-
International Journal of Biological Macromolecules 43 (2008)
401414
Contents lists available at ScienceDirect
International Journal of Biological Macromolecules
journa l homepage: www.e lsev ier .com/ locate / i jb iomac
Review
Chitosaand en
N.M. Alva 3Bs Researchon Tissue Enginb IBB-Institute
a r t i c l
Article history:Received 12 AuReceived in reAccepted 8
SepAvailable onlin
Keywords:ChitosanChitosan derivBiomedical
apBiomaterialsPolysaccharides
Contents
1. Introd2. Graft
2.1.2.2.2.3.2.4.
3. Specia3.1.3.2.3.3.
4. Smar4.1.4.2.
5. Applic5.1.5.2.5.3.5.4.5.5.
6. ConclRefere
CorresponEuropean InstiGuimares, Po
E-mail add
0141-8130/$ doi:10.1016/j.iuction . . . . . . . . . . . . . . .
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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . 402copolymerization . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . 402Grafting initiated by free
radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . 402Grafting using radiation . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 403Enzymatic grafting . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . 404Cationic graft polymerization . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . 405l cases
of chitin and chitosan modications . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . 405Phosphorylated chitin and chitosan . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. 405Combination of chitosan derivatives with cyclodextrins . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . 406Thiol-containing chitosan . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 407
t chitosan: example of new chitosan-based hydrogels exhibiting
temperature-responsive behaviour . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . 408Graft copolymerized
hydrogels . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . 408Chemically crosslinked blends . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 410ations for modied chitosan materials . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . 410Drug delivery
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . 410Tissue
engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . .
411Antimicrobial agents and other biomedical applications . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . 411Adsorption of metal ions . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . 412Dye removal . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . 412
usions . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . 412nces . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . 412
ding author at: 3Bs Research Group - Biomaterials,
Biodegradables and Biomimetics, Dept. of Polymer Engineering,
University of Minho, Headquarters of thetute of Excellence on
Tissue Engineering and Regenerative Medicine, AvePark, Zona
Industrial da Gandra, S. Cludio do Barco, 4806-909 Caldas das
Taipas,rtugal.ress: [email protected] (N.M. Alves).
see front matter 2008 Elsevier B.V. All rights
reserved.jbiomac.2008.09.007n derivatives obtained by chemical
modications for biomedicalvironmental applications
esa,b,, J.F. Manoa,b
Group - Biomaterials, Biodegradables and Biomimetics, Dept. of
Polymer Engineering, University of Minho, Headquarters of the
European Institute of Excellenceeering and Regenerative Medicine,
AvePark, Zona Industrial da Gandra, S. Cludio do Barco, 4806-909
Caldas das Taipas, Guimares, Portugalfor Biotechnology and
Bioengineering, Braga, Portugal
e i n f o
gust 2008vised form 5 September 2008tember 2008e 16 September
2008
ativesplications
a b s t r a c t
Chitosan is a natural based polymer, obtained by alkaline
deacetylation of chitin, which presents excel-lent biological
properties such as biodegradability and immunological,
antibacterial and wound-healingactivity. Recently, there has been a
growing interest in the chemical modication of chitosan in order
toimprove its solubility and widen its applications. The main
chemical modications of chitosan that havebeen proposed in the
literature are reviewed in this paper. Moreover, these chemical
modications leadto a wide range of derivatives with a broad range
of applications. Recent and relevant examples of thedistinct
applications, with particular emphasis on tissue engineering, drug
delivery and environmentalapplications, are presented.
2008 Elsevier B.V. All rights reserved.
-
402 N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414
1. Introduction
Chitosan is typically obtained by deacetylation of chitin
underalkaline comaterials, bannually byexoskeletoninsects. It
iscertain fungcomposedo (14) glycdegree of dered thatwhon the
origialong the chand in thesthe biodegricant decreafully
deacetobserved [1
Chitosanibility, biodnon-toxic, nfore,
chitosbiomedicinocculationsolutions, w
Recentlyication ofapplicationgroups to tgroups [10,1neutral
andter. Substitupolymers wmethods ofused.Graftitives by
covbackbone. Cgrafted. Firsondly, the hor deacetylprimary deobtain
mucidant propeto improvecomplexatiing adsorptmodies itsing
charact[20,21] and
The maiify chitosanexamples oused will besuch modidiscussed.
2. Graft co
As said btomodify chsystems suc(PPS), ceric
bromate (TCPB), potassium diperiodatocuprate (III) (PDC),
2,2-azobisisobutyronitrile (AIBN) and ferrous ammonium sulfate
(FAS)have been developed to initiate grafting copolymerization
[2326].
opoles. Tg efs theion,ng grf ther. Unariaultanve exg chi
aftin
ft codicalthe
ymetan
reactnalyciened wl chiing a
grafymetr wivesuminn deilityydro
scave. Acycarerizain wimewellPoly(y N-ly soft cocarrese
ny kithertiesvinyd [280%ed windi
graftstab
e incess awa
methnditions, which is one of the most abundant organiceing
second only to cellulose in the amount producedbiosynthesis. Chitin
is an important constituent of thein animals, especially in
crustaceans, molluscs andalso the principal brillar polymer in the
cell wall ofi. As shown in Fig. 1, chitosan is a linear
polysaccharide,f glucosamineandN-acetyl glucosamineunits
linkedbyosidic bonds. The content of glucosamine is called the
eacetylation (DD). In fact, in a general way, it is consid-en
theDDof chitin ishigher thanabout50% (depending
nof thepolymer andon thedistribution of acetyl groupsains), it
becomes soluble in an aqueous acidic medium,e conditions, it is
named chitosan. The DD also affectsadability of this polymer, and
for DD above 69% a signif-se in in vivo degradation has been found
[1]. In fact, forylated chitosan, no susceptibility to lysozyme has
been,2].displays interesting properties such as biocompat-
egradability [3,4] and its degradation products
areon-immunogenic and non-carcinogenic [5,6]. There-
an has prospective applications in many elds such ase, waste
water treatment, functional membranes and. However, chitosan is
only soluble in few dilute acidhich limits its applications.,
therehasbeenagrowing interest in the chemicalmod-chitosan in order
to improve its solubility and widen itss [79]. Derivatization by
introducing small functionalhe chitosan structure, such as alkyl or
carboxymethyl1] can drastically increase the solubility of chitosan
atalkaline pHvalueswithout affecting its cationic charac-tion with
moieties bearing carboxylic groups can yieldith polyampholytic
properties [12]. Among the variousmodication, graft
copolymerization has been themostngof chitosanallows the
formationof functional deriva-alent binding of a molecule, the
graft, onto the chitosanhitosan has two types of reactive groups
that can bet, the free amine groups on deacetylated units and
sec-ydroxyl groups on the C3 and C6 carbons on acetylatedated
units. Recently researchers have shown that afterrivation followed
by graft modication, chitosan wouldh improved water solubility,
antibacterial and antiox-rties [13,14]. Grafting chitosan is also a
common wayother properties such as increasing chelating [15] or
on properties [16], bacteriostatic effect [17] or enhanc-ion
properties [18]. Although the grafting of chitosanproperties, it is
possible to maintain some interest-
eristics such as mucoadhesivity [19],
biocompatibilitybiodegradability [22].n methods that have been used
to chemically mod-will be described in this paper. Some
representative
f the chemical reactions and experimental conditionspresented.
Finally the most important applications of
ed chitosan-based materials in different elds are also
polymerization
efore, graft copolymerization is the main method useditosan
chemically. In recent years, a number of initiatorh as ammonium
persulfate (APS), potassium persulfateammonium nitrate (CAN),
thiocarbonationpotassium
Graft cenzymgraftinsuch acentratresultiistics onumbethese vthe
ressentatigraftin
2.1. Gr
Grafree ratists incarboxAPS asMAA,were aing
efimprovypropyobtainwater.
Thecarboxinitiatoderivatchemilchitosaing abwith
haniongroupscarbonpolymlamidethree-dmers stimes.tosan bpartial
Graalso bePPS. Thon maas a leapropertion ofreporte70
andincreasresultsin theing thethat thtoughn
CANN,N-diymerization can also be initiated by -irradiation andhe
grafting parameters such as grafting percentage andciency are
greatly inuenced by several parameterstype and concentration of
initiator, monomer con-
reaction temperature and time. The properties of theaft
copolymers are widely controlled by the character-side chains,
including molecular structure, length, andtil now, many researchers
have studied the effects ofbles on the grafting parameters and the
properties oft grafted chitosan (e.g., Refs. [14,2326]). Some
repre-amples of the previously mentioned methods used fortosan will
now be described separately.
g initiated by free radicals
polymerization of vinyl monomers onto chitosan usinginitiation
has attracted the interest of many scien-last two decades. For
example, Sun et al. preparedhyl chitosan-grafted methacrylic acid
(MAA) by usinginitiator in aqueous solution [27]. The effects of
APS,ion temperature and time on graft copolymerizationsed by
determining the grafting percentage and graft-cy. After grafting,
the chitosan derivatives had muchater solubility. Similarly, Xie et
al. prepared hydrox-
tosan-grafted MAA by using APS initiator (Fig. 2)
[14],derivative that also presented a good solubility in
t copolymerization of maleic acid sodium (MAS) ontohyl chitosan
and hydroxypropyl chitosan using APSas reported [28]. The
antioxidant activity of thesewas evaluated as superoxide anion
scavengers byescence technology. Compared with chitosan, the
graftrivatives were found to have an improved scaveng-against
superoxide anion. Graft chitosan derivativesxypropyl groups had
relatively higher superoxidenging ability owing to the
incorporation of hydroxyllation of chitosan with maleic anhydride
furnishes
bon double bonds, which are available for subsequenttion. The
copolymerization of the derivative with acry-ater in the presence
of APS has been used to obtain
nsional crosslinked products [29]. The resulting copoly-ed
highly in water with a volume increase of 201503-hydroxy-butylate)
could also be introduced into chi-acylation, and the resulting
copolymer was found to beluble in water [30].polymerization of
vinyl monomers onto chitosan canied out using redox initiator
systems, such as CAN andsystems have been used to produce free
radical sitesnds of polymers. Poly(vinyl acetate) (PVAc) is knowny
and water-resistant polymer, which may improve theof chitosan
material and hence the graft polymeriza-l acetate onto chitosan by
using CAN as an initiator was3]. The monomer conversion was found
to be betweenafter 2h of reaction at 60 C. The grafting efciencyith
increasing amount of chitosan. The experimentalcated that the
chitosan molecules not only took partcopolymerization but also act
as a surfactant, provid-ility of the dispersed particles. The data
also showedorporation of PVAc to the chitosan chains increased
thend decreased the water absorption of chitosan.s also found to be
a suitable initiator for
graftingyl-N-methacryloxyethyl-N-(3-sulfopropyl) ammonium
-
N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414 403
Fig. 1. Chemical structure of chitosan.
[31], poly(acrylonitrile) (PAN) [32], polyacrylamide,
poly(acrylicacid) and poly(4-vinylpyridine) [33] onto chitosan.
Chitosan was modied with poly(acrylic acid), a well
knownhydrogel forming polymer, using a grafting reaction in a
homoge-neous phase [25]. The grafting was carried out in presence
of PPSand FAS as the combined redox initiator system. It was
observedthat the levvarying theThe maximrather highliterature
foThis result rtions takes pthe whole seffects of thefciency
opresence ofversion ofHmaterial wmay be usesynthetic
A novelto initiate ttosan in alkemployed asystem usethat there
iPDC as anemployingmerizationalkali aqueotors. Graft cby using
AIB
methacrylate, methyl acrylate, and vinyl acetate were grafted
ontochitosan with AIBN in aqueous acetic acid solutions or in
aqueoussuspensions [26].Here, the graftingpercentageswere generally
low[26]. Fentons reagent (Fe2+/H2O2) was also successfully used as
aredox initiator for grafting methyl methacrylate onto chitosan
[36].Although chitosan is an effective occulating agent only in
acidic
theionind b
aftin
entlysing
and cvestied dundsorbeg ofMA)er cund
studyitosag conbutydy,
onomthe csed.antsharpel of grafting could be controlled to some
extent byamount of ferrous ion as a co-catalyst in the reaction.um
efciency of grafting attained in this work (52%) isbut it is
comparablewith values reported recently in ther the grafting of
vinyl monomers onto polysaccharides.evealed that inhomogeneous
systems thegrafting reac-lace not only on the surface but also in
themolecules ofubstrate. Tahlawy and Hudson [34] have discussed
thee reaction conditions and temperature on the graftingf
2-hydroxyethylmethacrylate (HEMA) onto chitosan inredox initiators,
in this case TCPB. Here, the total con-EMAmonomerwas found to be up
to 75%. The resultingas found to increase the hydrophilicity and
therefored as textile nishes enhancing the hydrophilicity of
bers.redox system, PDC [Cu (III)chitosan], was employedhe graft
copolymerization of methyl acrylate onto chi-ali aqueous solution
[35]. In this work, Cu (III) wass an oxidant and chitosan as a
reductant in the redoxd to initiate the grafting reaction. The
result showeds a high grafting efciency and percentage when
usinginitiator. Since the activation energy of the reactionCu
(III)chitosan as an initiator is low, the graft copoly-is carried
out at a mild temperature of 35 C and inus medium, which makes it
superior to other initia-
opolymerization onto chitosan has also been attemptedN. Some
vinyl monomers such as acrylonitrile, methyl
media,zwitteracidic a
2.2. Gr
Recmers uchitinwas inadsorbwas fothe adgraftin(DMAEmonomwere
foIn thisonto chgraftintion ofthis stuthe mwhendecreasignicited
aFig. 2. Graft copolymerization of MAA on hydroxyderivatives having
side chain carboxyl groups showedc characteristics with high
occulation abilities in bothasic media.
g using radiation
, a great interest has been made to graft natural poly-the
radiation method. Grafting of polystyrene ontohitosan using 60Co
-irradiation at room temperaturegated [37,38]. The effect of
various conditions such asose, solvent and oxygen on grafting was
analysed. Itthat the grafting yield increased with the increase ind
dose. Singh and Roy have also reported radiationchitosan with
N,N-dimethylaminoethylmethacrylate[39]. Parameters such as solvent
composition,
oncentration, radiation dose rate, and total dose/timeto affect
the rate of grafting and homopolymerization., itwas found that
adesired levelof graftingofDMAEMAn lms was achieved by appropriate
selection of theseditions. Yu et al. have reported the graft
copolymeriza-l acrylate onto chitosan by using -irradiation [40].
Inan increasing grafting percentage was observed whener
concentration and total dose were increased orhitosan concentration
and reaction temperature wereUnder lower dose rates, the grafting
percentage had nochanges, whereas above 35Gy/min (dose rate)
exhib-decrease. Compared with the pure chitosan lm, thepropyl
chitosan.
-
404 N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414
chitosan grabicity and i
The grafhas been rethe sultematrix of gpolymerizamediator) wof
the chitostudy demochemical bi
Singh ethe microwtions [42].The effectsFig. 3. Enzymatic
grafting of chitosan with phenol
ft poly(butyl acrylate) lms have enhanced hydropho-mpact
strength.ting of poly(hydroxyethyl methacrylate) onto
chitosanported but in this case by applying UV light [41].
Here,oxidase enzyme was covalently immobilized onto therafted
polymer. After the completion of photo-inducedtion reaction,
P-benzoquinone (an electron transferas coupled onto the polymer
network for activation
sanpoly(hydroxyethyl methacrylate) copolymer. Thisnstrated the
feasibility of using chitosan in electro-osensor fabrication [41].t
al. grafted poly(acrylonitrile) onto chitosan usingave irradiation
technique under homogeneous condi-They have obtained 70% grafting
yield within 1.5min.of reaction variables as monomer and chitosan
con-
centration,copolymeriwith an inalso founddecreased.
2.3. Enzym
There arin polymerhealth andhazards assmental benexploited
totection stepand tyrosinase.
microwave power, and exposure time on the graftzation were
studied. The grafting was found to increasecrease in the monomer
concentration. Grafting wasto increase up to 80% microwave power
and thereafter
atic grafting
e several potential advantages for the use of enzymessynthesis
and modication [43,44]. With respect tosafety, enzymes offer the
potential of eliminating theociated with reactive reagents. A
potential environ-et for using enzymes is that their selectivity
may beeliminate the need forwaste full protection and depro-s.
Finally, enzymes specicity may offer the potential
-
N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414 405
tin and chitosan.
for preciselypolymer funyield chitosand adhesiv
Kumar elic compouconditionssubstrates i(pH 6), chitowith the
nawas solublethe degreehowever, requinones cabases or Miundergo
eitoligomer foreactions beof products
The feashexyloxyphmethod emo-quinone,with chitosachemicallyto
prepare ma syntheticproperties ochitosan, gring the surf
2.4. Cationi
Some yetions onto cpolymerizapoly(isobutwith controeffect of
mnumber ofgrafted polmolecularhindrancemolecular wpolymer
wagrafting. Th
3. Special c
Besidesducing sma
hemical modications of chitosan and chitin deserve to bed in
this chapter due to the potential applications of suchn
derivatives. These chemical modications are: phospho-n of chitosan
and chitin, combination of chitosan derivativesclodextrins and
thiolation of chitosan.
osphorylated chitin and chitosan
reaction of chitin with phosphorous pentoxide was
foundwater-soluble phosphorylated chitin of high degree of
ution (DS), constituting a strategy to overcome this majorck of
chitin and its derivatives. Phosphorylated chitin (P-and chitosan
(P-chitosan) were prepared by heating chitinosan with
orthophosphoric acid and urea in DMF [5052].itin and P-chitosan
were also prepared by the reaction of
or chacidn inobely thn ofity inylenhitosFig. 4. Synthesis of
phosphorylated chi
modifying macromolecular structure to better controlction
[45,46]. For instance, enzymaticmodication can
anderivativeswithuniquepH-sensitivewater solubilitye
properties.t al. [45] reported that enzymatic grafting of pheno-nds
onto chitosan confer water solubility under basic(Fig. 3).
Tyrosinase converts a wide range of phenolicnto electrophilic
o-quinones. In slightly acidic mediasan could be modied under
homogeneous conditionstural product chlorogenic acid. The modied
chitosanunder both acid and basic conditions, even when
of modication was low. The chemistry of quinones,mains poorly
characterized because of its complexity;n undergo two different
reactions to yield either Schiffchael type adducts. Since it is
possible for quinones toher or both type of reactions with amines,
as well asrming reactions with other quinones, it is common
fortween quinones and amines to yield complex mixtures.ibility of
using tyrosinase as a catalyst for graftingenol onto the chitosan
was also investigated [47]. Theployed tyrosinase to convert the
phenol into a reactivewhich undergoes subsequent non-enzymatic
reactionnunderhomogeneous conditions (Fig. 3). Fromthebio-
relevant quinones studied so far, it would seempossibleaterials
of medical interest. For instance, menadione,naphthoquinone
derivative having the physiologicalf vitamin K is particularly
prone to rapid reaction witheatly modifying its spectral
characteristics and increas-ace hydrophobicity of treated chitosan
lms [48].
c graft polymerization
ars ago, Yoshikawa et al. showed that grafting reac-hitosan can
also be performed by using living cationiction [49]. These authors
grafted chitosan with livingylvinyl ether) and
poly(2-methyl-2-oxazoline) cationlled molecular weight
distribution. In this study, theolecular weight of living polymer
cation on the molegrafted polymer was analysed. The mole number
of
other cincludechitosarylatiowith cy
3.1. Ph
Theto givesubstitdrawbachitin)or chit(Fig. 4)
P-chchitinphonicchitosafound tthat onporatiosolubilN-methusing
cymer chains was found to decrease with increasingweight of living
polymer cation, due to the stericof the functional groups of
chitosan with increasingeight of living polymer. The viscosity of
the resultings found to increase with the increasing percentage
ofis grafted polymerwas also found to be soluble inwater.
ases of chitin and chitosan modications
graft copolymerization and derivatization by intro-ll functional
groups to the chitosan structure, some Fig. 5. Chemicitosan with
phosphorous pentoxide in methane sul-[53,54]. The phosphorylation
reactions of chitin and
phosphorous pentoxidemethane sulphonic acid wereveryefcient
[5558].However, in this case itwas founde P-chitosan with low DS
was water soluble. The incor-methylene phosphonic groups into
chitosan allowedwater under neutral conditions [59]. A
water-solublee phosphonic chitosan (NMPC) was also synthesizedan,
phosphorous acid and formaldehyde [59].al structure of
N-lauryl-N-methylene phosphonic chitosan (LMPC).
-
406 N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414
Fig. 6. Synthesis of P-chitosan by grafting.
A simple methodology for the preparation of a new
chitosanderivative surfactant, N-lauryl-N-methylene phosphonic
chitosan(LMPC), has been developed [60] (Fig. 5). LMPC incorporated
N-methylene phosphonic groups as hydrophilic moieties and
laurylgroups as the hydrophobic ones.
N-Phosphonomethylation of chitosan reaction was studied
andoptimized using different reaction conditions [61]. The
reactionwas conducted with a large excess of both phosphorous acid
andformaldehyde at 70 C. The obtained white solid was found to
besoluble in neutral and acidic aqueous solutions.
Ramos et al. [62] prepared N-methylene phosphonic and
car-boxylic chitaldimine fohydride. Thcarboxylic a
P-chitos2-Carboxethtosan by us(EDC) medi
3.2. Combin
Cyclodexto eight (the enzymaThe d-glucoto form torgroups at
tside of thepositions ofCDs have gity, which isand other sbinding
siteis relatively
more important side of CD in binding studies [68,69]. The
stabilityof the CD-inclusion complex depends on the polarity of the
guestmolecule and on the compatibility of the size of the host and
thatof the guest [70].
Grafting CD molecules into chitosan-reactive sites may lead toa
molecular carrier that possess the cumulative effects of
inclu-sion, size specicity and transport properties of CDs as well
as thecontrolled release ability of the polymericmatrix [71]. The
differentmethods used to graft CD to chitosan and the inclusion
ability, sorp-tion and controlled release properties of the
products have beenreviewed recently [72]. Grafting of CD onto
chitosan has been per-
byith thive ey amcribearboer usHexano o(N
nkingitosaof uctivdicCD
nal gof arafte
rmyld byt, whin wan aosan (NMPCC) by using NMPC and glyoxallic
acid (viarmation) under reduction conditionswith sodiumboro-is new
chitosan multidentate ligand presents bothnd phosphonic groups
[62].an was also synthesized by graft copolymerization
[63].ylphosphonic acid was covalently attached onto chi-ing
1-ethyl-3-(3-dimethylaminopropyl) carbodiimideated coupling
reaction (Fig. 6).
ation of chitosan derivatives with cyclodextrins
trins (CDs) are cyclic oligosaccharides built from six=6, =7,
=8) d-glucose units and are formed duringtic degradation of starch
and related compounds [64].se units are covalently linked together
by 1,4 linkagesus-like structures (Fig. 7). All the secondary
hydroxylhe 2- and 3-positions of the glucose units are on onetorus,
and all the primary hydroxyl groups at the 6-the glucose units are
on the other side of the ring [65].ained prominence in recent years
because their cav-hydrophobic in nature, is capable of binding
aromaticmall organic molecules, and therefore provides ideals
[66,67]. Selective functionalization at the 6-positioneasy.
However, the secondary side is shown to be the
formedEDC wan actprimaral. despling coligom
1,6-of amigroupscrossliin a chgroups
Redthemoduce
afunctiomation-CD-g2-O-fofolloweproducsolublehavingFig. 7. Chemical
structure of CDs.adopting distinct strategies. A possible way is to
reacte carboxyl group of carboxymethylated -CD to form
ster intermediate. The intermediate can react with aine of
chitosan to form an amide linkage. Furusaki etd the preparation of
a -CD-grafted chitosan by cou-xymethylated -CD and a partially
deacetylated chitining water-soluble EDC [73].methylene
diisocyanate (HMDI), a strong crosslinkerr hydroxyl groups since it
possesses two isocyanateaCaO) has also been used [72]. It is
assumed that theof the hydroxyl groups of chitosan with HMDI
resulted
nHMDI complex, which then binds with the hydroxyl-CD to form
-CD-g-chitosan.e amination, one of the major reactions applicable
toation of chitosan, has been successfully applied to intro-residue
into chitosan. CD derivatives with aldehyderoups are useful to
graft CD into chitosan by the for-Schiffs base. Tanida et al.
reported the synthesis ofd chitosan by the formation of a Schiffs
base between
methyl--CD and chitosan in acetate buffer at pH 4.4,reduction
with sodium cyanoborohydride [74]. The
ich had a degree of substitution of 37%, was found to beater at
neutral and alkaline conditions. Porous beadsbility to form
inclusion complexes with specic sub-
-
N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414 407
onate
strates wereof chitosanquent crosswere furtheof sodium cgrafted
chitintroductiofrom the wisituation mbeen shownof CDs couconstant
of
Recentlychitosan ussuch as CANCD onto chpared by reusing
CANestericatiothen the pein the graftant producconcentratireactive
site
her intera
guesto
undsorptnd hFig. 8. Reaction scheme for the synthesis of CD
itac
synthesized by adding an aqueous acetic acid solutioninto
ethanolic aqueous sodium hydroxide and subse-linking with HMDI in
DMF [75]. The resulting beadsr treated with 2-O-formylmethyl--CD in
the presenceyanoborohydride in acetate buffer at pH 4.4, giving
CD-osan beads. In terms of CD-inclusion complexes, then of a
guestmolecule in the cavity classically takes place
also otbond inguest
Duewas fothe adterol ader secondary hydroxyl groups side
although the otheray also be encountered, depending on the guest.
It hasthat the steric hindrance effects due to substitution
ld result in an important decrease of the associationcomplexes
[76]., a new synthetic route was reported to graft-CD ontoing an
epoxy-activated chitosan [77]. Redox systems,and potassium
persulfate have also been used to graft
itosan. For example, -CD-grafted chitosan was pre-acting -CD
itaconate vinyl monomer with chitosan[78]. In this work, -CD
itaconate was prepared byn of -CD with itaconic acid in a semidry
process andndent double bonds of -CD itaconate were utilizedt
copolymerization onto chitosan (Fig. 8). The resul-t was then
subjected to crosslinking using differentons of glutaraldehyde.
This work showed that not onlys play an important role in the
sorptionmechanism, but
with iodinewith p-nitrthiopurine,
3.3. Thiol-c
Thiol-coobtained th(Fig. 9). In th[79]. EDC isin the 4.06has
been wamines. Thigroup of chboxylic acida O-acylurethe primary
Fig. 9. Synthesis of thiol-containing chit-g-chitosan using
CAN.
teractions, probably physical adsorption and hydrogenctions, due
to the crosslinking agent, and hydrophobict interactions.the CD
moiety present in the chitosan backbone, itthat -CD-grafted
chitosan has some selectivity forion of TNS, bisphenol A,
p-nonylphenol, and choles-as the stronger inclusion and slow
release ability
[72]. CD-grafted polymers form hostguest complexesophenol,
p-nitrophenolate, tert-butylbenzoic acid, 6-p-dihydroxybenzene, and
copper ions [72].
ontaining chitosan
ntaining chitosan, also called thiolated chitosan, isrough the
reaction between chitosan and thiolactic acidis reaction,
EDCcanbeused to graft these twomaterialsawater-soluble carbodiimide
that is typically employed.0 pH range. It is a zero-length
crosslinking agent thatidely used to couple carboxylic acid groups
to primaryolactic acid is covalently attached to the primary
aminoitosan under the formation of amide bonds. The car-moieties of
thiolactic acid are activated by EDC forminga derivative as an
intermediate product that reacts withamino groups of chitosan. When
compared with other
osan.
-
408 N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414
f chit
modied chadvantageohesive andsolutions ofphysiologic
4. Smart chydrogels e
Smart hyphase chantors. Amongbeen the mapplicable
itemperaturtive thermotemperaturuids, due ting a LCSTinjectable aa
well knoaround 32
below thewater.
Great atcations, towith uniquand biologithermo-respolymeric
cpolysaccharhave been cdue to the ppolymer wstimuli-respvehicles
thain the humpolymeric g
al msom
aft co
roges typof 25g chentorphBN, 2, N,N,chniqFig. 10. Reaction
scheme for the preparation o
itosan materials, thiolated chitosans have numerousus features,
such as signicantly improved mucoad-permeation enhancing properties
[8085]. Moreover,thiolated chitosans display in situ gelling
properties atal pH values [82].
hitosan: example of new chitosan-basedxhibiting
temperature-responsive behaviour
drogels canundergo a reversible discontinuous volumege in
response to various external physicochemical fac-them, temperature
and pH-responsive hydrogels haveost widely studied, because these
two factors can ben vivo. Polymer solutions have a lower critical
solution
chemicwell as
4.1. Gr
Hydvariourangeswellindependand mAPS, AI(AIBA)tion tee (LCST)
contract byheating above the LCST. Thesenega--reversible hydrogels
can be tuned to be liquid at roome and to undergo gelation when in
contact with bodyo an increase in temperature. Therefore, polymers
hav-below human body temperature have a potential forpplications.
Poly(N-isopropylacrylamide) (PNIPAAm) iswn thermally reversible
polymer, exhibiting a LCSTC in aqueous solution [86]. PNIPAAm
hydrogels swellLCST and shrink above the LCST, when immersed in
tention has been paid, especially for biomedical appli-the
development of stimuli-responsive polymeric gelse properties such
as biocompatibility, biodegradabilitycal functionality. They may be
prepared by combiningponsive polymers such as PNIPAAm with natural
basedomponents, to form smart hydrogels [8791]. Someides, such as
chitosan, alginate, cellulose and dextran,ombined with
thermo-responsive materials. Moreover,H-sensitive character of
chitosan, combination of this
ith a thermo-responsive material will produce dual-onsive
polymeric systems that can be used as deliveryt respond to
localized conditionsof pHand temperaturean body. A review on
natural based stimuli-responsiveels has been recently published
[92]. Next the twomain
Fig. 10 showPNIPAAm u
Chitosansoapless emAIBA may bthe copolympH value.
Graft cohave beenprepared bswelling ratpH and tem
Kimet aepoxy-termUV irradiattosan wereThe
graftingincreasingdose. The sincreased wcated that tamount of t
Graft cosation reacosan-g-PNIPAAm.
odications used to prepare these smart hydrogels ase relevant
examples are presented.
polymerized hydrogels
ls prepared by graft copolymerization of NIPAAm ontoes of
polysaccharides have shown a LCST in the34 C. Properties such as
volume phase transfer andaracter of the hydrogels, were found to be
mainlyon their polymers weight ratio, crosslinking densityology. A
number of initiator systems, such as
CAN,,2-azobis-(2-methylpropionamidine)
dihydrochlorideN,N-tetramethylethylene diamine (TEMED) and
radia-ues have been reported to graft NIPAAm onto chitosan.
s the reaction that can be used to prepare chitosan-g-
sing CAN [93].-g-PNIPAAm particles can also be synthesized by
aulsion copolymerization method [94]. Either APS ore used as
initiators. In this case the swelling ratio ofer decreased with
increasing crosslinking density and
polymers based on a maleilated chitosan and NIPAAmsynthesized by
UV radiation. Maleilated chitosan wasy reacting chitosan with
maleic anhydride [95]. Theioofmaleilated
chitosan-g-PNIPAAmdependedonbothperature of the aqueous solution.l.
synthesized hydrogels based on grafting chitosanwithinated
poly(dimethylsiloxane) (PDMS) also by usingion [96]. Hydrogels
based on PNIPAAm-grafted chi-obtained but in this case by applying
-irradiation [97].percentage and the grafting efciency increased
with
the monomer concentration and the total irradiationwelling
ratios of these chitosan-g-PNIPAAm hydrogelsith the increase of the
grafting percentage, which indi-he swelling behaviour of the
hydrogels depends on thehe grafted branches.polymers can also be
prepared by using the conden-tion in the presence of EDC. Lee et
al. synthesized
-
N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414 409
comb-typeterminatedcatalyzes thacid groupgroups ofof
carboxytosan is shcomb-typesensitivitychitosan mtively.
Recentlymulti-respobecause ofcomponentpared fromFig. 11.
Preparation of carboxyl-terminated PNIPAAm and c
graft hydrogels, composed of chitosan and carboxyl-PNIPAAm by
using this carbodiimide [98]. EDCe formation of amide bonds between
the carboxylics of carboxyl-terminated PNIPAAm and the
aminechitosan. The reaction scheme for the preparationl-terminated
PNIPAAm, and its grafting onto chi-own in Fig. 11. In the
swelling/deswelling behaviour,graft hydrogels showed rapid
temperature and pHbecause of the free-ended PNIPAAm attached to
theain chain and the chitosan amine group itself, respec-
, microgels with more complex structures, such as ansive
coreshell, have received increasing attentionthe tunable properties
of the individual responsives. Various types of coreshell microgels
have been pre-the PNIPAAm-grafted polysaccharides. Leung et al.
[99,100] detemperaturPAAm andco-NIPAAmacid (MMA[101]. Herewas
preparwas prepare
BesidesPNIPAAm wsensitive grcase of thosbased on p(PPO), knowet
al. prepaon chitosanomb-type graft hydrogel.
veloped smart microgels that consist of well-denede-sensitive
coreswith pH-sensitive shells based on PNI-chitosan. The properties
of crosslinked poly(chitosan-)/poly[methacrylic acid
(MAA)-co-methyl methacrylic)] coreshell type copolymer particles
were examined, the crosslinked copolymer of NIPAAm and chitosaned
as the core, and the copolymer of MAA and MMAd as the shell.the
many works that propose the association ofith chitosan, other few
examples of distinct thermo-aft copolymerized hydrogels can be
found. This is thee systems that combine amphiphilic block
copolymersoly(ethylene oxide) (PEO) and poly(propylene oxide)n as
poloxamers, with chitosan. For instance, Creuzet
red this kind of hydrogels by grafting PEOPPO blocks[102].
-
410 N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414
4.2. Chemically crosslinked blends
Stimuli-responsive hydrogels can also be obtained by blend-ing
biopolyvarious meassembly ois synthesizsystem is ccomponentthe
linear fform a gel tbeen well dsoluble polsuch as gluin the
presmers seemSomeworktosan/glutais this kindotosan and Pincreases
asincreases. Kbased on chural crosslihydrogels smakes the g
A full-IPtion of a menetwork wiThe authorincluding ttransition
bthe swellinmicrostructing semi-IPswell fasterswelling
rattemperatur
5. Applicat
The potimportant neering andattempt isand future p
5.1. Drug de
As said ical charactetoxicity [5,6enzymes, ethese favortives in
druyears. Moretant that chproperties emacromole
Many wand its derhas been strimethyl cfeature of a
drug delivery [10,108,109]. Acrylic acid grafts of chitosan as
pos-sible means of creating hydrophilic and mucoadhesive
polymers,have been reported recently [27,110]. Chitosan-grafted
poly(acrylic
artichydrepa
nkedteroiitis [1ldehcha
ymetwastissumeriomye wng mbeenhitosn [1as a
rophed chionsnothof bobtay sysodicy on sealianxesmplalianf bior
tond pue frepaxy-omed ind inn (Pateds wet 9 wing taftedd
DNationciencellsonducy.y recAMwereccessfferemonethaationmermers
with synthetic thermo-responsive materials bychanisms of chemical
crosslinking. When we have anf two crosslinked polymers and at
least one of whiched and crosslinked in the presence of the other,
thisalled an interpenetrated network (IPN). If only oneof the
assembly is crosslinked leaving the other in
orm, the system is termed as semi-IPN. The ability tohrough the
crosslinking of chitosan with PNIPAAm hasocumented. Many hydrogels
are formed from water-
ymers by crosslinking them using crosslinking agentstaraldehyde
or polymerizing hydrophilic monomersence of a crosslinker.
Chemically crosslinked poly-to be one of the candidates to improve
wet strength.s reporting the preparation of PNIPAAm-containing
chi-raldehyde gels can be found [103,104]. Another examplef blends
is glutaraldehyde crosslinked semi-IPNsof chi-AN [105]. Of course,
the water uptake of these systemsthe molar ratio of the hydrophilic
groups of chitosanhurma et al. reported the preparation of
semi-IPNsitosan and poly(vinyl pyrrolidone) (PVP) by using a
nat-nking agent, genipin [106]. It was found that PVP-richwelled
themost, because increasing the amounts of PVPel structure less
compact, and more inhomogeneous.N hydrogel was synthesized by the
chemical combina-thylenebis(acrylamide) (MBAM) crosslinked
PNIPAAmth a formaldehyde crosslinked chitosan network [107].s [107]
demonstrated that the properties of the gels,he extractability of
PNIPAAm within it, the phaseehaviour, the swelling dynamics in
aqueous phase,g behaviour in ethanol/water mixtures and even theure
were quite different from those of the correspond-N hydrogels. It
was found that the semi-IPN hydrogelsthan the corresponding
full-IPN hydrogels, and that theio for the semi-IPN hydrogels is
almost independent ofe [107].
ions for modied chitosan materials
ential applications of modied chitosan in variouselds, such as
environment, drug delivery, tissue engi-other biomedical
application are here discussed. An
also made to discuss some of the current applicationsrospects of
modied chitosan.
livery
n Section 1, chitosan has interesting biopharmaceuti-ristics
such as pH sensitivity, biocompatibility and low]. Moreover,
chitosan is metabolised by certain humanspecially lysozyme, and is
biodegradable [5]. Due toable properties, the interest in chitosan
and its deriva-g delivery applications has been increased in
recentover, in such applications it is also extremely impor-itosan
be hydro-soluble and positively charged. Thesenable it to interact
with negatively charged polymers,cules and polyanions in an aqueous
environment.orks related with potential applications of
chitosanivatives can be found in literature. For instance, ithown
that chitosan and its derivatives, such as N-hitosan or
N-carboxymethyl chitosan, have the specialdhering to mucosal
surfaces, being useful for mucosal
acid) pers foret al. pcrosslia
nonsarthrhglutaracalciumcarboxgroupscerousof polylike ble
Somapy usiit haslated cchitosatosan wby hydalkylatattract
In aponentand
todeliveracid-mefcienchitosamammcompleDNAcomammposedoin ordetime
atechniq[117] pmethoimprovvitro anchitosaformulsphereat leasby
varyPEG-grplasmiconjugtion eftumorbeing cefcien
Vera PAMchainsand sutwo diwas dedexamferentidendriles have been
proposed as hydrophilic drug carri-rophilic drugs and sensitive
proteins [111]. Kumbarred microspheres of
polyacrylamide-grafted-chitosanwith glutaraldehyde to encapsulate
indomethacin (IM),dal anti-inammatory drug used in the treatment
of12]. Microspheres of grafted chitosan crosslinked withyde were
prepared to encapsulate nidine (NFD), annel blocker and an
antihypertensive drug. N-Laurylhyl chitosan with both hydrophobic
and hydrophilicstudied in connection with the delivery of taxol to
can-es [113]. Other examples are related to the productionc
vesicles for encapsulation of hydrophobic compoundscin [114].orks
related with intracellular delivery for gene ther-odied
chitosan-based materials were reported. In factargued that the most
important application of alky-an is in DNA delivery such as proven
with dodecyl
15]. The high transfection efciency of alkylated chi-ttributed
to the increasing entry into cells facilitatedobic interactions and
easier unpacking of DNA fromitosan carriers, due to the weakening
of electrostatic
between DNA and alkylated chitosan.er work [116], deoxycholic
acid, which is the main com-ile acids, was used to modify chitosan
hydrophobicallyin self-assembling macromolecules for non-viral
genetem. The self-aggregateDNA complex fromdeoxycholiced chitosan
was shown to enhance the transfectionver monkey kidney cells [116].
The feasibility of theself-aggregates for the transfection of
genetic material incellswas investigated. Self-aggregates can
formcharge
when mixed with plasmid DNA. These self-aggregateexes are
considered tobeuseful for transfer of genes intocells in vitro and
served as good delivery system com-degradablepolymericmaterials.
PEGylationof chitosanincrease its solubility, elongate the plasma
circulationrolong the gene transfer has been another proposedor the
sustained DNA release. For example, Zhang et al.red chitosanDNA
complexes conjugated with alpha-ega-succinimidyl PEG, and the gene
expression wascomparison with the chitosanDNA complex both in
vivo. Microspheres physically combining PEG-grafted-EG-g-CHI)
with poly(lactide-co-glycolide) (PLGA) wereby Yun et al. [118].
They reported that these micro-re capable of sustained release of
PEG-g-CHI/DNA foreeks, and the rate of DNA release was not
modulatedhe amount of PEG-g-CHI. In another work [119]
folate-chitosan was synthesized and proposed for targeted
A delivery to tumor cells. The authors found that folatein this
system signicantly improved gene transfec-cy due to promoted uptake
of folate receptor bearing. In vitro and in vivo studies of gene
transfection arected in the laboratory to evaluate its gene
transfection
ently novel water-soluble nanoparticles that consist ofdendrimer
core with grafted carboxymethyl chitosan
successfully synthesized [120]. The non-cytotoxicityful
internalization of these dendrimer nanoparticles bynt types of
cells, i.e., cell lines and primary cultures,strated in this work.
The authors also showed that thesone-loaded nanoparticles induced
the osteogenic dif-of rat bone marrow stem cells in vitro. So,
these novel
nanoparticles may be used as targeted drug-delivery
-
N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414 411
carriers to cover a wide range of applications that involve the
ef-cient intracellular delivery of biological agents to modulate
thebehaviour of cells.
Thiol-coused as a coIt has beenbe used astration sincthe
stomach
Chitosanbeen propoto the presetems provid
Finally, sdrug loadinIn particulashown druand temperThis kind
ofery. For insNIPAAm/vinexamined tcells againstransfectionby
dissociating the cultlipofectamifection [126
5.2. Tissue e
The presbased on thmatrixes. Aserveas thehave been rals
becausewithout inTEapplicatible for electproteoglyca
Some retosan and tbeen reportgrafted PLLtheselmsratio of PLLof
biodegrachitosanwiof two cellatocytes), cand tendedsame speedto
clarify thdifferentiatphology andin tissue en
Very recposed as tirelease carrstructure, inated within
It has bean adequateit seems po
by pouring a liquid thiolated chitosan cell suspension in a
mold.Furthermore, liquid polymer cell suspensions may be applied
byinjection forming semi-solid scaffolds at the site of tissue
damage.
seefacesdem
hospportsansts, shtheater
stronsmarPLL
6], wtherfor Titionounrepaitiond mdditichicel
ratursiveof m
mersl appg ves
timi
tosanapp
ostate tettibacder negat
tivityesses tombrsyst
iodonDTA0]. C
d antosa,s [14osanton rount].as bebe uspatiefcardthatmaye
usntaining chitosan beadswere synthesized in order to bentrolled
and pH-responsive drug delivery system [79].shown that P-chitosan
beads have a great potential tocontrolled drug release systems
through oral adminis-e the release in the highly acidic gastric uid
region ofis avoided [63,121].
-based systems bearing -cyclodextrin cavities havesed as a
matrix for controlled release [122,123]. Duence of the
hydrophobic-cyclodextrin rings, these sys-e a slower release of the
entrapped hydrophobic drug.timuli-responsive hydrogels have shown
an improvedg capacity, and a sustained release behaviour [92].r,
systems that combine chitosan and PNIPAAm haveg release proles that
can be controlled by both pHature [124,125], constituting very
promising materials.smart systems has also been proposed for gene
deliv-
tance, Sun et al. [126] coupled a carboxyl-terminatedyl laurate
(VL) copolymer with chitosan (PNVLCS) and
he gene expression of PNVLCS/DNA complexes in C2C12t temperature
change. The results indicated that theefciency of PNVLCS/DNA
complexes was improved
ion of the gene from the carrier by temporarily reduc-ure
temperature to 20 C. By contrast, naked DNA andne did not
demonstrate thermo-responsive gene trans-].
ngineering
ent generation of tissue engineering (TE) research ise seeding
of cells onto porous biodegradable polymerprimary factor is the
availability of good biomaterials totemporarymatrix. Recently,
chitosanand itsderivativeseported as attractive candidates for
scaffolding materi-they degrade as the new tissues are formed,
eventuallyammatory reactions or toxic degradation [116,127]. Inons
thecationicnatureof chitosan isprimarily responsi-rostatic
interactions with anionic glycosaminoglycans,ns and other
negatively charged molecules.search works where the biological
properties of chi-he mechanical properties of PLLA are combined
haveed. The in vitro broblast static cultivation on chitosan-A lms
for 11 days showed that the cell growth rate onwas faster than in
chitosan anddecreasedwhen the feedA to chitosan increases [128].
Surface functionalizationdable PLLAwas achieved by plasma coupling
reaction ofth PLLA [129]. Theproliferation andmorphology
studieslines, L-929 (mouse broblasts) and L-02 (human hep-ultured
on this surface showed that cells hardly spreadto become round, but
could proliferate at almost theas cells cultured on glass surface.
This insight will helpe mechanism of the switch between cell growth
andion. Thisgraftedpolymercanbeused tocontrol themor-function of
cells, and hence has potential applications
gineering.ently novel PLLAchitosan hybrid scaffolds were
pro-ssue engineering scaffolds and simultaneously drugiers [130].
In this innovative system a chitosan porouswhich cells and tissues
would mostly interact, is cre-the pore structure of a stiffer PLLA
scaffold.en shown that thiolated chitosan [81,131] can
providescaffold structure: due to the in situ gelling
properties
ssible to provide a certain shape of the scaffold material
So theySur
in vitrocium pbeen reP-chitocemennamelystart mphateto
thegraftedpH [13
Anotosanrecognsugar-bThey precogncells an
In agraftedtrollingtemperesponculturecopolyclinicatreatin
5.3. An
Chihealingbacteridiaminthe anthat ungram-nbial acmakesor
bindcellmehealingof perwith Euse [14showeaeruginS. aureuof
chitchophythe ampH [17
It htial tobiocomgrowthused instratedHEMAtial to bm to be
promising candidates for such applications.that can induce the
formation of an apatite layeronstrate improved bone-binding
properties and cal-
hate growth on P-chitin bers and P-chitosan lms hased after
soaking with Ca(OH)2 [132,133]. Water-solublehave been mixed with
different calcium phosphateowing an improvement in their properties
[134,135],mechanical strength, setting time, dissolubility of
theials of the cements and they also bind calcium phos-gly
afterwards. Moreover it has been shown that duet nature of
chitosan, the apatite formation of chitosan-A lms reinforced with
Bioglass can be controlled byhich could also have relevance in bone
TE applications.approach regarding the chemical modication of chi-E
applications has been to introduce the specicof cells by sugars. A
recent example of the synthesis ofd chitosan can be found in the
work of Kim et al. [137].red mannosylated chitosan (MC) having the
specicto antigen presenting cells such as B-cells, dendritic
acrophages.on to applications in controlled drug release,
PNIPAAm-tosan-based materials have been exploited for con-l
adhesion/detachment by changing the incubatione above or below its
LCST [138,139]. Temperature-chitosan-graft-PNIPAAm [139] were
applied for theesenchymal stem cells (MSCs). Chitosan-g-PNIPAAmwith
chondrogenic MSCs revealed the possibility of
lications, particularly as cell therapy technologies
foricoureteral reux [138].
crobial agents and other biomedical applications
derivatives present interesting properties for wound-lications,
because such materials can exhibit enhancedic activity with respect
to pure chitosan. Ethyleneraacetic acid (EDTA) grafted onto
chitosan increasesterial activity of chitosan by complexing
magnesiumormal circumstances stabilizes the outer membrane ofive
bacteria [140]. The increase in chitosan antimicro-is also observed
with carboxymethyl chitosan, which
ntial transition metal ions unavailable for bacteria [141]the
negatively charged bacterial surface to disturb theane [142].
Therefore, thesematerials are used inwound-ems, such as
carboxymethyl chitosan for the reductiontal pockets in dentistry
[141] and chitosan-graftedas a constituent of hydro-alcoholic gels
for topicalhitosan and chitooligosaccharide-grafted
membranesibacterial activity against Escherichia coli,
Pseudomonasmethicilin-resistant Staphylococcus aureus (MRSA),
and3]. Also, it was observed that the antimicrobial activityand
graft copolymers against Candida albicans, Tri-
ubrum, and Trichophyton violaceum depends largely onand type of
grafted chains, as well as on the changes of
en shown that chitosan derivatives have great poten-ed in other
biomedical applications. As a result of theble properties such as
good blood compatibility and cellciency, grafted chitosan materials
have potential to beio-vascular applications [144,145]. It has been
demon-the permeability of chitosan membranes grafted withbe
controlled through plasma-treatment having poten-ed in dialysis
[146].
-
412 N.M. Alves, J.F. Mano / International Journal of Biological
Macromolecules 43 (2008) 401414
5.4. Adsorption of metal ions
The high sorption capacities of modied chitosan for metal
ionscan be of gtreatment oderivativesions by incbone. The nincrease
thmetal sorptsorption sel
The graregarded apropertiesto design c[147,148]. Aboxylic
funanhydrides
The grafsubject of mresins [150fully testedmetals, owimetal
ions.to improve[153].
N-Halochypochloritmany otherby reactingacid exhib[155].
P-chitinwas foundof the otherline earth mphosphate gered that
theven more
The commetal ion salso been athe producheavy metause of dendfor
this kinof chitosandendrimer-these systewhen the gequal to 2 afor
Au3+ anterminatedones [161].
A great dether on chiSchiffs basemesocyclictivity for
Cpropertiescrown ethe(CTDA)wasthese new tcations for
tenvironmen
5.5. Dye removal
Chitosan, due to its high contents of amine and hydroxyl
func-groucludol [1catio] recderivhobiyl grin acatioith
catio[168tosanto fos, ant maile dyn desorper an
clus
diffeensivwedin as son dewateuch asue e
nces
TomihW. Ch3921Kumav. 104. Sanitosanns, ElA.A. M. BersKuritatt.
27SashiHerasJayakuLu, L.0738A.A. M9214.M. X9917.M. XiK. YanChen,O.
Jun1317. Than7126S. Hof(1997
A. TaskOno, Yreat use for the recovery of valuable metals or
thef contaminated efuents. A great number of chitosanhave been
obtained with the aim of adsorbing metalluding new functional
groups onto the chitosan back-ew functional groups are incorporated
into chitosan toe density of sorption sites, to change the pH range
forion and to change the sorption sites in order to
increaseectivity for the target metal.fting of carboxylic functions
has frequently beens an interesting process for increasing the
sorptionof chitosan. Usually, the aim of these modications
ishelating derivatives for the sorption of metal cationsnother way
to achieve the grafting of carbonyl and car-ctions may consist in
reacting chitosan with carboxylic[149].ting of sulphur compounds on
chitosan has been theany studies for the design of chelating
chitosan-based
152]. These sulphur derivatives have been success-for the
recovery of mercury and the uptake of preciousng to the chelating
afnity of sulphur compounds forSulphonic groups have been also
grafted on chitosansorption capacity for metal ions in acidic
solutions
hitosans prepared by reacting chitosan with sodiume are good
occulants for metallic oxides along withcontaminants [154].
N-Chloroacetyl chitosan, preparedchitosan with chloroacetic
anhydride in chloroacetic
ited high afnity for cations such as Cu2+, Fe3+
and P-chitosan have a strong metal-binding ability. Itthat their
adsorption of uranium is much greater thanheavy metal ions [52].
Also, the binding ability to alka-etals was signicantly enhanced by
the introduction ofroups [156]. In fact, Schwarzenbach et al. [157]
consid-e phosphonic complexing agents were as effective or
than those containing carboxylic groups.bination of CDs with
chitosan for manufacturing neworbents, typically by using a Schiffs
base reaction, hasdopted [158,159]. Other very recent approach
involvestion and use of thiolated chitosan lms for aqueousl ions
detection, in particular for mercury [160]. Therimers combinedwith
chitosan is currently under studyd of applications [161]. Qu et al.
synthesized a seriesderivatives by grafting ester- and
amino-terminatedlikePAMAMintochitosan [161]. The results
showedthatms were completely insoluble in dilute acid
solutionsenerations of grafted dendrimers were greater than ornd
that they exhibited excellent adsorption capabilitiesd Hg2+.
Moreover the adsorption capabilities of amino-products were higher
than those of ester-terminated
eal of attention has been paid to the grafting of crowntosan
formanufacturingnewmetal ion sorbents using areaction [162,163].
Aza crownether-graft-chitosan anddiamine-g-chitosan crown ether
showed high selec-u2+ in presence of Pb2+ [164]. The static
adsorptionof Ag+, Cd2+, Pb2+, and Cr3+ by chitosan hydroxyl azar
(CTS-DA) and chitosan dihydroxyl mesocyclic diaminereported
[15,165]. So, it is expected that in a near futureype chitosan
crownetherswill havewide ranging appli-he separation and
concentration of heavy metal ions intal analysis.
tionaldyes innaphthity areal.
[169fonatehydropCarboxdonorsadsorbbeadswtion ofY (BB)
Chiabilitypoundsorbenof textchitosarate ofpolym[166].
6. Con
Thethe extter, shosolubleaqueouchitosawastetions sand tis
Refere
[1] K.[2] Y.
21[3] R.
Re[4] P.A
Chtio
[5] R.[6] P.C[7] K.
Le[8] H.[9] A.
[10] R.[11] G.
38[12] R.
19[13] W
16[14] W[15] Z.[16] S.[17] B.
17[18] M
11[19] A.
38[20] R.[21] K.ps, has an extremely high afnity for many
classes ofing disperse, direct, reactive, anionic, vat, sulphur
and66,167]. The only class for which chitosan has low afn-nic dyes
[167,168]. To overcome this problem Crini etently suggested the use
of N-benzyl mono- and disul-atives of chitosan in order to enhance
its cationic dyec adsorbent properties and to improve its
selectivity.oups grafted onto chitosan may also serve as electronn
alkaline environment to confer chitosan the ability tonic dyes from
aqueous solutions. Modied chitosan gelphenol derivativeswere found
to be effective in adsorp-nic dyes, such as crystal violet (CV)
andBismarck brown].grafted with CDs, in particular -CD derivatives,
have
rm complexes with a variety of other appropriate com-d are very
promising materials for developing noveltrices [16,170]. Martel et
al. showed that the adsorptiones from the efuent can be carried out
with -CD-g-rivatives [166]. Moreover, these systems have
superiortion and global efciency than that of parent chitosand of
the well-known cyclodextrinepichlorohydrin gels
ions
rent chemical modications of chitosan developed bye work of many
researchers, summarized in this chap-that it is possible to obtain
chitosan derivatives not onlycidic aqueous solutions but also in
neutral and basiclutions. Moreover it has been demonstrated that
theserivatives present the adequate properties for safe use inr
treatments and, in particular, in biomedical applica-s controlled
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Chitosan derivatives obtained by chemical modifications for
biomedical and environmental applicationsIntroductionGraft
copolymerizationGrafting initiated by free radicalsGrafting using
radiationEnzymatic graftingCationic graft polymerization
Special cases of chitin and chitosan modificationsPhosphorylated
chitin and chitosanCombination of chitosan derivatives with
cyclodextrinsThiol-containing chitosan
"Smart chitosan": example of new chitosan-based hydrogels
exhibiting temperature-responsive behaviourGraft copolymerized
hydrogelsChemically crosslinked blends
Applications for modified chitosan materialsDrug deliveryTissue
engineeringAntimicrobial agents and other biomedical
applicationsAdsorption of metal ionsDye removal
ConclusionsReferences