorptionchelating capacity Therefore Burke et al [375] report
that chitosan may be a suitable ironadsorbing agent in biological
systems (human blood serum) and can be used as orally active iron
chelating agent for treatment of thalassemics A potential utilisation
of chitosan and chitosan modified adsorbents (ie chitosancoated
dialdehyde cellulose) as oral adsorbent for urea and ammonia have
also been described by Yogi et al [376] the therapeutic effect in
this case may be assigned to the high adsorption capacity for water
and nitrogen compounds in gastrointestinal tract of the rats [376]
As drug carrier chitosan and chitosan derivatives must be biocom
patible Chin et al [377] specify that between the material biocom
patibility with blood and protein adsorption capacity is a strong
relationship Therefore Benesh et al [378] notice that large amount
of fibrinogen and other plasma proteins bound to chitosan (and not
to acetylated chitosan) and this is a result of the procoagulant be
haviour of chitosan Among bloodcompatible chitosan derivatives
ocarboxylmethylchitosan obutyrylchitosan partially Nacylated
chitosan derivatives as Nhexanoyl chitosan and some zwitterionic
chitosan derivatives have a great interest [379381]
A current challenge in medicine is the management of acciden
tal poisoning with drugs Ali et al [382] proved that chitosan could
be used as an effective adsorbent for propranolol hydroxide – a
betaadrenergic receptor blocking drug that can be toxic and even
fatal in overdoses Recently the application of chitosan and chito
san derivatives in dentistry was formulated Therefore Pimenta et
al [383] reported that the chelation of calcium ions in dentin result
ing in the depletion of inorganic matter from the smear layer and
del CarpioPerochena et al [384] assess the effect of the chelating
capacity of chitosan on root canal dentin The ability to chelate
essential nutrients metal ion and trace elements necessary for the
bacteria and fungi development make chitosan interesting in agri
culture too
Nowadays chitosan based adsorbents are industrially available
in different forms such as flakes beads fibers microspheres pow
der or porous membranes the last one being preferred due to ease
separation after process higher capacity of adsorption faster kinet
ics and better reusability [363]
5 BIODEGRADABILITY OF CHITOSAN AND ASSOCI
ATED DERIVATIVES
As many studies deals with the use of chitosan and derivatives
for medical purpose such as drug delivery their biodegradation is
of major importance It is needed that polymers undergoes a degra
dation process after ingestion or injection to allow the controlled
release of the active molecule but also to be eliminated further by
the body Both chemical and enzymatic biodegradation could be
observed Chemical degradation is often related to acid degradation
in the stomach whereas enzymatic degradation will occurs mainly
in the intestinal tract or the blood circulation Nevertheless chitosan
biodegradation has also been studied in other applications’ context
especially for environmental purpose of life cycle assessment and
recyclability of material Even if several authors studied the biodeg
radation of chitosan and its precursor chitin mechanisms remains
sometimes unclear and there is a lack of information concerning
chitosan derivatives degradation
51 In vitro Studies
Degradation of polymers is generally monitored by molecular
mass andor viscosity measurements as both will decrease [385] 658 Current Organic Chemistry 2018 Vol 22 No 7 Laroche et al
Chitin the natural precursor of chitosan can be enzymatically de
graded by glycoside hydrolases and especially by chitinases They
specifically hydrolyze the constitutive glycosidic bond between
(14)NacetylDglucosamine (GlcNAc) and glucosamine (GlcN)
Some of them have also shown degradation activity on chitosan
and are expressed by several bacteria strains some of them being
identified in the human colon [386] For in vitro biodegradation
assays chitosan could be incubated with various microorganisms
or more easily with lyzozyme Some proteases have also been de
scribed to degrade chitosan films with leucine aminopeptidase
being the most effective with 38 over 30 days [387] Pectinase
from Aspergilus niger has also been identified to allow obtaining
low MW fragments at low pH [101 388] Another study has shown
that almond emulsin betaglucosidase can efficiently degrade chito
san [389] It is to notice that enzyme degradation never lead to a
complete hydrolysis of polymer but only to oligosaccharides forma
tion with depending on studies MW ranging from 2 to 50 kDa The
main parameter influencing chitosan degradation has been identi
fied as DD Several authors have observed an increase in the bio
degradation rate with decreasing DD [263 390 391] Moreover
Ratajsaka et al [392] studied the biodegradation process of chito
san samples with similar values of deacetylation degree but differ
ent molecular weights using microorganisms from an activated
sludge The shortest time of biodegradation was observed for the
lowest MW chitosan They also tested several incubation tempera
tures recommending 30°C for faster degradation
Another way to reduce polymerization degree of chitosan is the
use of physicochemical treatment such as oxidationreduction
reaction [393] or free radical degradation [394] Nordtveit et al
[395] demonstrated that the viscosity of chitosan solution decreased
rapidly in the presence of hydrogen peroxide (H2O2) and FeCl3
Chang et al [396] studied the degradation of chitosan using hydro
gen peroxide Low concentrations of hydrogen peroxide (0515)
induced random degradation of chitosan with a degradation rate
increasing with temperature Finally Tanioka et al [397] showed
that Cu(II) ascorbate and UVH2O2 systems gradually reduced the
molecular weight of chitosan They postulated that the hydroxyl
radicals generated in the experimental systems caused the polymer
degradation
Much less studies are available concerning the biodegradation
of chitosan derivatives but impact of DD seems to follow the same
trend In the work of Ganji et al [398] biodegradation of an N
isopropylacrylamide (NIPAAm) grafted chitosan was studied As
for native chitosan the degradation rate decreased (75 to 55
weight loss) with increasing the degree of deacetylation (825 to
9834) Moreover the polymer concentration was found to have
significant impact on biodegradation as over 30 days of degrada
tion sample with 1 polymer content was degraded 70 whereas
sample with 2 polymer content was only degraded 55 It can
then be concluded that as the chitosan concentration increases the
degradation rate decreases Another graftedchitosan polymer (chi
tosangraftpoly(1 4dioxan2one)) has been studied for drug re
lease application showing less biodegradation susceptibility than
native chitosan [399]
McConnell et al [400] studied the degradation of crosslinked
chitosan films The amount of enzymes needed to degrade chitosan
films was influenced by the crosslinker as the sample prepared
with glutaraldehyde was more degraded than the one with tripoly
phosphate When using 10mM APSTMEDA (ammonium persul
fate NNN’N’tetramethylethylenediamine) as crosslinker the
resulting polymer was found to be stable during more than 18 days
as no dry weight loss was observed during the period in presence of
lyzozyme [401]
Lee et al [402] prepared 2060 Nacyl chitosans with various
carboxylic anhydrides (acetic propionic nbutyric nvaleric and n
hexanoic) and studied their biodegradation Results have shown that
NAcyl chitosans had a high susceptibility to lysozyme It was con
sidered that the amount of derivatized groups and the physical form
of Nacyl chitosans contributed to biodegradability Finally Lu et
al [403] developed a carboxymethylchitosan crosslinked with
EDC hydrochloride for nerve repair purpose and studied its biode
gradability Results have shown a similar degradation rate than for
native chitosan during the 2 first weeks followed by an increase in
degradation rate after this period
52 In vivo Biodegradation
There is much less studies concerning degradation of chitosan
in vivo and the mechanism of degradation is currently unclear
However studies indicate that as for in vitro studies degradation
and elimination processes are strongly dependent on DD and mo
lecular weight
Yang et al [404] studied the biodegradation of chitosan fibers
implanted between two nerve stumps of the rat sciatic nerve gap (6
months) The results suggested that chitin fibers were more biode
gradable than chitosan and the biodegradation rate can be controlled
to desirable extent by the variation of acetylation degree It is sug
gested that Nacetylated chitosan is mainly depolymerized by
lysozyme and not by other enzymes or other depolymerization
mechanisms In vivo the lysozyme can be released from phagocytic
cells including macrophages and neutrophils being available for the
degradation of chitin and chitosan Same conclusions were done by
other authors who implanted chitosan in bones [405]
In rabbits chitosan oligosaccharides enhanced lysozyme activ
ity in the blood when injected intravenously It was suggested that
the possible sites of degradation could implied kidney and liver
[406] For chitosan orally administered degradation seems to occur
mainly in the gut but digestion level varied depending on the ani
mals tested For rabbits 3983 degradation was observed
whereas it reached 6798 for hens [407]
When studying subcutaneous implantation of chitosan Kofuji
et al [408] observed a degradation of polymer within 3 days for 70
and 80 DD samples whereas the 90 DD polymer remained
intact for a longer time For drug release applications DD is then an
important parameter to control When a longer remaining time is
needed a crosslinkedchitosan can be used Jameela and
Jayakrishnan [409] prepared microspheres of 74 DD chitosan
crosslinked with glutaraldehyde and observed that 3 months were
needed for significant in vivo degradation in rat muscle For skin
substitute purpose a glutaraldehyde crosslinked chitosancollagen
as been tested subcutaneously in rabbits showing longer degrada
tion time as compared to collagen alone [410]
6 LIFECYCLE OF CHITOSAN AND DERIVATIVES
Sustainable chemistry is the attempt to design chemical prod
ucts and processes that reduce or eliminate the use and generation
of hazardous substances minimize waste and energy consumption
favor renewable resources and integrate aspects of recycling Life
cycle assessment (LCA) is a technique to evaluate the environ
mental aspects related to a product where the product is followed Bioactivity of Chitosan and its Derivatives Current Organic Chemistry 2018 Vol 22 No 7 659
from raw materials extraction through production and use to its
disposal LCA must take into account each step of the products’
life evaluating its impact on several categories such as ecosystem
impact climate change land use energy consumption health…
Since the last decade many studies of LCA have been published
but in many cases do not concern the complete lifecycle of a prod
uct Complete LCA have been essentially conducted for the envi
ronmental impact estimation of biofuels or pharmaceutical drugs
productions [411414] Some studies related to biobased products
exists and have shown low environmental impact compared to pe
troleumbased products [415]
The only studies dealing with chitosan lifecycle assessment
were conducted by Leceta et al [416 417] on chitosan films for
food packaging Results have shown globally a lower environ
mental impact than for polypropylene or other biobased films
The different steps of chitosan lifecycle are summarized on
Fig (7) It can be defined 5 steps including extraction of chitin
chemical modification (deacetylation chemical modification to
produce derivatives) manufacturing (in which we can include for
mation of films beads hydrogels… depending on the application)
use and at the end the biodegradation or the recycling of product
Chitosan is usually extracted from crustaceans which are the most
abundant source of chitin and is available as byproduct This ex
traction step generally implies hydrochloric acid and sodium hy
droxide having a negative impact on the final score as well as the
chemicals used for deacetylation or the acetic acid used to dissolve
chitosan Nevertheless it can be assumed that the global score of
chitosan should be good Compared to polypropylene films studied
by Leceta et al [416 417] the biodegradation ability of chitosan
gives an advantage Furthermore the production of chitin does not
require land use which is a negative point for several other bio
based products Nevertheless it can be assumed that environmental
impact of the production of chitosan derivatives should be less fa
vorable than chitosan mainly due to chemical reagents use
In the next future due to the increasing number of applications
for chitosan and derivatives it would then be essential to analyze
the sustainability of chitosan using lifecycle assessment methods
CONCLUSION
Chitosan and its derivatives in the pharmaceutical biomedical
and biological fields have probably been the most wellstudied
chemicals since the last decade As mentioned earlier much pro
gress has been reported in modification of chitosan by physical
chemical and enzymatic ways Overall many features try to en
hance the chitosan applicability in a large pH range Chitosan has
many functional groups and hydrophilic andor hydrophobic can be
easily attached to modulate its properties implying unlimited pos
sibility of applications The major concern is still the molecular
variability of natural crustacean chitin This heterogeneity can have
a great impact for creating new active derivatives especially for
medicine or pharmaceutics The use of fermentation process for
microbial production of chitinchitosan as an alternative seems
promising but needs further development to reduce costs Finally
significant advances in chitosan modifications and associated bio
logical activities could be made in future thanks to research by
scholars with various scientific backgrounds
LIST OF ABBREVIATIONS
AD Alzheimer’s Disease
AmpCSMNP Ampicillinchitosan Magnetic
Nanoparticules
APSTMEDA Ammonium Persulfate NNN’N’
Tetramethylethylenediamine
CI Crystallinity Index
CMCTSgMAS Maleic Acid Sodium (MAS)
Grafted Onto Carboxymethylchito
san Sodium (CMCTS)
CdS Cadmimum Sulfide
DD Degree of Deacetylation
DNA Deoxyribonucleic Acid
DMEC Dimethylethylchitosan
DPPH 22diphenyl1picrylhydrazyl
DS Degree of Substitution
DSP Dibasic Sodium Phosphate
EDC 1Ethyl3(3Dimethylaminopropyl)
Carbodiimide
EDGE Ethylene Glycol Diglycidyl Ether
EDTA Ethylenediaminetetraacetic Acid
EPA Environmental Protection Agency
FDA Food and Drug Administration
GAL Galantamine
GAL@CeHApCMC Galantamine Lceriacontaining
carboxymethyl chitosancoated hy
droxyapatite
GPTMS Glycidoxypropyltrimethoxysilane
GSH Glutathione
HMWC High Molecular Weight Chitosan
HPCTgMAS Maleic Acid Sodium (MAS)
Grafted Onto Hydroxypropyl Chito
san (HPCT)
HSA Human Serum Albumin
Fig (7) Lifecycle steps of chitosan and derivatives
Raw chitin
extraction
Chitosan or chitosan
derivatives
production
Manufacturing
Use
Biodegradation or
recycling
From crustacean
insects fungi
Deacetylation
Chemical modification
to produce derivatives
Production of films
hydrogels beads660 Current Organic Chemistry 2018 Vol 22 No 7 Laroche et al
HTCC N(2Hydroxy) Propyl3trimethyl
Ammonium Chitosan Chloride
LCA Life Cycle Assessment
LMWC Low Molecular Weight Chitosan
MDR MultiDrug Resistance
MIC Minimum Inhibitory Concentration
mRNA Messenger Ribonucleic Acid
MW Molecular Weight
NCS NSuccinyl Chitosan Derivatives
NIPAAm NIsopropylacrylamide
OCH OleoylChitosan Derivatives
OTMCS NOctylNTrimethyl Chitosan
PCCsGMA Glycidic Methacrylatephosphoryl
Cholinechitosan
PLGA Poly(lactidecoglycolide)
QDs Quantum Dots
RNA Ribonucleic Acid
ROS Reactive Oxygen Species
RSM Response Surface Methodology
siRNA Small Interfering Ribonucleic Acid
TEC Triethylchitosan
TEMPO 2266Tetramethylpiperidine1
oxyl
TMC Trimethyl Chitosan Chloride
TRH ThryrotropinReleasing Hormone
CONSENT FOR PUBLICATION
Not applicable
CONFLICT OF INTEREST
The authors declare no conflict of interest financial or other
wise
ACKNOWLEDGMENTS
The authors thank Dr Chen Yu for providing the opportunity to
contribute to this fullthematic special issue
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