reactive & functional polymers

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

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0141-8130/$ doi:10.1016/j.iuction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 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.


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


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).


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-


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.


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


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].


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


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].


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 delivery of drugs or other bioactive agentsngineering.

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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

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