International Journal of Biological Macromolecules 40 (2007) 175–181
Review
Sulfated chitin and chitosan as n
Abstract
Chitin and
and chitosan
of chitin and
The sulfated
antibacterial
chitin and ch
From the stu
© 2006 Else
Keywords: A
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
2. Synthesis of sulfated chitin and chitosan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
3. Applications of sulfated chitin and chitosan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
3.1. Blood anticoagulant and hemagglutination inhibition activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
3.2. Adsorbing metal ions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
3.3.
3.4.
3.5.
4. Conc
Ackn
Refer
1. Introdu
Chitin,
supporting
consist of
2-deoxy-d-
exceptiona
∗ Correspon
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doi:10.1016/jAntimicrobial agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
Drug delivery applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
Anti HIV-1 activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
lusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
owledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
ences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
ction
a naturally abundant mucopolysaccharide, and the
material of invertebrates such as crustaceans, insects,
a homopolymer of -(1→4) linked 2-acetamido-
glucopyranose residues. Its immunogenicity is
lly low, in spite of the presence of nitrogen. It is a
ding author. Tel.: +81 6 6368 0871; fax: +81 6 6330 3770.
dress: tamura@ipcku.kansai-u.ac.jp (H. Tamura).
highly insoluble material resembling cellulose in its solubility
and chemical reactivity due to close chemical structure. Chi-
tosan is the deacetylated derivative of chitin [1,2]. Chitin and
chitosan are of commercial interest due to their high percentage
of nitrogen (6.89%) compared to synthetically substituted
cellulose (1.25%). As most of the present-day polymers are
synthetic materials, their biocompatibility and biodegradability
are much more limited than those of natural polymers such
as cellulose, chitin, chitosan and their derivatives. However,
these naturally abundant materials also exhibit a limitation in
their reactivity and processability. In this respect, chitin and
– see front matter © 2006 Elsevier B.V. All rights reserved.
.ijbiomac.2006.06.021R. Jayakumar, N. Nwe, S. Tokura, H. Tamura ∗
Biofunctionalization Laboratory, Faculty of Engineering and HRC, Kansai University, Osaka 564-8680, Japan
Received 8 June 2006; received in revised form 27 June 2006; accepted 28 June 2006
Available online 1 July 2006
chitosan are known to be natural polymers and they are non-toxic, biodegradable and biocompatible. Chemical modification of chitin
with sulfate to generate new bifunctional materials is of interest because the modification would not change the fundamental skeleton
chitosan, would keep the original physicochemical and biochemical properties and finally would bring new or improved properties.
chitin and chitosan have a variety of applications, such as, adsorbing metal ions, drug delivery systems, blood compatibility, and
field. The purpose of this review is to take a closer look about the different synthetic methods and potential applications of sulfated
itosan. Based on current research and existing products, some new and futuristic approaches in this context area are discussed in detail.
dies reviewed, we concluded that sulfated chitin and chitosan are promising materials for biomedical applications.
vier B.V. All rights reserved.
dsorbing metal ions; Biomaterials; Blood anticoagulant; Drug delivery; Sulfated chitin and chitosanovel biomaterials

176 R. Jayakumar et al. / International Journal of Biological Macromolecules 40 (2007) 175–181
chitosan are recommended as suitable functional materials,
because these natural polymers have excellent properties
such as b
adsorption
aqueous so
and chitos
water, biom
It shows s
antibacteria
been propo
Chemic
biofunction
cedure wou
chitosan wo
ical proper
[1–8]. The
hydroxyl g
products fo
of sulfated
logues of t
biomolecul
and antivir
Sulfona
inevitably f
ity in poly
uncertainty
from rando
can reveal
articles on
pharmaceu
mental fiel
there is no
synthetic m
tematise re
preparation
chitosan. T
rent applic
chitosan.
2. Synthes
Several
chitosan ha
chemical p
ers it could
ing propert
sulfating ag
sulfation o
the sulfatio
in a hetero
rides are in
used as rea
dure. Cons
the product
fated chitin
and phosph
age molecu
n sh
re b
ed un
mpe
in. C
ed a
nera
arry
-chl
]. T
ution
–5.3
ns. S
ties
sul
by re
nder
er d
actio
sal
ielde
N-s
scop
that
yme
ic ac
so pr
) and sulfur trioxide [36]. O-Sulfated N-acetyl chitosan
nthesized by reacting N-acetylated chitosan, DMF with
trioxide [36]. Sulfated O-CM-chitosan was prepared by
O-CM-chitosan, DMF and sulfur trioxide [36]. All the
ts were isolated in sodium or sodium acid salts to get
ield. Similarly, O-sulfated N-hexanoyl chitosan was pre-
y treating N-hexanoyl chitosan, DMF with sulfur trioxide
tosan sulfates (Fig. 2) were prepared by different methods
ve been reported [38]. Pseudo-homogeneous method of
d chitosan was prepared by using 2% chitosan solution,
rous mixture of DMF-dichloroacetic acid with chlorosul-
cid. The reaction was run at room temperature for 4 h and
llowed by the formation of gel. At the end of the reactioniocompatibility, biodegradability, non-toxicity and
properties. Both polymers are highly insoluble in
lution. Chitosan is soluble in organic acids. Chitin
an derivatives are used in various fields: treating
edical, cosmetic and agricultural or food industrial.
ome biological activities such as immunological,
l, wound healing activity, drug delivery and has
sed for tissue engineering applications.
al modification of chitin and chitosan to generate new
al materials is of primary interest because such pro-
ld not change the fundamental skeleton of chitin and
uld keep the original physicochemical and biochem-
ties depending on the nature of the group introduced
site specifies chemical modification of the amino and
roups in chitin and chitosan with sulfate can generate
r pharmaceutical applications, because the structure
chitin and chitosan served as nearest structural ana-
he natural blood anticoagulant heparin, demonstrate
ar mechanism of anticoagulant activity, antisclerotic
al activities [9–13].
tion reactions of multi-functional polysaccharides are
ollowed by the appearance of structural heterogene-
mer chains. On the other hand, this gives rise to
but on the other hand the some structures that emerge
m distribution of modified groups along the chain
new features of biological functions. A few review
the potential applications of chitin and chitosan for
tical, veterinary medicine, biomedical and environ-
d have already been reported [7,14–23]. However,
review about sulfated chitin and chitosan and its
ethod and applications. This review intends to sys-
lated issues that includes the various methods of
and potential applications of sulfated chitin and
he present review is an attempt to discuss the cur-
ations and future prospects of sulfated chitin and
is of sulfated chitin and chitosan
techniques to obtain sulfate derivatives of chitin and
ve been proposed due to the interesting biological and
roperties of such as heparin compounds. Among oth-
be mentioned their antibactericidal and metal chelat-
ies. Various methods which involve combinations of
ents and the reaction media have been used for the
f polysaccharides [24,25]. The common difficulty of
n of polysaccharides is that the reaction is performed
geneous medium, because most of the polysaccha-
soluble or only slightly soluble in the organic solvents
ction medium in the conventional sulfation proce-
equently, it can be assumed that the constitution of
is heterogeneous. Nagasawa et al. [26] prepared sul-
and chitosan by using sulfuric acid, tetrahydrofuran,
orous pentoxide at −20 ◦C, respectively. The aver-
lar weight and yield of the both sulfated chitin and
chitosa
structu
migrat
tion te
of chit
prepar
and ge
tosan c
using 2
[34–35
substit
be 1.39
positio
proper
The
tosan
salt, u
polym
The re
sodium
tion y
ture of
spectro
dence
carbox
sulfon
was al
(DMF
was sy
sulfur
using
produc
high y
pared b
[37].
Chi
and ha
sulfate
anhyd
fonic a
was foFig. 1. Structure of N-sulfofurfuryl chitosan.
owed the extent of degradation of the polysaccharide
y concentrated sulfuric acid. Each sulfated product
iformly as a single spot on electrophoresis. The reac-
rature and time has influenced the depolymerization
hitin and chitosan sulfate esters have been widely
nd reported in view of their anticoagulant activity
l interest as polyampholytes [27–33]. Sulfoethyl chi-
ing sulfonic acid groups have also been prepared by
oroethane sulfonic acid sodium salt in alkaline media
he sulfoethyl chitosan was obtained with a degree of
of 0.11–0.35 and the sulfur content was found to
2%. Substitution was involved both the O-6 and N-2
ulfoethyl chitosan films had good antithrombogenic
[34].
fonic acid function was also introduced into chi-
acting with 5-formyl-2-furansulfonic acid, sodium
the mild conditions of the Schiff reaction to avoid
egradation and O-substitution was reported [35].
n of chitosan with 5-formyl-2-furansulfonic acid,
t produced a viscous solution that upon hydrogena-
d N-sulfofurfuryl chitosan sodium salt. The struc-
ulfofurfuryl chitosan was shown in Fig. 1. Infrared
y, alkalimetry and elemental analysis provided evi-
the degree of substitution was 0.26. Sulfoethyl N-
thyl chitosan was synthesized from 2-chloroethane
id in organic media [35]. N,O-Sulfated chitosan
epared by using chitosan, N,N-dimethyl formamide