polysaccharide biomaterials

DOI: 10.1002/ijch.201300062

Polysaccharide BiomaterialsEameema Muntimadugu,[a] Diana E. Ickowicz,[b] Abraham J. Domb,[b] and Wahid Khan*[a, b]

1. Introduction

Over the past three decades the use of polymeric materi-als has increased dramatically for biomedical applica-tions.[1–3] Polysaccharides belong to the class of naturalpolymers and are comprised of carbohydrate monomersattached by glycosidic linkages. Increasing numbers of re-ports in the literature have focused on specific biologicalactivities of polysaccharides and have attracted researchinterest. Inside the human body they perform unique bio-logical functions from cell signaling to immune recogni-tion.[4] Polysaccharides are readily available from variousnatural sources, such as algae (alginates), plants (pectin,guar gum), animals (chitosan, chondroitin), and microor-ganisms (dextran, xanthan gum).[5] From the viewpoint ofpolyelectrolytes, polysaccharides can be divided into poly-electrolytes and non-polyelectrolytes. The former can befurther divided into positively charged polysaccharides(chitosan) and negatively charged polysaccharides (algi-nate, heparin, hyaluronic acid (HA), pectin, etc.).[6]

Polysaccharides differ from proteins and nucleic acidsby forming branched structures.[7] Many polysaccharidederivatives are synthesized by easily modifying variousfunctional groups present on molecular chains of polysac-charides. Synthetic polysaccharide derivatives with alteredphysical properties, and their biological activities offerpotential applications in drug and gene delivery.[8] Poly-saccharides are capable of forming complex assemblies inthe nanoscale range. These new polysaccharide nano-structures are being used for the stabilization and deliveryof drugs, proteins, and genes; the engineering of cells andtissues; and as new platforms for the study of biochem-istry.[9] Polysaccharides are extremely useful in food, cos-metic, biomedical, and pharmaceutical industries,[10] be-

cause of their unique biochemical and physical properties.This review briefly lists key features of some importantpolysaccharides and their applications in different areas.

2. Chitosan, Cyclodextrins, Dextran, and DextranDerivatives

Major cationic polysaccharides used as polysaccharidebiomaterials in drug and gene delivery purposes areeither natural (chitosan, cyclodextrin (CD), dextran) orsemisynthetic derivatives (dextran�spermine, etc.), asshown in Table 1.

3. Glycosaminoglycans

Glycosaminoglycans (GAGs) are the most abundant, nat-ural hetero-polysaccharides. GAGs are linear polysaccha-rides composed of a variable number of repeating disac-charide units. Each disaccharide consists of one hexosa-

[a] E. Muntimadugu, W. KhanDepartment of PharmaceuticsNational Institute of Pharmaceutical Education and Research(NIPER)Hyderabad 500037 (India)fax: (+91) 40-23073751e-mail: [email protected]

[b] D. E. Ickowicz, A. J. Domb, W. KhanSchool of Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalem 91120 (Israel)

Abstract : An entire new genus of “polymer therapeutics”has emerged with wide applicability, including as mechani-cal supports, mechanical barriers, artificial tissue/organs,and pro-drug preparations with pharmacological effects.Polysaccharides are a class of biopolymers formed frommany monosaccharide units joined together by glycosidiclinkages. The physical properties of carbohydrates, such assolubility, gelation, and surface properties, are dictated bythe monosaccharide composition, chain shapes, and molec-

ular weight. These macromolecules exhibit good hemocom-patibility, are non-toxic, and show unique biological func-tions, ranging from cell signaling to immune recognition.With few exceptions, they are more economical in compari-son with others biopolymers. Polysaccharide-based poly-mers have been widely proposed as scaffold materials intissue engineering applications as well as carriers for drugdelivery.

Keywords: biological activity · biomaterials · drug delivery · natural products · polymers

Isr. J. Chem. 2013, 53, 787 – 794 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 787

Review

mine (d-galactosamine or d-glucosamine) and one uronicacid (d-glucuronic acid or l-iduronic acid) or neutralhexose (d-galactose).[26] According to the type of themonosaccharide units and the glycosidic bonds betweenthem, GAGs can be divided into various categories. HA,chondroitin sulfate (CS), dermatan sulfate (DS), heparin,heparin sulfate (HS), and keratan sulfate (KS) are someof the important compounds in this class.[9,27]

GAGs are molecules with a high negative charge andwith an extended conformation that imparts high viscosityto the solution. The high viscosity and low compressibilityof these molecules make them ideal as a lubricating fluidin joints.[28] GAGs are covalently attached to core proteinmolecules in the body comprising proteoglycans, whichconfer important properties in cells, connective tissues,and basal membranes.[29] These molecules are responsiblefor some physiological properties, such as the capacity tobind and store specific growth factors, and they have thepotential to act as co-receptors in cellular adhesion, aswell as to interact with extracellular matrix molecules,such as laminin and fibronectin.[30] GAGs also play an im-portant role in various pathological conditions; hence, thestudy of changes in GAG expression and fine structuremay lead to the development of innovative therapies forvarious diseases.[31] Table 2 shows major GAGs used aspolysaccharide biomaterials.

4. Miscellaneous

4.1. Arabinogalactan

Arabinogalactan is a highly branched polysaccharide con-sisting of a galactan backbone with side chains of galac-tose and arabinose (Figure 1). It is extracted from theLarix tree and is available in a 99.9% pure form with a re-producible molecular weight and physicochemical proper-ties. It is highly water soluble and possesses a high degreeof biocompatibility. High water solubility, biocompatibil-ity, and biodegradability make arabinogalactan a potentialdrug carrier or an intermediate in the synthesis of pro-drugs. It is stable in powders and aqueous solutions andhas been tested in pharmaceuticals as a binder and for de-livery to the colon, where its enzymatic degradation pro-duces the porosity needed for planned release.[50–53] Av-ramoff et al. reported a once-daily, delayed, controlled-re-lease formulation for diltiazem with a unique controllingmembrane containing arabinogalactan as a channelingagent to achieve a delayed, controlled-release profile ofthe drug.[50] Arabinogalactan provided a suitable channel-ing agent to control in vitro drug release from this formu-lation. The formulation achieved a modified release pro-file in vitro suitable for once-daily administration.[54]

Abraham J. Domb is Professor for Me-dicinal Chemistry and Biopolymers atthe Institute of Drug Research, Schoolof Pharmacy-Faculty of Medicine, TheHebrew University of Jerusalem, Israel.He earned Bachelor degrees in chemis-try, pharmacy, and law studies, anda PhD degree in chemistry from TheHebrew University. He did his postdoc-toral training at Syntex Inc. CA, USA,and at MIT and Harvard Universities,Cambridge, USA, and was R&D manag-er at Nova Pharm. Co. Baltimore, USA,from 1988 to 1992. From 2007 to 2012 he headed the Division ofIdentification and Forensic Sciences of the Israel Police. His primaryresearch interests are in biopolymers, controlled drug delivery,cancer therapy, nanoparticulate systems, and forensic sciences.

Wahid Khan obtained his Master’s andPhD degrees in pharmaceutics at theNational Institute of Pharmaceutical &Educational Research (NIPER), Mohali,India, and worked with Prof. AbrahamJ. Domb in The Hebrew University ofJerusalem, Israel, for his post-doctoralresearch. Currently, he is working asAssistant Professor in the Departmentof Pharmaceutics, NIPER, Hyderabad,India. He has experience of working inareas of drug delivery, drug targeting,nanomedicine, and the biodesign ofimplantable medical devices.

Diana E. Ickowicz is currently a PhDstudent at the Institute for Drug Re-search, School of Pharmacy-Faculty ofMedicine, The Hebrew University ofJerusalem. Her Master’s work focusedon polysaccharide�drug conjugates forreduced drug toxicity in mammaliancells. Her research interests includepasty polyesters for injectable drug de-livery.

Eameema Muntimadugu is currentlypursuing a PhD degree from the Na-tional Institute of Pharmaceutical Edu-cation and Research, Hyderabad. Sheworked on lipid-based oral formula-tions during her Master’s studies. Herresearch areas of interest include poly-mer- and lipid-based nanoformulations,drug targeting, and designing formula-tions for enhancing bioavailability.

788 www.ijc.wiley-vch.de � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Isr. J. Chem. 2013, 53, 787 – 794

Review W. Khan et al.

http://www.ijc.wiley-vch.de

Table 1. Major cationic polysaccharides used as polysaccharide biomaterials.

Polysaccharide Key features Applications Marketed products

Chitosan[11–15]* Cationic linear polymer

obtained by deacetylationof chitin

* Molecular weight rangesfrom 10–1000 kDa

* Biologically renewable,biocompatible, non-im-munogenic, non-toxicand bio-functional mate-rial

* Capable of absorbingheavy-metal ions

* Plays an important rolein hemostasis

* Bioadhesive polymer andenhances drug uptakeacross mucosal barrier

* Not approved by the USFood and Drug Adminis-tration (FDA) for drugdelivery

* Wound healing/wounddressing

* Treatment of burns* Artificial skin and absorba-

ble sutures* Oral sustained, nasal and

ocular drug deliveries* Forms polyplexes with

DNA and helpful in genedelivery

CeloxTM, topical he-mostatic pasteAquanova� Ag,super adsorbentdressingHemCon�,dental dressingChitoseal� PAD

Cyclodextrins (CDs)[16–20]* Cyclic oligosaccharides

with hydrophilic outersurface and lipophiliccentral cavity

* a, b, g-CDs contain 6, 7,and 8 glucopyranoseunits, respectively

* Water-soluble derivativesare produced by chemi-cal modification of hy-droxyl groups

* Hydroxypropyl deriva-tives of aCD, bCD, ran-domly methylated bCD,sulfobutylether bCD, etc.are of pharmaceutical in-terest

* CDs form inclusion com-plexes with several drugs

* Bioavailability enhance-ment of Biopharmaceuti-cals Classification System(BCS) class II and class IVdrugs

* Successful drug deliverythrough various routes

* Protein and peptide deliv-ery

* Controlled drug delivery* In vivo delivery of oligonu-

cleotides by improving cel-lular uptake and stabilityagainst endonucleases

* Incorporation of CDs in thedesign of some novel drug-delivery systems, such asliposomes, microspheres,microcapsules, nanoparti-cles

* Development of self-assem-bled CD-based hydrogelsystems is an emerging re-search areas

Caverject Dual�

Pansporin T�

Nicorette�

Meiact�

Sporanox�

Vfend�

Aerodiol�

Cardio Tec�

Voltaren ophtha�

Dextran[21,22]* Water-soluble polysac-

charide* Molecular weight ranges

from 3–2000 kDa* Extensively exploited as

a carrier for attachingdrugs because of its highreactivity

* Plasma volume expander* Thrombosis prophylaxis* Lubricant in eye drops* Reversible dextran drug

conjugates for site specificor targeted deliveryCationization of dextran in-creases its gene delivery ef-ficiency

DexFerrum�

Infed�

Tears naturale�

Debrisan�Hyskon�

Isr. J. Chem. 2013, 53, 787 – 794 � 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.ijc.wiley-vch.de 789

Polysaccharide Biomaterials


4.2. Alginic Acid

Alginic acid, also called algin or alginate, is an anionicpolysaccharide (Figure 1). Alginates are naturally derivedpolysaccharide block copolymers composed of regions ofsequential b-d-mannuronic acid monomers (M blocks),regions of a-l-guluronic acid (G blocks), and regions ofinterspersed M and G units; they have a structural role ingiving flexibility and strength to marine plants. Commer-cial alginates are extracted from the brown algae Lamina-ria hyperborean, Ascophyllum nodosum, and Macrocystis.Bacterial alginates have also been isolated from Azoto-bacter vinelandii and several Pseudomonas species.[55] Al-ginates undergo reversible gelation in aqueous solutionunder mild conditions through interactions with divalentcations, such as Ca2+. Zhao et al. reported the use of algi-nate/calcium carbonate/DNA nanoparticles for genetransfection.[56] Alginates were used for the delivery ofgrowth factors bone morphogenetic protein (BMP-2 andBMP-7) using complexed microspheres of poly(4-vinylpyridine) and alginic acid for bone tissue engineering.[54]

Several alginate-based wound dressings are commerciallyavailable, namely, Nu-Derm

�

sold by Johnson & Johnsonin the USA and Curasorb

�

by Covidien, formerly regis-tered as Kendall or AlgiSite

�

by Smith & Nephew in theUSA.

4.3. Starch

Starch is a physical combination of branched (amylopec-tin) and linear polymers (amylose) with d-glucopyrano-side repeating units (Figure 1). Amylose is crystallinesolid (MW 500 kDa) and soluble in boiling water, where-as amylopectin is insoluble in boiling water. The hydroxyfunctionality can be used for chemical modifications. Ace-tylated starch is more hydrophobic and has a better struc-tural fiber or film-forming capability than that of nativestarch. Its biodegradability, easy availability, and renewa-ble nature make it one of the promising natural polymersfor use in tissue engineering applications. Starch�polycap-rolactone (PCL) microparticles have been reported re-cently for the controlled release of bioactive agents fordrug delivery and tissue engineering applications.[55] Overthe years, several materials have been blended withstarch to improve its processability. Reis et al.[57,58] haveproposed starch-based materials (blends of starch withdifferent synthetic polymers, such as ethylene vinyl alco-hol, poly(lactic acid) (PLA), cellulose acetate and PCL)as materials with potential for biomedical applica-tions,[57,58] as bone cements,[59,60] and as drug-delivery sys-tems.[60–62]

Table 1. (Continued)

Polysaccharide Key features Applications Marketed products

DEAE dextran[23]* Diethyl amino ethyl

(DEAE) dextran* Polycationic derivative of

dextran* Molecular weight 1000

kDa

* Vaccine adjuvant* Gene transfecting agent* Viral infectivity enhancer* Enhancer of protein and

nucleic acid uptake

Dextran spermine[24,25]* Polycationic derivative of

dextran* Mainly reported as a gene

transfecting agent




Table 2. Major glucosaminoglycans (GAGs) used as polysaccharide biomaterials.

GAG Key features Applications Marketed products

Hyaluronic acid (HA)[32–36]* Non-sulfated GAG* Molecular weight is in

the order of millions* Water soluble and

forms highly viscoussolutions with uniqueviscoelastic and rheo-logical properties

* In vivo degradation byhyaluronidase

* Conjugation of multiplefunctional groups pro-mote receptor-mediat-ed intracellular signal-ing

* Interactions with aggre-gating proteins are im-portant in tissue mor-phogenesis, remodel-ing, and angiogenesis

* Immobilization of spe-cific proteins (neuro-can, brevican, CD44) indesired locationswithin the body

* Covalent attachment oftherapeutic moleculesto HA gels

* Diagnosis of malignantmesothelioma, rheuma-toid arthritis, liver dis-eases

* Wound-healing applica-tions

* Preparation of immu-nologically unrecogniz-able liposomes

* Vitreous humor andsynovial fluid substitute

Restylane TM, Hyla-form�, Perlane�,Hyalgan�, Synvisc-OneTM

Chondroitin sulfate (CS)[37–40]* Structural role in carti-

lage; induces osmoticswelling, resists com-pression, and supportsweight bearing

* Molecular weight 20kDa

* Surgical aid in cataractextraction and lens im-plantation

* Management of osteo-arthritis

* CS-based hydrogels fordrug-delivery applica-tions

* CS-based therapeuticsin cancer treatment

* Free radical scavengingactivity of 4-sulfatedtracheal CS

* Reduction of allergic re-sponses

* Derivatives of CS pos-sess inhibitory actionon microbial infections

Integra�, Viscoat�

Dermatan sulfate (DS)[41–43]* CS B* Ubiquitous element of

the extracellular matrix* Stabilizer, co-receptor

for growth factors, cyto-kines, and chemokines

* Signaling molecules inresponse to cellulardamage

* Weak anticoagulant* Prophylactic in venous

thromboembolism* Useful in the design of

medical devices and ar-tificial tissues, e.g.,prosthetic meniscus,arterial prosthesis

* DS-based therapeuticsin cancer treatment

* Questionable functionin wound repair

* Derivatives of DS pos-sess inhibitory actionon microbial infections




4.4. Pullulan

Pullulan is a natural water-soluble polysaccharide witha repeated unit of maltotriose condensed through the a-1,6 linkage (Figure 1). It is non-toxic, non-immunogenic,non-mutagenic, and non-carcinogenic in nature.[63] Stablecomplexes have been produced from cationic modifiedpullulan/DNA as a temperature-sensitive gene carrier.[64]

Thomsen et al. used cationic non-viral gene carriers pre-pared from pullulan and spermine for conjugation withplasmid DNA and to transfect rat brain endothelial cellsand human brain microvascular endothelial cells.[65] Simi-larly, complexes have also been studied for liver-targetinggene expression.[63] Cationic pullulan, dextran, andmannan complexed with pDNA have also been tested incellular models and in vivo mice models. Cationized pul-lulan is reported to be a promising non-viral carrier ofpDNA for mesenchymal stem cells[66] and for gene-deliv-ery applications targeted to liver cells.[67] Polyethyleneimine (PEI)-conjugated pullulans have been developedand investigated for possible use in gene-delivery applica-tions. The pullulan�PEI conjugate seems to be a promis-ing gene-delivery vector with good hemocompatibilityand low toxicity, without compromising the transfectionefficacy of PEI.[68]

4.5. Schizophyllan

Schizophyllan is a natural b-(1–3)-d-glucan polysaccha-ride produced by fungus of the genus Schizophyllum(Figure 1). Applications of schizophyllan include film for-mation, as a filler in different forms, and in solid dosageform for use as a binder, disintegrant, and so forth. Modi-fied schizophyllan forms stable complexes with antisenseoligonucleotides and, when studied in different melanomaand leukemia cell lines, negligible cytotoxicity. Schizo-phyllan can act as a new potential candidate as an anti-sense oligonucleotides carrier.[69,70]

4.6. Cellulose and Cellulose Derivatives

Cellulose forms the backbone of many excipients used inmarketed drug products. Pharmaceutical grades of cellu-lose are obtained by either mechanical or chemical proc-essing, or through a combination of both. Pure cellulosecan be ground mechanically or following additional treat-ment with hydrochloric acid. The resultant powder is cel-lulose powder or microcrystalline cellulose. Hydroxyprop-yl cellulose is a cellulose derivative with both water andorganic solvent solubility. Xu et al. reported hydroxyprop-yl cellulose modified with cationic poly[(2-dimethylami-no)ethyl methacrylate] as gene vectors. Chains complexedwith plasmid DNA have been used as an efficient gene-delivery system with low cytotoxicity in HEK293 cells.[71]

Table 2. (Continued)

GAG Key features Applications Marketed products

Heparin and heparin sulfate (HS)[44–48]* Biomolecule with the

highest negative chargedensity

* Heparin is largely con-fined to mast cells

* HS is present on cellsurfaces or in the extra-cellular matrix in theform of proteoglycans

* Mediate biologicalfunctions, such as celladhesion, regulation ofcellular growth, inhibi-tion of blood coagula-tion, and cell surfacebinding

* Anticoagulant* Prophylactic against

post-operative throm-bosis

* Heparinized coronarystents and tissue engi-neering scaffolds withlower thrombogenicpotential

* Controlled release ofheparin binding growthfactors

Lipo-Hepin�, Pan-heparin�, HeparinLock Flush

Keratan sulfate (KS)[49]* Present in cornea, carti-

lage, brain, and bone inthe form of proteogly-cans

* Maintains tissue hydra-tion for corneal trans-parency




5. Conclusions

The scope of this review was to describe the role of poly-saccharides in the domain of biomaterials for applicationsin pharmaceutical and biomedical fields. The most impor-tant polysaccharides commercialized for such applicationsare cellulose, chitosan, and CD. Currently, numerous HAproducts are approved by the US FDA for different ap-plications. Chemical modification is simple for polysac-charides. It may even be possible to introduce differentsmall molecules, such as drugs, peptides, or other entitiescapable of being polymerized, to lead to a grafted ora cross-linked copolymer. The use of polysaccharides inthe living world is open for new developments. Certainlypolysaccharides will play a very important role in facili-tating future human treatment.

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Received: June 12, 2013Accepted: August 29, 2013




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