A Review of Bioactive Plant Polysaccharides: Biological Activities, Functionalization, and Biomedical Applications

Bioactive Carbohydrates and Dietary Fibre 5 (2015) 31–61
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A review of bioactive plant polysaccharides:

Biological activities, functionalization,
and biomedical applications
Jun Liun, Stefan Willför, Chunlin Xun,1

Process Chemistry Centre, c/o Laboratory of Wood and Paper Chemistry, Åbo Akademi University, Porthansgatan 3-5,
FI-20500, Turku/Åbo, Finland
art i cle i nfo ab st rac t
Article history: Natural polysaccharides from different sources have long been studied and widely used in
Received 1 July 2014 different areas, such as food and feed, medicine and pharmaceutics, and in papermaking.
Received in revised form In recent decades, there has been an increased interest in the utilization of polysacchar-
11 October 2014 ides, particularly bioactive ones, for various novel applications owing to their biocompat-
Accepted 8 December 2014 ibility, biodegradability, non-toxicity, and some specific therapeutic activities. The main
goal of this paper was to review the sources, natively biological activities, isolation,
Keywords: characterization, and the structural features of natively bioactive polysaccharides. More-
Polysaccharides over, the article has also been forcused on the chemical/chemo-enzymatic functionaliza-
Biological activity tions that may create novel opportunities to maximally exploit the various valuable
Functionalization properties of polysaccharides, particularly from wood species, in previously unperceived
Biomedical application applications especially for biomedical applications, such as tissue engineering, wound
healing, and drug delivery. This article was to review novel strategies to tailor functional
materials with above mentioned application potentials for the polysaccharides from wood
species.
& 2014 Elsevier Ltd. All rights reserved.
Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2. Sources and biological activities of bioactive polysaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2.1. Bioactive polysaccharides in dietary fibers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2.2. Bioactive polysaccharides in herbs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2.3. Bioactive polysaccharides in algae and lichens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2.4. Bioactive polysaccharides in wood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.5. Bioactive polysaccharides from other sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
3. Isolation of bioactive polysaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
4. Functionalization of polysaccharides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
n
Corresponding authors. Tel.: þ358 22154987.
E-mail addresses: jun.liu@abo.fi (J. Liu), swillfor@abo.fi (S. Willför), cxu@abo.fi (C. Xu).
1
Tel.: þ358 22154601.
http://dx.doi.org/10.1016/j.bcdf.2014.12.001
2212-6198/& 2014 Elsevier Ltd. All rights reserved.
32 Bioactive Carbohydrates and Dietary Fibre 5 (2015) 31 –61
4.1.
Cellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4.2.
Hemicelluloses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
4.2.1. Xylans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.2.2. Galactomannans, glucomannans, and galactoglucomannans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.2.3. Xyloglucans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.3. Pectins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
4.4. Starch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4.5. Chitin and chitosan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4.6. Alginate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.7. Hyaluronic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
5. Structural analysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
6. Biomedical applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
6.1. Tissue engineering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
6.2. Wound healing and wound dressing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
6.3. Drug delivery and controlled release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
7. Concluding remarks and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
1. Introduction biomolecules, e.g. proteins, polynucleotides, lipids, lignin, and

some inorganic mineral substances (Yang & Zhang, 2009).
Polysaccharides along with oligosaccharides, the most abun- Therefore, comprehensive understanding the important roles
dant group of biopolymers, have been found to participate in of the bioactive polysaccharides in life science and exploring
many biological processes, such as cell–cell communication, their application call for the multidisciplinary collaboration
embryonic development, infection of bacteria and/or virus, from experts on plant and microbial polysaccharides, glyco-
and humoral and cellular immunity (Cooke, An, Kim, Solnick, chemistry, glycobiology, glycomedicine, phytology, and zoology
& Lebrilla, 2007; Dube & Bertozzi, 2005; Varki, 1993). Therefore, (Colegate & Molyneux, 2008).
polysaccharides together with polynucleotides, proteins, and The aim of this article was to review the state-of-art in
lipids constitute the most important four biomacromolecules identification, isolation, functionalization, characterization,
in life science. In this review, the bioactive polysaccharides and application of bioactive polysaccharides derived from
refer to those polysaccharides that show biological effects on natural sources. Exploration of biomedical applications such
organisms and those polysaccharides that can be produced by as tissue engineering, wound healing, and drug delivery for
living organisms or functionalized from sugar-based materials. polysaccharides were emphasized. The goal was to seek
Additionally, the biological effects that polysaccharides can novel strategies to tailor functional materials with above
exert are limited to therapeutic activities for diseases of mentioned application potentials for the polysaccharides
humans and animals, and toxic activity responsible for caus- from plants.
ing human and animal disease (Colegate & Molyneux, 2008).
Although polysaccharides have been used for decades in
various industrial applications, e.g. pharmaceuticals, biomater- 2. Sources and biological activities of bioactive
ials, food stuff and nutrition, and biofuels, growing under- polysaccharides
standing and deeper investigations of the importance of
polysaccharides in life science are driving the development of Polysaccharides can be classified in many possible ways, such
polysaccharides for novel (biomolecular) applications (Alonso- as on the basis of structure, chemical composition, solubility,
Sande, Teijeiro-Osorio, Remunan-Lopez, & Alonso, 2009; Crini, sources, and applications. With regard to the chemical
2005; García-González, Alnaief, & Smirnova, 2011; Kamerling composition, the polysaccharides are classified into two
& Boons, 2007; Pitarresi, Calabrese, Palumbo, Licciardi, & types, i.e. homo-polysaccharides or homoglycans, which are
Giammona, 2009; Spizzirri et al. 2010; Suh & Matthew, 2000). made up of a single type of monosaccharide, for example,
The biological activities of polysaccharides are strongly affected cellulose and glycogen consist of glucose; hetero-polysaccharides
by their chemical structure and chain conformations. However, or heteroglycans, which consist of more than one type of
the macromolecular structures of plant cell wall polysacchar- monosaccharide, such as heparin which consists of, α-L-idopyr-
ides, especially hetero-polysaccharides or so-called hemicellu- anosyluronic acid 2-sulfate and 2-deoxy-2-sulfoamino-α-D-gluco-
loses, are extremely complex due to the presence of different pyranose 6-sulfate (Xiao et al., 2011). According to the glycosides
monosaccharides as building blocks, which usually are isobaric linked onto the glycan, polysaccharides can also be classified as
stereoisomers, variations in sequence, linkage, branching, and proteoglycans and glycoproteins, glycolipids, and glycoconju-
distribution of side chains (An & Lebrilla, 2011; Cancilla, Penn, & gates (Berg, Tymoczko, & Stryer, 2012; Gatti, Casu, Hamer, &
Lebrilla, 1998; Mäki-Arvela, Salmi, Holmbom, Willför, & Murzin, Perlin, 1979). Based on the origins, bioactive polysaccharides
2011). Besides, the polysaccharides in microorganisms (fungi, from plant (dietary fibers, herbs and wood plants), algae and
yeasts, and bacteria), algae, plants, and animals are alwa- lichen, and other bioactive polysaccharides which are derived
ys physically and/or chemically tangled together with other from animals (e.g. heparin, chondroitin sulfate, and hyaluronan)
Bioactive Carbohydrates and Dietary Fibre 5 (2015) 31 –61 33
and possess similar structural features (e.g. sulfate) as certain the main or key components of herbal medicines generally
plant ones are reviewed in this paper. Specifically, the sources, include low-molar-mass compounds, such as alkaloids (e.g.
chemical composition, molecular structure, and biological activ- phenanthridine alkaloid in Lycoris radiata herb, protoberber-
ities of naturally bioactive polysaccharides are reviewed below ine alkaloids in Rhizoma coptidis), terpenoids (e.g. Rabdosia
based on their original sources, to understand their presence and diterpenes and quassinoids), flavonoids (e.g. scutellaria fla-
biological function. vones), saponins; and high-molar-mass proteins, tannins,
and most importantly polysaccharides (Tang, Hemm, &
2.1. Bioactive polysaccharides in dietary fibers Bertram, 2003a,b). Of these fractions in herbal medicines,
polysaccharides have been identified as one of the major
The dietary fiber was defined by the Food and Agriculture active ingredients responsible for various pharmacological
Organization (FAO) as a variety of indigestible plant poly- activities, such as immunostimulatory activity, antiviral
saccharides including cellulose, hemicelluloses, pectins, oli- activity, antioxidant activity, antitumor activity, radioprotec-
gosaccharides, gums, and various lignified compounds. tion effect, hepatoprotection effect, and antifatigue effect.
Polysaccharides in the dietary fibers may be active in their (Harlev, Nevo, Lansky, Ofir, & Bishayee, 2012; Jin, Huang,
native form or after chemical/enzymatic treatments. For Zhao, & Shang, 2013; Li & Peng, 2013; Thakur et al., 2012;
example, the cellulose and hemicellulose can directly stimu- Tian, Zhao, Guo, & Yang, 2011). Polysaccharides in various
late the bowel movement, while the inulin needs to be herbs are believed to be active in their native form to
fermented into short-chain fatty-acids by microflora so as stimulate human immune systems, to inhibit viral replica-
to prevent numerous gastrointestinal disorders (Pool-Zobel, tion, to scavenge free radicals, and to inhibit lipid oxida-
2005). Among the constituent in dietary fibers, polysacchar- tion (Harhaji Trajkovic et al., 2009; Ke et al. 2011; Li & Peng,
ides play an important role in disease prevention. For exam- 2013). A brief summary of the recent advances in the study
ple, pectins, inulin, and gums are able to slow the movement and application of bioactive polysaccharides from herbal
of food in the digestive tract, to reduce the blood cholesterol medicines for disease control and treatment is presented
level, and to slow the speed of sugar absorption from the food in Table 1.
into the blood, avoiding sudden hyperglycemia after food
intake. Cellulose, hemicellulose and lignin constitute the
insoluble fibers of dietary fibers which are able to stimulate 2.3. Bioactive polysaccharides in algae and lichens
the movement of bowel, speeding up the passage of waste
through digestive tract, and to prevent constipation, diverti- The polysaccharides in algae and lichens have attracted an
culosis, and hemorrhoids (Chawla & Patil, 2010; Tungland & increasing interest due to their excellent physical properties,
Meyer, 2002). Numerous convincing epidemiological and such as thickening, gelling, and stabilizing ability, and also
clinical studies suggest that moderate or higher intakes of due to their beneficial biological activities, such as antic-
dietary fiber can effectively lower risks for developing dis- oagulant, antithrombotic, antioxidative, antiviral, anti-
eases like diabetes (Weng, Lee, Yeh, Ho, & Pan, 2012), inflammation, antitumour, and immunomodulating activity.
cardiovascular diseases including stroke (Casiglia et al., (Kim & Li, 2011; Olafsdottir & Ingólfsdottir, 2001).
2013), coronary heart disease and hypertension (Viuda- The sulfated polysaccharides are one group of the most
Martos et al., 2010; Whelton et al., 2005), hypercholesterole- interesting and attractive components in the marine algae, such
mia, hyperlipidemia (Chau, Huang, & Lin, 2004; Kendall, as fucoidans and laminarans in brown algae (Phaeophyceae),
Esfahani, & Jenkins, 2010), obesity, and gastrointestinal (col- carrageenans in red algae (Rhodophyceae), and ulvans in green
orectal) cancer (Lunn & Buttriss, 2007). Generally, dietary fiber algae (Chlorophyceae) (Wijesekara, Pangestuti, & Kim, 2011). Antic-
intake provides many benefits, including a decrease in oagulant activity could be the most attractive property of the
intestinal transit time and an increase in stools bulk, and sulfated polysaccharides. For example, the sulfated galactans
decreases in blood total cholesterol, and postprandial blood (carrageenan) from red algae and the sulfated fucoidans from
glucose, and/or insulin levels (Anderson et al., 2009; Brown, brown algae have been identified with high anticoagulant
Rosner, Willett, & Sacks, 1999; Lunn & Buttriss, 2007). activity. Sulfated polysaccharides from algae were reported to
Considering the importance of dietary fibers to human possess similar or even stronger activity than those of heparin
health and its specific working mechanism, we included the (Maeda, Uehara, Harada, Sekiguchi, & Hiraoka, 1991). There are
dietary fibers as a source of bioactive polysaccharides. The several other beneficial biological activities of sulfated polysac-
main sources, structure, composition, and biological effects charides from algae that have also been intensively studied. For
of dietary fiber polysaccharides from follow-up investiga- example, (1) the highest antioxidant activity expressed as protec-
tions, intervention trials, and/or randomized-controlled trials tion of the human body against damage from reactive oxygen
are summarized in Table 1. species was found in fucoidan (followed by alginate and lami-
naran); (2) the anticancer activity of the algae was found to
2.2. Bioactive polysaccharides in herbs originate from its free-radical scavenging and antioxidant activ-
ity (Chattopadhyay et al., 2010); (3) the antiviral activity of
In traditional medicines of many countries, such as the carrageenans, fucoidans, and sulfated rhamnogalactans was
traditional Chinese medicines, Japanese Kampo medicines, proved by exerting inhibitory effects on the entry of herpes
Indian Ayurveda, and Phyto-medicines in western countries, and HIV viruses into cells (Wijesekara et al., 2011); (4) imm-
herbs have been used to treat various types of illnesses. unomodulatory activity of algae-derived polysaccharides was
Modern pharmacological experiments have identified that shown by enhancing the phagocytic and secretory activity of
Table 1 – A brief summary of bioactive polysaccharides from different sources.
Type Name Composition Sources Physiological effects Ref.
Dietary Cellulose β-(1-4) linked-D-glucopyranose, Grains, fruit, Increase stool bulk Viuda-Martos
fiber linear and homopolysaccharides vegetables, nuts and help to regulate et al. (2010)
bowel movement
Hemicelluloses Four classes of structurally Vegetative and Immunomodulating Doliška et al.
different cell-wall storage tissues of activity, (2012),
polysaccharides including annual and antithrombotic Ebringerová et al.
xylans, mannans, β-glucans with perennial plants, activity, free radicals (2008), Heinze
mixed linkages and xyloglucans fruit, legumes, eliminating activity, (2005), Mudgil
and nuts antioxidant activity, and Barak (2013),
bowel movements Wu and Chen
regulating and (2011)
cholesterol lowering
effect
Pectins α-(1-4)-D-Galacturonic acid and Plant primary cell Intestinal immune Mudgil and Barak
rhamnose backbone, arabinose, wall, soft tissues system modulating (2013), Suh et al.
galactose, xylose side chains, of fruit and activity, cholesterol (2013), Yu,
partially O-methyl/acetylated vegetable lowering effect, Kiyohara,
decrease gastric Matsumoto,
emptying and small Yang, and
intestine transit time Yamada (2001)
β-Glucans β-(1-4)-D-Glucose and β-(1-3)- Oats, barley Cholesterol lowering Charlton et al.
D-glucose grains effect, control of (2012), Chen and
blood glucose level Raymond (2008),
and lipids; reduction Marques, Dhont,
of hypertension, Sorgeloos, and
stimulation of Bossier (2006),
immune system Wolever et al.
(2011)
Resistant starch α-(1-4) and/or (1-6) linked Cooked and Prevention of colonic Bird, Conlon,
D-glucopyranosyl cooled potatoes, cancer, hypoglycemic Christophersen,
rice, green and and Topping
bananas, hypocholesterolemic (2010), Fuentes-
legumes, food effects, role as Zaragoza,
containing prebiotic, inhibition Riquelme-
modified starch of fat accumulation, Navarrete,
enhance the Sánchez-Zapata,
absorption of and Pérez-
minerals Álvarez (2010)
Gums Galactan, xylan, xyloglucan, Locust bean gum, Hypocholesterolemic Chawla and Patil
glucuronic mannan, galacturonic gum arabic, and and (2010), Whistler
rhamnosan type guar gum which hypotriglyceridemic and BeMiller
are exudates of effects, influence on (1993)
trees or isolated postprandial
from seeds glycemia, lipemia,
and lipoprotein
composition, gel-
forming to increase
satiety, slow gastric
emptying
Inulin β-(1-2)-D-Fructofuranosyl Chicory root, Hypolipidemic Capriles and
wheat, onion, effects, prebiotic Areas (2013),
garlic properties which Cherbut (2002),
influence gut Russo et al. (2012)
microbiota, stimulate
mineral (calcium,
magnesium)
absorption
Konjac β-(1-4)-Linked D-glucose and Amorphophallus Cholesterol lowering, Al-Ghazzewi
glucomannan β-(1-4)-linked konjac plant bulking for weight et al. (2007)
D-mannose reduction, reduces
the risk of
constipation
Herbs Ginseng (1-4)-Linked homogalacturonan Ginseng, the root Antirotavirus activity Baek etb al. (2010)
polysaccharides backbone. (1-2(3))-Linked of Panax ginseng
rhamnose on position 4 as a part
Table 1 (continued )
of backbone or ramified regions.

(1-5(2))-Linked arabinose with
branch points at position 3. (1-3
(4))-Linked terminal galactose
Astragalus α-(1-4)-D-Glucan with α-(1-6)- Astragalus roots Immunemodulating Li et al. (2011), Li
polysaccharides branches activity, antiviral and Peng (2013)
activity
Acanthopanax Seven monosaccharides Acanthopanax Antioxidant and Chen et al. (2011)
senticosu including rhamnose, xylose, senticosus leaves immunobiological
polysaccharides glucose, mannose, arabinose, activity
galactose, and glucuronic acid in
a molar ratio of
7.45:18.63:25.15:0.93:8.35:2.79:5.69
Polygonum Mainly glucose Polygonum Antioxidant activity Lv, Cheng, Zheng,
multiflorum multiflorum and antiglycation Li and, Zhai (2014)
Thunb Thunb root
polysaccharides
Platycodon (1-4(6))-Linked Platycodon Antiangiogenic Xu, Dong, Qiu,
grandiflorum galactopyranosyl residues, with grandiflorum root activity Cong, and Ding
polysaccharides branches attached to O3 of (1- (2010)
6)-linked galactose residues.
Arabinose and galactose in the
molar ratio of 1.42:1.0
Algae Green algae (1-3(6))-Linked galactose, (1-3 Green algae, Antiviral activity (Ghosh et al.,
and sulfated (4))-linked arabinose, (1-4)- Caulerpa racemosa (herpes simplex virus 2004)
lichens polysaccharides linked glucose and terminal, (1- type 1 and 2)
4)-linked xylose residues.
Sulfations occur on O6 of
galactose and O3 of arabinose.
Sulfate ester content: 9%
Brown algae Fucan: (1-3)-linked α-L- Brown algae, Antiviral activity Ponce, Pujol,
sulfated fucopyranosyl backbone, mostly Adenocystis (herpes simplex virus Damonte, Flores,
polysaccharides sulfated at C4, and branched at utricularis type 1 and 2), and Stortz (2003),
C2 with non-sulfated Antiretroviral activity Trinchero et al.
fucofuranosyl and fucopyranosyl (HIV-1) (2009)
units, and 2-sulfated
fucopyranosyl units. Galactan: D-
galactopyranose units linked on
C3 and C6, and sulfation mostly
on C4. Sulfate ester content: 30–
34%/21–24%
Red algae Backbone of alternating β-(1-3)- Red algae, Antioxidant Zhang et al. (2010)
sulfated linked D-galactosyl units and α- Porphyra activities,
polysaccharides (1-4)-linked L-galactosyl, (1-6)- haitanensis anticoagulant
(porphyran) sulfate or 3,6-anhydro-α-L- activities
galactosyl units. Sulfate ester
content: 17%
Green algae (1-2)-Linked L-rhamnose Green algae, Anticoagulant Li et al. (2012a),
sulfated residues with sulfate groups Monostroma activity Mao et al. (2009)
rhamnan substituted at positions of C3 latissimum
and/or C4. Sulfate ester content:
23%/25%
Algal fucoidan Fucose, galactose. Sulfations Brown algae, Anti-inflammatory Kang et al. (2011)
occur on position-2 and -3. Ecklonia cava activity
Sulfate ester content: 41–92%
Brown algae Mainly composed of fucose Brown algae, Antiproliferative Athukorala et al.
sulfated (82%), galactose (14%), and small Ecklonia cava activity, anticancer (2009)
polysaccharides amounts of xylose and mannose activity
Sulfate ester content: 92%
Galactofuranomannans,
β-glucan lichenan
Galactofuranomannans, Lichen Thamnolia Immunomodulating Omarsdottir,
β-glucan vermicularis var. activity Freysdottir, and
subuliformis Olafsdottir (2007)
β- Lichenan: β-(1-3 Lichens, Cetraria islandica/ Immunomodulating Omarsdottir,

Glucans (4))-linked glucan Umbilicaria proboscidea/Thamnolia activity Olafsdottir, and
lichenan Isolichenan: α- vermicularis var. subuliformis/ Freysdottir (2006)
(1-3(4))-linked Peltigera canina
glucan Pustulan:
β-(1-6)-linked
glucan partially
acetylated at O3
Heteroglycan
Other Heparan sulfate/ (1-4) Linked glucuronic/ Animal granules Anticoagulant Linhardt (2003),
sources heparin iduronic acid and N- of mast cell activity Schedin-Weiss
(derived acetylglucosamine disaccharide (heparin); Animal et al. (2008)
from unites with variable 2/3/6-O- tissues, e.g.
animal) sulfonation porcine intestine,
bovine lung
Chondroitin (1-3) linked glucuronic/iduronic Animal Modulating cellular Barnhill et al.
sulfate/dermatan acid and (1-4) linked N- cartilaginous growth and signaling, (2006), Hitchcock,
sulfate acetylgalactosamine tissue, e.g. bovine maintaining the Costello, and Zaia
disaccharide unites with variable trachea, and extracellular matrix (2006), Takegawa
2/3/6-O-sulfonation shark cartilage integrity et al. (2011)
macrophages and by inducing the production of reactive oxygen nutrition research (Aachary & Prapulla, 2011). However, most
species, nitric oxide, and cytokines (Schepetkin & Quinn, 2006). polysaccharides do not show biological activity unless some
Polysaccharides isolated from lichens are primarily linear or modifications are carried out. Cellulose derivatives, such as
scarcely substituted α- and/or β-glucans. Such glucans from methylcellulose, hydroxyethylcellulose, hydroxypropylcellu-
lichens have been reported to possess a variety of biological lose, and hydroxylpropylmethylcellulose, have found promis-
activities like antitumour activity, immunomodulating effect, and ing applications in various fields such as food, medical,
antiviral activity (Olafsdottir & Ingólfsdottir, 2001; Omarsdottir, pharmaceutical, and cosmetics (Li & Mei, 2006). Therefore,
Freysdottir, & Olafsdottir, 2007; Zambare & Christopher, 2012). further review of wood polysaccharides will be presented in
The β-glucans from lichens and lichenan showed the immuno- the later functionalization/modification section. There, the
modulating activity by stimulating a wide range of immune strategies to functionalize wood polysaccharides towards
responses such as cytokine release, generation of reactive oxygen bioactive applications will be discussed in detail.
species and nitric oxide, and release of arachidonic acid metabo-
lites (Schepetkin & Quinn, 2006). Lichenan with a galactogluco- 2.5. Bioactive polysaccharides from other sources
mannan structure showing anticoagulant and antithrombotic
activity was also reported (Martinichen-Herrero, Carbonero, The sulfated glycosaminoglycans such as the heparan sulfate
Sassaki, Gorin, & Iacomini, 2005). (HS), chondroitin sulfate (CS), dermatan sulfate (DS), and keratin
Biological activities of the sulfated polysaccharides from sulfate represent another group of bioactive polysaccharides that
both algae and lichens highly depend on their structural are mainly derived from animals. HS chains are made up of
features, such as the sulfate content and distribution of variably sulfated and N-acetylated repeating disaccharide unites,
sulfate groups on the main chain, molar mass, and stereo- i.e. glucuronic/iduronic acid and glucosamine (Chappell & Liu,
chemistry. Therefore, modification of the native sulfate poly- 2013; Linhardt, 2003; Sakiyama-Elbert, 2014). Heparin, the most
saccharides to obtain the bioactive polysaccharides with highly sulfacted heparan sulfate, has been widely used as the
desired molecular size and functional property for applica- most effective clinical anticoagulant. Anticoagulant activity of
tion is needed (Ngo & Kim, 2013; Wijesekara et al., 2011). A the heparin highly relies on its specific structure sequence,
brief summary of recent research advance is listed in Table 1. within which the binding site of an important protein (antith-
rombin III) is crucial for heparin to prevent the generation of a
2.4. Bioactive polysaccharides in wood fibrin clot which is formed by the action of thrombin (Schedin-
Weiss, Richard, Hjelm, & Olson, 2008). Understanding of this
Polysaccharides from wood mainly include cellulose and a structure–activity relationship of heparin offers the opportunity
few primary groups of hemicelluloses, i.e. xylans, glucoman- to develop drugs with higher specificity and better regulation of
nans, arabinans, galactans, and glucans (Fraser-Reid, Tatsuta, coagulation and to explore other therapeutic applications such
& Thiem, 2008; Gatenholm & Tenkanen, 2004; Heinze, 2005). as infection, inflammation, cancer and wound-healing treatment
Galactoglucomannans and pectins from wood have been (Linhardt, 2003; Rajangam et al., 2006; Sakiyama-Elbert, 2014;
reported to show immunostimulating activities and radical- Zhang et al., 2013a; Zhang, Wardwell, & Bader, 2013b). CS/DS
scavenging activities (Ebringerová et al., 2008; Le Normand chains are composed variably sulfated N-acetylgalactosamine
et al., 2014). Xylans or Xylooligosaccharides from hardwood, and glucuronic acid or its epimeride iduronic acid disaccharides
softwood, and dietary fibers have also been found to possess repeating units (Silbert & Sugumaran, 2002; Takegawa et al.,
great prebiotic potential for application in both medical and 2011). Growing research evidence reveals the previously less or
unperceived functions of CS/DS (Sugahara et al., 2003), for In recent years, novel and effective extraction methods, such
example being a key molecule of the brain extracellular matrix as supercritical fluid extraction, microwave-assisted extraction,
(Kwok, Warren, & Fawcett, 2012), regulating the cell adhesion, and the most promising hot-water extraction, have gained
proliferation and migration during wound healing (Zou et al., increasing attention due to their environmentally friendly
2004), signaling of growth factor in skeleton (Alliston, 2010). process, higher extraction efficiency, cost effectiveness, and
Hyaluronic acid (HA), which is mainly drived from animal structure-preservation ability (Chao, Ri-fu, & Tai-qiu, 2013; Le
and plant tissues, is a linear non-sulfated glycosaminoglycan Normand et al., 2014; Song, Pranovich & Holmbom, 2013). For
with repeating disaccharide units of β-(1-4)-D-glucuronic acid example, Cheng et al. (2013) compared hot-water, ultrasonic
and β-(1-3)-N-acetyl-D-glucosamine. HA is an essential com- assisted, enzyme, and microwave-assisted extractions to isolate
ponent of the extracellular matrix, mediating cellular signal- bioactive polysaccharides and discovered that the yielded four
ing, wound repair, morphogenesis, and matrix organization polysaccharides had similar physicochemical properties, how-
and thus HA and its derivatives have been clinically used for ever, the antioxidant activity of the polysaccharides obtained by
medical applications, such as viscosupplementation, eye sur- hot-water extraction was stronger than those isolated with
gery, and drug delivery for decades (Balazs, 2009; Gaffney, other methods. Hot-water extraction combined with some
Matou-Nasri, Grau-Olivares, & Slevin, 2010; Prestwich, 2011). novel assistant methods, such as microwave, ultrasonic, and
Chitin, the second most abundant polymer after cellulose, is a enzymatic pretreatment, increases the extraction efficiency and
co-polymer of β-(1-4)-linked N-acetyl-glucosamine (acetylated yield of products. For example, enzymatic pretreatment of the
unit) and N-glucosamine (deacetylated unit) which randomly raw material before extraction normally results in a reduction
distributed along the chain (Khan & Ahmad, 2013). Chitin can in extraction time, lowers energy consumption, minimizes the
primarily be found in the exoskeleton of arthropods (e.g., shells usage of solvents, increases the yield, and maximally preserves
of crabs and shrimp) and in the cuticles of insects, however it biological activities of the product when compared to non-
have been identified and extracted in the cell walls of fungi and enzymatic methods (Chen et al., 2014; Dong, Wang, & Wang,
yeast (Bartnicki-Garcia, 1968; Logesh, Thillaimaharani, Sharmila, 2011; Jia et al., 2013; Lazaridou, Chornick, Biliaderis, &
Kalaiselvam, & Raffi, 2012). So the chitin and chitosan will be also Izydorczyk, 2008; Puri, Sharma, & Barrow, 2012). Recently, ionic
reviewed in this paper even if there are not belonging to the liquids have also been developed to extract polysaccharides at
plant kingdom. Partial deacetylation of chitin under alkaline low temperature and short time (Abe, Fukaya, & Ohno, 2010).
conditions or by chitin deacetylase yields the most important Further purification of bioactive polysaccharides from
derivative of chitin, i.e. chitosan. Generally, when the number of crude extracts is of high importance, which ensures under-
N-glucosamine units is higher than 50%, the term chitosan is standing of the relationship between structures and the
used (Fig. 4) (Khor & Lim, 2003). Oligomers from partial acid safety of the furture biomedical, pharmaceutical, and food
hydrolysis of chitin and chitosan were recognized for their applications. This can be done with a combination of several
bioactivity, including hemostatic action, anti-inflammatory techniques, such as ethanol precipitation, fractional precipi-
effect, antitumoral, antibacterial, and fungicidal properties, elicit- tation, ion-exchange chromatography, gel filtration, and affi-
ing chitinase, and regulating plant growth (Rinaudo, 2008). nity chromatography by taking advantages of particular
properties of the desired compound such as acidity, polarity,
and molecular size (Jin et al., 2013).
3. Isolation of bioactive polysaccharides
Generally, (bioactive) polysaccharides are present together with 4. Functionalization of polysaccharides

various other components such as proteins, polynucleotides,
lipids, extractives, lignin, and some inorganic mineral sub- The naturally bioactive polysaccharides from different sources
stances. However, the desired biological activities of the naturally could offer numerous bioactive properties and benefit human-
bioactive polysaccharides may be undermined by other com- ity in health care, as reviewed above. It is known that the
pounds, which may even cause antagonistic effects or undesir- structural features of the polysaccharides, such as degree and
able toxicity. In other words, pure bioactive polysaccharides steric configuration of substitutions, linkages of monosacchar-
could enable the safe, reproducible and accurate dosage for ides and substitutes, and molar mass and its distribution play
experimental or therapeutic applications, and also enable the a critical role on their physicochemical (e.g. solubility and fluid
investigation of structure/activity relationship, facilitating the capability) and bioactive properties (Ngo & Kim, 2013). There-
development of new compounds with similar or higher desirable fore, the modification of natively bioactive polysaccharides to
bioactivities (Colegate & Molyneux, 2008). Thus, the isolation of extend their applications in both traditional and newly
natural polysaccharides that have biological activities toward explored biomedical areas, such as tissue engineering, con-
organisms from various sources plays an important role in the trolled drug delivery and release, and wound healing/dressing,
investigation and application of bioactive polysaccharides. is of high importance. Besides, the functionalization of those
Generally, bioactivities of polysaccharides are highly polysaccharides that do not possess innate bioactivity to
dependent on their structural information, such as molar introduce bioactivity by designing cost-effective approaches
mass, extent of side chains/groups or substitution and their is also attracting increasing attention. This section will focus
distribution on the backbone. Thus, how to isolate the on the functionalization of polysaccharides, mainly including
polysaccharides from the complex matrix networks, mean- plant derived polysaccharides, i.e. cellulose and hemicellu-
while minimizing any loss of the desired bioactivity, is one of loses, and starch as summarized in Table 2. Other non-plant
the most important tasks to deal with. derived polysaccharides such as chitin and chitosan, alginate,
Table 2 – Summary of polysaccharide modification and applications of the functionalized derivatives.
Polysaccharides Modification Description of reactions or Potential applications Ref.

approaches products
Cellulose Etherification Methyl-/carboxymethyl-/ Pharmacy Kalia, Kaith, and Inderjeet

ethyl-/hydroxyethyl-/ (2011), Li and Mei (2006)
hydroxypropyl-/
hydroxypropylmethyl-/
cyanoethyl-cellulose
Selective TEMPO mediated oxidation, Drug delivery system, wound Lacin (2014),
oxidation periodate oxidized 2,3- healing, regulation of Shimotoyodome et al.
dialdehyde cellulose postprandial glucose and (2011), Valo et al. (2013),
insulin level Zhu et al. (2001)
Graft Chemical redox initiation or Stimuli-responsive drug Mohd Amin et al. (2013),
copolymerization irradiation methods to delivery Thakur, Thakur, and
introduce different monomers, Gupta, (2013b)
e.g. acrylic acid, acrylamide,
acrylonitrile, methyl
methacrylate, ethyl acrylate
etc.
Chitin/chitosan Etherification O-carboxymethyl and N- Target drug delivery, Zhang et al. (2010)
carboxymethyl derivatives hemostatic dressings
obtained when the
carboxymethylation takes
place at carboxyl groups and
free amino groups respectively.
Quaternization Trimethyl chitosan chloride, N- Absorption enhancer for test Mourya and Inamdar
(etherification) propyl-N,N-dimethyl chitosan, drugs, gene carriers, controlled (2008)
N-furfuryl-N,N-dimethyl drug releaser, antibacterial
chitosan, N- agents
diethylmethylamino chitosan.
Different degree of
quaternization (methylation)
of amino groups in chitosan
can be achieved with methyl
iodide in alkaline solution of N-
methyl pyrrolidinone
Graft Initiated by free radicals Wound-dressing materials, Alves and Mano (2008), Ito
copolymerization initiator systems, irradiation drug delivery, tissue et al. (2013)
methods, or grafting via engineering, antimicrobial
enzymatic methods (e.g. agents
tyrosinase)
Alginate Esterification Propylene glycol alginate, Amorphous solid dispersion of d’Ayala et al. (2008); Pawar
synthesized by reaction with drugs and Edgar (2013)
propyleneoxide. Dodecyl
alginate, prepared by reaction
of tetrabutylammonium salts
of alginic acid with dodecyl
bromide
Oxidation Selectively breaks the vicinal Tissue engineering Bouhadir et al. (2001), Kim
glycols and introduces new et al. (2012)
reactive groups, i.e. two
aldehyde groups
Graft Chemical redox initiation, Temperature and pH Gao, Liu, Chen, Jin, and
copolymerization microwave initiated synthesis, responsive hydrogel for Chen (2009), Isiklan and
or microwave assisted delivery of proteins or drugs, Kucukbalci (2012), Pawar
synthesis to introduce wound healing dressing and Edgar (2012), Wong
different monomers (vinyl or (2011), Xu et al. (2013)
acrylic compounds, e.g. poly(N-
isopropylacrylamide))
Layer-by-layer Repeated deposition of Cell adhesion and spreading, Caridade et al. (2013), Hu
self-assembly oppositely charged polymers drug and DNA delivery and Tsou (2014), Liu, Liu,
(e.g. negative charged alginate Liu, Li, and Liu (2013),
and positive charged chitosan Silva et al. (2013a)
in acid conditions) on material
surfaces as polyelectrolyte
multilayers
Starch Esterification Tupa et al. (2013)
Polysaccharides Modification Description of reactions or Potential applications Ref.

approaches products
Prepared by reaction of starch Used as superdisintegrant and

with fatty acid chlorides/vinyl matrix former in capsules and
esters/anhydride/carboxylic tablet formulations, controlled
acids as reactants. E.g. Starch release, maintaining human
acetates, starch butyrates colonic function
Etherification Methyl/hydroxypropylmethyl/ Pharmaceutical application BeMiller and Whistler
hydroxyethyl/ (2009), Tharanathan (2005)
hydroxyethylmethyl starch
Hyaluronic acid Esterification Esterification of HA by Cell carrier for skin wounds, Benedetti et al. (1993),
(HA) alkylation using akyl halides drug carrier Schanté et al. (2011)
(chlorides, iodides, bromide),
by using diazomethane, and by
using epoxides
Amidation Amidation of HA in water or of HA–drug conjugates for Oh et al. (2010) Bulpitt and
HA’s TBA salt in organic controlling release, target Aeschlimann (1999), Kong,
solvent with coupling agents, specific delivery of Oh, Chae, Lee & Hahn
e.g. EDC, NHS biomolecules (2010)
Ugi condensation Formation of diamide linkage Controlled drug delivery Crescenzi et al. (2003),
between polysaccharides Maleki, Kjoniksen, and
chains by using formaldehyde, Nystrom (2007)
cyclohexyl isocyanide and
diamine
Xylans Graft- Free radical graft Adsorption, separation, and Peng et al. (2011)
copolymerization copolymerization of xylan-rich drug release applications.
hemicelluloses with acrylic
acid yielded ionic xylan-rich
hydrogels
Amidation & Conjugating of tyramine with Cell culture, tissue Kuzmenko et al.
Enzymatic spruce arabinoglucuronoxylan engineering.
modification by EDAC/NHS first then cross-
linking using horseradish
peroxidase and H2O2
(Galacto) Hydrolysis Partial hydrolysis of Konjac Food ingredient and prebiotic Al-Ghazzewi et al. (2007)
glucomannans glucomannan by acid or
enzymes
Esterification Methacrylated Drug delivery Edgar, Heinze, and
galactoglucomannan cross- Buchanan, (2009)
linked hydrogel
Oxidation TEMPO-mediated oxidation Further functionalization Leppänen et al. (2013)
platform, e.g. functional
biocomposites
Enzymatic Selectively oxidize the primary Potential platforms for further (Gatenholm and
modification hydroxyl groups of galactosyl functionalizations, e.g. Tenkanen (2004),
to aldehyde functionalities development of new Leppänen et al. (2014),
using galactose oxidase anticoagulant and Parikka et al. (2012),
antithrombotic drugs Parikka et al. (2009), Xu
et al. (2012)
Xyloglucan Chemo- Incorporation of different Potential platforms for further (Brumer et al. (2004), Xu
enzymatic chemically reactive groups or functionalizations, e.g. et al. (2012)
modification functional moieties, such as functional biocomposites,
biotin into the xyloglucan by in vitro diagnostics,
xyloglucan biomolecular capture or
endotransglycosylase. detection
Regioselectively oxidize the
primary alcohols of galactosyl
to aldehydes using galactose
oxidase
Pectins Graft Grafting with poly(N- Colon-targeted dug delivery Fares, Assaf, and Abul-
copolymerization vinylpyrrolidone) to prepare Haija (2010)
hydrogel copolymer
Cross-linking Cross-linking via calcium or Controlled drug delivery Liu et al. (2003)
prepare composites with other
polymers such as
ethylcellulose and
hydroxypropylmethyl cellulose
and hyaluronic acid are also subjected to review. The aims of (Fig. 1): (1) 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and
modification or functionalization include, but are not limited its derivatives; (2) N-hydroxyphthalimide (NHPI), N-hydroxy-
to, the improvement and/or introduction of bioactivity, bio- benzotriazole (HBT), and violuric acid (VA). (Biliuta et al., 2013;
compatibility, control of biodegradability, as well as manufac- Coseri et al., 2009). Lately, oral administration of TEMPO-
turing and shaping for biomedical, pharmaceutical, and food oxidized cellulose with glucose and glyceryl trioleate to mice
applications (Cumpstey, 2013; d’Ayala, Malinconico, & Lau- was found to exhibit characteristic biological activities in
rienzo, 2008). When considering the application of the mod- reducing postprandial blood glucose, plasma insulin, glucose-
ified or functionalized polysaccharides, safe and green appr- dependent insulinotropic polypeptide, and triglyceride con-
oaches such as enzymatic methods are preferred because of centrations. This finding may suggest potential applications
their selectivity and non-toxic solvent medium. of TEMPO-oxidized cellulose in biomedical fields for human
health (Shimotoyodome, Suzuki, Kumamoto, Hase, & Isogai,
4.1. Cellulose 2011). The carboxyl groups introduced by these approaches
can be utilized for further functionalization. For example, by
Cellulose is the most abundant polysaccharide in nature. Its grafting amine-terminated polyethylene glycol chains (PEG)
value has been recognized in numerous traditional indus- onto carboxylic sites of the TEMPO-oxidized cellulose, a better
tries, such as construction, pulp and papermaking, and textile steric stabilization and salt tolerance property can be
industries. For upgrading the value of cellulose, various achieved (Araki, Wada, & Kuga, 2000). Besides, topological
value-added cellulose derivatives after chemical transforma- modification of films prepared from oxidized cellulose via
tion or functionalization have been developed and utilized in 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N-hy-
other industries such as food, cosmetic, (bio)medical, and droxysuccinimide (NHS) chemical activation to produce non-
pharmaceutical. However, the application of cellulosic mate- porous, water-resistant substrates for immunoassays and
rial is limited due to the difficulty in processing, for example, diagnostics application, or to introduce linking biomolecular
the high crystallinity degree and rigid intra/intermolecular onto cellulose for immobilizing antibodies and other func-
hydrogen bonds which result in its insolubility in most tionalities for medical and biological application have also
solvents (Tashiro & Kobayashi, 1991). been studied recently (Fig. 1) (Arola, Tammelin, Setälä, Tullila,
Generally, the hydroxyl group is the most targeted reactive & Linder, 2012; Orelma et al., 2012a; Orelma, Johansson,
group on the cellulose chain. Chemical functionalizations of Filpponen, Rojas, & Laine, 2012b). Ascribed to the gelling
cellulose based on hydroxyl group include esterification, properties, biodegradability, biocompatibility, and bioactivity
etherification, selective oxidation, graft copolymerization, of TEMPO oxidized NFC, its structured hydrogel and aerogel
and intermolecular crosslinking reaction (Pérez & Samain, materials have been used for biomedical applications such as
2010) as summarized in Table 2. However, the primary and scaffold for wound-healing and 3-D cell culture, and drug
secondary hydroxyl groups show different reactivity in dif- carrier and controlled release, cosmetic applications such as
ferent conditions. For example, the reactivity order of these thickeners and water-retaining agents, and other applications
hydroxyl groups during etherification reactions in alkaline (Bhattacharya et al., 2012; Dong, Snyder, Tran, & Leadore, 2013;
condition is C2–OH4C6–OH4C3–OH, while the reactive order Sehaqui, Zhou, & Berglund, 2011; Shimotoyodome et al., 2011;
of cellulose acetylation in LiCl/acetic acid dimethylamide Valo et al., 2013).
(DMAc) shows as C6–OH4C3–OH4C2–OH, but when the reac- Another selective oxidation approach is the periodate
tion takes place in LiCl/1,3-dimethyl-2-imidazolidinone, the oxidation (Fig. 1), which selectively oxidizes the adjacent
corresponding order is C6–OH4C2–OH4C3–OH (Heinze, 2005). hydroxyl groups (C2–OH and C3–OH) of cellulose yielding a
In addition to the inherent reactivity difference of hydroxyl sugar ring opened product with two aldehyde groups in the
groups, regioselective control of the substitution of desired C2 and C3 position of the glucopyranose units (Calvini,
hydroxyls with functional groups can be achieved via various Gorassini, Luciano, & Franceschi, 2006). This opens up
protecting and activating approaches as shown in Fig. 1. The untapped possibilities for further functionalization and appli-
difference in accessibility, reactivity, and regioselective con- cation. For example, sulfonation of the periodate oxidized 2,3-
trol of hydroxyl groups provides the possibility to prepare dialdehyde cellulose with sodium bisulfite yields the corre-
cellulose derivatives with specific molecular structures for sponding C2/3 sulfonates possessing stronger water retention
various applications. ability (Zhang, Jiang, Dang, Elder, & Ragauskas, 2008).
Oxidation of cellulose is one of the most important Other oxidant systems, such as N2O4/CCl4, NO2/CCl4, and
modification methods to prepare value-added cellulose deri- HNO3/H3PO4–NaNO2 have also been developed to selectively
vatives for further applications. For example, oxidized cellu- oxidize cellulose (Fig. 1) (Coseri et al., 2009; Kumar & Yang,
lose and regenerated cellulose are widely used as excellent 2002; Wu et al., 2012). Oxidized cellulose has shown anti-
hemostatic materials in various surgical operations and tumor, immunostimulant, wound healing, and adhesion-
postsurgical adhesion prevention layers (Wu, He, Huang, prevention properties (Novotna et al., 2013; Zimnitsky,
Wang, & Tang, 2012). Selective oxidation of cellulose by Yurkshtovich, & Bychkovsky, 2004). For example, the cal-
converting the primary alcohol groups into carboxyl groups cium/sodium salts of oxidized cellulose prepared from nitro-
is of significance and has been studied intensively, especially gen oxides in nitric acid have shown immunomodulatory
for the preparation of nanofibrillated cellulose in recent years effects in both in vitro and in vivo tests (Jelinkova, Briestensky,
(Isogai, Saito, & Fukuzumi, 2011). Selective oxidation of Santar & Rihova, 2002). The carboxyl groups of the HNO3/
cellulose primary hydroxyl groups into carboxyl and/or alde- H3PO4–NaNO2 oxidized cellulose open up possibilities for
hyde groups can be achieved through two oxidation systems immobilization of drugs, the products of which have found
Fig. 1 – Selected pathways for regioselective functionalization of cellulose (adapted from Arola et al., 2012; Biliuta et al., 2013;
Coseri et al., 2009; Koschella, Fenn, Illy, & Heinze, 2006; Wu et al., 2012; Zhang et al., 2008).
potential applications as biodegradable macromolecules used acrylonitrile (Dahou, Ghemati, Oudia, & Aliouche, 2010).
in drug delivery systems (Zhu, Kumar, & Banker, 2001). Stimuli-responsive bacterial cellulose-g-poly(acrylic acid-co-
Graft copolymerization is another approach for cellulose acrylamide) hydrogels as drug delivery carriers have been
modification via chemical redox initiation methods (ceric synthesized by graft copolymerization of the monomers onto
ammonium nitrate or ferrous ammonium sulfate–potassium bacterial cellulose fibers using microwave irradiation. The
persulfate) or irradiation methods (UV, microwave, and grafted cellulose hydrogels demonstrated a pH-responsive
γ-rays). Intensive studies have been carried out on the graft swelling behavior (reaching maximum swelling at pH 7),
copolymerization of cellulosic polymers with suitable hydro- suggesting a suitable controlled release in the lower gastro-
phobic monomers to introduce desired functionalities into intestinal tract (Mohd Amin, Ahmad, Pandey, & Jue Xin, 2013).
the cellulosic backbone, so as to overcome the sensitivity of
cellulosic fibers towards water/moisture absorption and poor 4.2. Hemicelluloses
chemical resistance and thus to improve the existing physi-
cochemical properties of the cellulosic polymers (Bashar, Hemicelluloses are a type of heterogeneous polysaccharides
Khan, & Idriss Ali, 1995; Kaur, Kumar, & Sharma, 2010; and are widely distributed in biomass. Hemicelluloses mainly
Rattan, Maitra, Misra, & Kaur, 2008; Thakur, Thakur, & include xylans, glucomannans, arabinans, galactans, and glu-
Gupta, 2013a). A biocide cellulose carbamate with antimicro- cans. The diversity of hemicelluloses originates from: (a) sugar
bial properties was prepared by impregnating the fibers in constituents, which mainly include glucose, xylose, mannose,
aqueous thiourea solution and subsequently grafting with galactose, arabinose, fucose, (4-O-methyl)glucuronic acid, and
galacturonic acid; (b) glycosidic linkages position and con- 4.2.2. Galactomannans, glucomannans, and
formation between monosaccharides, e.g. , arabnformation, galactoglucomannans
1-2,3,4,5,6 linkages; and (c) side group/chain types, distribu- The galactomannans and glucomannans belong to the mannan-
tion, and linkages. Such structural and compositional complex- type polysaccharides, but with different structures. Typical seed
ities result in previously unperceived applications. However, as (carob, guar, locust bean, tara, etc.) galactomannans contain a
a group of important biopolymers, hemicelluloes have found a β-(1-4)-linked D-mannan backbone to which is attached single
broad spectrum of applications both in native and in their α-D-galactose at the C6 position of D-mannose (Srivastava &
modified forms. Generally similar to other polysaccharides, Kapoor, 2005). The glucomannans consist of random distrubtion
chemical modifications of hemicelluloses mainly include partial of β-(1-4)-linked D-glucose and β-(1-4)-linked D-mannose in the
hydrolysis, graft polymerization, (regioselective) oxidation, main chain. In softwoods, there are additionally side chains of α-
reduction, etherification, esterification, and cross-linking. The D-galactose linked to the mannan backbone, i.e. galactogluco-
modifications bring in new functionality and therefore create mannans (GGMs). GGMs from wood, such as spruce, are partially
novel opportunities to exploit them for various applications substituted with O-acetyl groups at hydroxyl groups of C2 and C3,
such as in food, cosmetic, biomedical, and pharmaceuticals. yielding O-acetyl-galactoglucomannans (Willför et al., 2003).
Chemical modifications of galactomannans by esterification,
4.2.1. Xylans etherification, oxidation, and hydroxypylation could lead to
Xylans are a diverse group of polysaccharides with the com- derivatives such as carboxymethyl, hydroxylpropyl, and carbox-
mon feature of a backbone of β-(1-4)-linked xylopyr- ymethylhydroxypropyl galactomannans (Kamerling & Boons,
anosyl units. Substitution or side groups/chains are varying 2007). Cationic, anionic, and nonionic GGM have been synthe-
according to different sources and methods of isolation. sized and reported in our group as summarized in Fig. 2.
For example, O-acetyl-4-O-methylglucuronoxylans with (1-2) GGM from wood, e.g. spruce, represents the main hemicellu-
linked 4-O-methyl-α-D-glucuronic acid side groups and lose component of softwoods and as such have been reported to
O-acetyl group at C2 or C3 are the major hemicelluloses in show immunomodulating and radical-scavenging activities in
hardwoods and account for 15–30% of the dry wood. Xylans in native as potential additives with immune-potentiating and
softwood account only for 5–10% of the dry wood, and mainly antioxidant properties in food products and pharmaceutical
exist as arabino-4-O-methylglucuronoxylans, which have 1-3) formulations (Ebringerová et al., 2008; Laine et al., 2010). Chemi-
linked α-L-arabinofuranose and (1-2) linked 4-O-methyl-α-D- cal modifications of GGM from forestry sources have also been
glucuronic acid side groups (Teleman, Tenkanen, Jacobs, & extensively studied (Kisonen et al., 2012, 2014; Leppänen et al.,
Dahlman, 2002; Viikari, Poutanen, Tenkanen, & Tolan, 2002). 2013). For example, methacrylation reaction has been taken to
Recently, xylans have gained increasing attention as basis for prepare cross-linked GGM hydrogel for drug delivery (Lindblad,
new functional biopolymeric materials by chemical modifica- Dahlman, Sjöberg, & Albertsson, 2009). Sulfation and carboxy-
tions. Various functional groups can be introduced to xylans by methylation of GGM have been studied by Doliška et al. (2012) to
esterification, etherification, and cross-linking for different appli- increase their antithrombotic properties, and the synergistic
cations, such as drug delivery, wound dressing, and antimicro- effect of carboxymethylation and sulfation was found to play
bial agents. (Ebringerová & Heinze, 2000; Petzold-Welcke, the most important role in the antithrombotic effect.
Schwikal, Daus, & Heinze, 2014; Pohjanlehto, Setälä, Kamm- Enzymatic modification with different enzymes provides
iovirta, & Harlin, 2011). For example, introduction of antioxidant alternative environmentally friendly and specific approaches
activity to xylans for biomedical applications could be achieved (Tenkanen, 2003). Regioselective oxidation of galactose-
by esterification with ferulic acid and sinapic acid (Wrigstedt containing polysaccharides, e.g. GGM from spruce and guar
et al., 2010). Pentosan polysulfate, an FDA-approved oral medi- gum (galactomannan) from the seed of leguminous shrub
cine, was prepared by sulfation of beechwood xylan. It has been Cyamopsis tetragonoloba, can be achieved by using galactose
known for its anticoagulant properties, anti-inflammatory and oxidase which selectively oxidizes the primary hydroxyl
anticancer effects, and for lowering cholesterol and triglyceride groups of the galactosyl to aldehyde functionalities (Fig. 2).
levels (Doctor & Sauls, 1983; Schuchman et al., 2013). Product The oxidized galactose-containing polysaccharides can be
derived from xylan and chitosan via the Maillard reaction was further tailored at the selectively introduced aldehyde groups
found to exert antioxidant and antimicrobial activity (Wu et al., towards further functionalizations, e.g. development of
2014). Peng, Ren, Zhong, Peng, and Sun (2011) reported ionic new anticoagulant and antithrombotic drugs applications
xylan-rich hydrogels with rapid and multiple responses to pH, (Hartmans et al., 2003; Leppänen et al., 2014; Parikka et al.,
ions, and organic solvents, which may allow the use in drug 2012; Xu, Spadiut, Araújo, Nakhai, & Brumer, 2012).
release systems. An in situ forming spruce xylan-based hydrogel Partially acidic or enzymatic hydrolysis have been applied
was synthesized chemo-enzymatically for stem cell culture to degrade native konjac glucomannan for food ingredient
application (Kuzmenko, Hägg, Toriz, & Gatenholm). This xylan- and prebiotic applications, the resultant konjac glucomannan
based hydrogel showed mechanical integrity, interconnected with low molecular mass has been reported to show some
porous structure, high degree of swelling, and supporting the attractive biological activities, such as cholesterol lowering,
differentiation of mesenchymal stem cells inside the gel, which bulking for weight reduction, and to reduce the risk of
is worthful for further evaluation for tissue engineering pur- constipation (Al-Ghazzewi, Khanna, Tester, & Piggott, 2007).
poses. Other typical modifications to prepare xylan derivatives,
such as cationic, ionic, and non-ionic xylan derivatives have 4.2.3. Xyloglucans
been previously reviewed (Heinze, Koschella, & Ebringerová, Xyloglucans are the major hemicelluloses in the primary cell
2003; Petzold-Welcke et al., 2014). walls of higher plants, they have a common structure of
Fig. 2 – Chemical modifications of spruce galactoglucomannan to prepare anionic/cationic/nonionic derivatives (adapted from
Doliška et al., 2012; Kisonen et al., 2012, 2014; Leppänen et al., 2013, 2014; Xu et al., 2011).
β-(1-4)-linked D-glucan, and three out of four glucose resi- Another important chemo-enzymatic approach is to regio-
dues are substituted with α-D-(1-6) xylose. Depending on the selectively oxidize the primary hydroxyl groups of galactose on
source of the xyloglucans, further substituted residues of the side chains of xyloglucan to aldehydes by using galactose
xylose is β-(1-2)-linked D-galactose, which in turn is some- oxidase (Parikka et al., 2009). Judicious choices of the func-
times substituted with α-fucosyl residures (Gidley et al., 1991; tional group allow further in situ surface modification. For
Kochumalayil, Zhou, Kasai, & Berglund, 2013). example, Xu et al. (2012) attached propargylamino groups to
Xyloglucans provide stronger bioavailability of drug and yield multialkynylated conjugates, which are clickable by
longer residence times, and therefore, has been used as skin “click chemistry” for desired applications, such as in vitro
patches, oral or rectal drug delivery, and for intraperitoneal diagnostics, (bio) molecular capture, and detection as illu-
injections (Coviello, Matricardi, & Alhaique, 2006). Chemical strated in Fig. 3.
or chemo-enzymatic modifications to prepare various xylo-
glucan derivatives can be performed for medical and other
applications. For example, sulfated xyloglucan and its sele- 4.3. Pectins
nious ester have been reported to show antioxidant activity
and antitumor activity (Cao & Ikeda, 2009). Pectins are heterogeneous polysaccharides with three main
Chemo-enzymatic modifications of xyloglucan have also domains: α-(1-4)-linked linear homo-galacturonic backbone
been intensively studied. Xyloglucan endotransglycosylase (HG) alternating with two types of highly branched rhamno-
(XET), which transfers glycosyl moieties to carbohydrate galacturonans regions designated as RG-I and RG-II. RG-I is
acceptors, readily accepts not only xyloglucan polymers, but substituted with side chains of arabinose and galactose units.
also xyloglucan oligosaccharides, even after chemical mod- RG-II has a highly conserved structure, consisting of a HG
ifications. Thereby, various functional moieties, such as backbone branched with eleven different monosacchari-
biotin, aminoalditol and its derivatives, can be introduced des, including some rare sugars such as 2-O-methylxylose,
to xyloglucan. By taking advantage of the high affinity 2-O-methylfucose, apiose, aceric acid, 2-keto-3-deoxy-d-
between xyloglucan and cellulose, the functionalized xylo- manno-octulosonic acid, and 3-deoxy-d-lyxo-2-heptulosaric
glucan can be bound to different cellulosic surfaces to pre- acid (Le Normand et al., 2014; Ridley, O’Neill, & Mohnen,
pare functional materials as shown in Fig. 3 (Brumer, Zhou, 2001). In all natural pectins, some of the carboxyl groups exist
Baumann, Carlsson, & Teeri, 2004). in the methyl ester form.
Fig. 3 – Chemo-enzymatic modifications of xyloglucan via XET techniques and regioselectively oxidization plus click
chemistry. (pathway up) adapted with permission from (Brumer et al., 2004). Copyright (2004) American Chemical Society.
(pathway below) adapted with permission from (Xu et al., 2012). Copyright (2012) Wiley.
Pectins, mainly from citrus peel and apple pomace, are Quaternary ammonium cationic starches, the major commer-
widely used in the food industry as gelling or thickening cial starch ethers, are commonly prepared by the reaction of an
agents and in the pharmaceutical industry as an excipient aqueous alkaline solution of 2,3-epoxypropyltrimethyl ammo-
due to its non-toxicity, low production costs, and gelling nium chloride or 3-chloro-2-hydroxypropyltrimethyl ammonium
activity properties. Because pectin is intact in the upper chloride (Pigorsch, 2009). The quaternary ammonium-substituted
gastrointestinal tract and degraded by colonic microflora, cationic starches may form nanoparticles with anionic sodium
pectin-derived drug carriers provide promising potential for tripolyphosphate. The nanoparticles could entrap hydrophobic
colon-specific drug delivery. Gelation of pectin, calcium molecules, providing a great potential as nanosized carrier in
cross-linked pectinate, composites of pectin and other poly- health care and environmental sciences (Rutkaite, Bendoraitiene,
mers such as ethylcellulose and hydroxypropylmethylcellu- Klimaviciute, & Zemaitaitis, 2012).
lose have been examined and tested for controlled drug Hydroxyethyl starch is semisynthetic starch ether by react-
delivery (Liu, Fishman, Kost, & Hicks, 2003). Modification of ing with ethylene oxide in alkaline medium, and it has been
pectin via grafting with poly(N-vinylpyrrolidone) (PVP) has used as a plasma volume expander and cryoprotectant in
also been reported to form an effective hydrogel that can medicine. Further functionalization by esterification with lauric,
make effective colon-targeted drug delivery (Fares, Assaf, & palmitic, and stearic acid using dicyclohexyl carbodiimide and
Abul-Haija, 2010). In addition to food and pharmaceutical dimethylaminopyridine has been used to prepare a fully
applications, a recent study reported that pectins (rhamno- biodegradable amphiphilic polymer for drug carrier application
galacturonan RG-I domain ramified with highly-branched (Besheer, Hause, Kressler, & Mader, 2007). Lately, a nanocarrier
arabinans) extracted from spruce bark showed immunomo- based on hydroxyethyl starch for active receptor-mediated
dulating activities, which suggested a potential application as targeting was synthesized (Baier et al., 2012). The hydroxyethyl
immunostimulant (Le Normand et al., 2014). The hydrogel of starch folic acid conjugate nanocarriers could be of high interest
pectin has been explored in tissue engineering applications for the development of receptor mediated targeting using
for bone cells culture and promoting the nucleation of polymeric nanocapsules to deliver and accumulate their encap-
minerals, and in wound healing applications for binding sulated molecules to the targeted area.
active drugs or growth factors and protecting against bacter- Selective oxidation of starch with N2O4 or a TEMPO/
ials (Munarin, Tanzi, & Petrini, 2012). NaClO/NaBr system can exclusively yield carboxylates on
the primary hydroxyl groups. Such oxidation approaches
can also be applied to selectively oxidize starch derivatives,
4.4. Starch which bear another oxidation candidate primary hydroxyl
group (e.g. hydroxyethyl starch) (BeMiller & Whistler, 2009).
Starch is a biopolymer synthesized in a granular form by Dialdehyde starch can be prepared by oxidation of vicinal
green plants and consists of two major components, i.e. alcohol groups to aldehyde groups at the C2 and C3 by using
linear amylose with α-(1→4)-D-glucopyranose, and branched periodic acid or periodate. The yielded aldehyde groups
amylopectin with α-(1-4)-D glucopyranose backbone and may react with alcohols, amines, hydrazines, and hydra-
5–6% of α-(1-6)-branch linkages (Pérez & Bertoft, 2010). Minor zides to provide additional functionialized products and
constituents such as lipids, proteins, and minerals are pre- applications (Haaksman, Besemer, Jetten, Timmermans, &
sent in starch and the levels vary with the origin Slaghek, 2006).
(Waterschoot, Gomand, Fierens, & Delcour, 2014). Starch is
an excellent material for industrial uses due to its non-toxic,
renewable and biodegradable properties. However, the intrin- 4.5. Chitin and chitosan
sic properties such as thermal, mechanical, and biological
properties and poor processability of starch have limited its Application of chitin/chitosan has been extensively developed,
direct applications (Khan & Ahmad, 2013). Thus, various e.g. in oral administration for lowering serum cholesterol con-
chemical, physical, and enzymatic modifications or blending centration and hypertension and in ophthalmic preparations for
with other materials have provided solutions to achieve more improving the retention and biodistribution of drugs applied
desirable properties. topically onto the eyes (Muzzarelli & Muzzarelli, 2005). However,
Similar to the cellulose, conventional chemical modifica- due to the semi-crystalline structure of chitin with extensive
tions of starch based on the primary and secondary hydroxyl hydrogen bonds, the chitin is insoluble in common solvents, and
groups include esterification, etherification, oxidation, and this has limited the development and processing of chitin for
graft copolymerization (Table 2). practical applications. The chitosan is normally insoluble in
Starch esters are generally prepared by reacting with fatty aqueous solution above pH 7, but its free amine groups can be
acid chlorides, fatty acid vinyl esters, carboxylic acids, and protonated in dilute acids (pH 6) and the chitosan molecule
fatty acid methyl ester in organic solvents such as pyridine, becomes soluble. Such pH-dependent solubility might provide
toluene, DMSO, and DMAc/LiCl (Grote & Heinze, 2005; Xie & potential applications as sensors. Nevertheless, it also poses
Wang, 2011). Starch esters have been developed for pharma- challenges, especially for biological applications that require
ceutical applications, e.g. used as superdisintegrant and neutralized environment. Therefore, further modification of
matrix former in capsules and tablet formulations; and for chitin and chitosan to introduce desired physicochemical and
medical application to maintaining human colonic function biochemical properties without any changes in their fundamen-
and preventing colonic disease (Tupa, Maldonado, Vazquez, tal skeleton is of significance for a breakthrough in utilization of
& Foresti, 2013). their unique features and activities (Oliveira & Reis, 2011).
The active groups or the possible reaction sites of both microsphere of 6-O-carboxymethyl chitin was reported as a
chitin and chitosan mainly include the free amino groups, potential vehicle for targeted drug delivery to the liver due to
primary and secondary hydroxyl groups, and acetamido its preferentially located and long retainment in the liver and
groups. As summarized in Fig. 4, chemical reactions spleen after i.v. injection (Hata, Onishi, & Machida, 2000). An
targeted at the hydroxyl groups, such as etherification, amphiprotic ether derivative that contains both carboxyl
esterification, cross-linking, graft copolymerization, and groups and amino groups can be prepared when the sub-
O-acetylation, can be used for modification. Chemical stitution moieties bear carboxyl groups (Alves & Mano, 2008).
reactions targeting the amino groups of chitin and chit- Simultaneous incorporation of substituents, for example
osan include acetylation, quaternization, Schiff base reac- carboxymethyl groups, onto some of the amino and primary
tion (reactions with aldehydes and ketones), and grafting hydroxyl sites of the glucosamine units can also be achieved
(Jain et al., 2013; Pillai, Paul, & Sharma, 2009). Modification by using chitosan, sodium hydroxide, isopropanol with chlor-
of chitosan with sugars onto the amino groups (Fig. 4, oacetic acid as solvent (Khan & Ahmad, 2013).
method (A), method (B)) provides a promising approach to Graft copolymerization is an important approach for
introduce desired sugars for various applications in spe- modification of the chitin and chitosan towards medical
cific drug, DNA, and antibody carriers by incorporation of and pharmaceutical applications, such as in orthopedic/
cell-specific sugars that are specifically recognized by periodontal materials, wound-dressing materials, tissue engi-
cells, viruses, and bacteria (Kim, 2013; Yao, 2012). neering, and controlled drug/gene delivery (Ito, Yoshida, &
Carboxymethylation can take place at hydroxyl groups of Murakami, 2013). Graft copolymerization of chitin and chit-
chitin and chitosan to yield O-carboxymethyl derivatives, and osan can be initiated by chemical (free radicals) initiator
can also take place at the free amino groups of chitosan to systems, by radiation methods and by enzymatic grafting
yield N-carboxymethyl derivatives (Fig. 4). Derivatization of methods (Alves & Mano, 2008). Graft copolymerization of
chitosan by introducing alkyl or carboxymethyl groups onto chitosan with “presynthesized” polymers instead of their
the C3 and/or C6 hydroxyl groups to prepare e.g. O-carbox- monomers can help to control the side-chain molar mass
ymethyl chitosan can significantly increase the solubility at and avoid the absence of residual monomers. For example,
neutral and even alkaline conditions at the same time Lu, Xu, Zhang, Cheng, and Zhuo (2008), prepared a chitosan-
maintaining the cationic properties. Such O-carboxymethyl based copolymer, which had a good potential as efficient
chitosan was used to enhance the biocompatibility of poly- nonviral gene vectors, through grafting polyethylenimine
lactic acid film surfaces, which had higher cell adhesion and (800 Da) to N-maleated chitosans. Kumar et al. (2012) utilized
proliferation than that of the unmodified one (Alves & Mano, polyacrylamide, instead of normal acrylamide monomer, for
2008; Cai, Yao, Li, Yang, & Li, 2001). Carboxymethyl chitin, a grafting onto chitosan with high grafting efficiency (GE¼92%)
water-soluble anionic polymer was selectively modified to and grafting ratio (GR¼263%). The resulting macroporous
prepare antitumour drug conjugates (Rinaudo, 2008). A polyacrylamide-grafted-chitosan exhibited superior neuronal
Fig. 4 – Chemical modification of chitin/chitosan (adapted from Kean, Roth, & Thanou, 2005; Khan & Ahmad, 2013; Kim, 2013;
Nemtsev, Gamzazade, Rogozhin, Bykova, & Bykov, 2002).
cell infiltration owing to the anisotropic porous architecture, 2008; Spiller, Maher, & Lowman, 2011). However, the draw-
high-molar-mass mediated robustness, and superior hydro- backs of inadequate mechanical properties, uncontrollable
philicity, as well as surface charge due to the acrylic chains degradation profiles, and lack of cell recognition signals have
and the substrate could act as a potential neural cell carrier limited its medical application. Notably, carboxyl groups and
applied in scaffolds for neural tissue engineering. hydroxyl groups along the backbone of the alginate enable
Based on graft copolymerization and a molecular imprint- various modification approaches to enhance or tailor the
ing technique, chitosan has been used to prepare recognition properties such as physicochemical, biological, mechanical,
materials, such as metal ions, dyes, and proteins, and there- and other desired properties (Oliveira & Reis, 2011).
fore, could be used for special absorption of template Conventional chemical modification of alginate mainly
molecules mimicking natural recognition materials such as include graft copolymerization, oxidation, crosslinking with
antibodies for diagnostics (Kyzas, Lazaridis, & Bikiaris, 2013; polyvalent cations and/or cationic polymers, sulfation, and
Monier & El-Mekabaty, 2013). For example, Dan et al. (2013), esterification targeting the hydroxyl groups and carboxyl
prepared a molecular imprinted chitosan gel to recognize the groups, and also aldehyde groups after rupture of C2 and C3
template ovalbumin. Their resulting gels showed notable carbon-carbon bond as reviewed previously (Khan & Ahmad,
adsorption capacities and high special selectivity to the 2013; Yang, Xie, & He, 2011) and summarized in Fig. 5.
template protein. Similarly, Fu, Zhao, Yu, Liu, and He (2007) Esterification as a simple method to introduce alkyl groups
synthesized a molecularly imprinted polymer (MIP) gel using onto the backbone of the alginate was successfully commer-
bovine serum albumin (BSA) as a template and based on cialized decades ago; and the propylene glycol alginate (PGA,
copolymerization of acrylamide with N,N0 -methylenebisacry- Fig. 5) is currently the most representative commercial
lamide on chitosan in aqueous medium. The resultant MIP product (d’Ayala et al., 2008). Esterification of alginate to
gels were found not only to show significantly higher introduce long alkyl chains can be achieved by reaction with
imprinting efficiency and specificity for BSA, but also much alkyl halides, but the alginate needs to be converted into its
better stability in rebinding of the imprint molecules after tetrabutylammonium salt (TBA) at first. For example, dodecyl
adsorption–regeneration cycles. alginate was prepared by the reaction of the TBA salt of
Blends or composites of chitin or chitosan with synthetic alginic acid with dodecyl bromide in DMSO (Pawar & Edgar,
or natural polymers, such as polyethylene glycol, polylactic 2013). However, the partial or total substitution of carboxyl
acid, polypyrrole, collagen, starch, and with inoraganic mate- groups after esterification might result in a reduced gelling
rials such as bioactive glass and ceramics, for drug delivery capacity, which is the most attractive feature of alginate.
systems, tissue-engineering, and other medical applications The periodate oxidation that selectively cleaves the
have recently been intensively studied (Jayakumar et al., vicinal glycols (C2–OH, C3–OH) and introduces new reactive
2011; Kumar, Muzzarelli, Muzzarelli, Sashiwa, & Domb, 2004; groups is an alternative approach to modify the alginate
Nakamatsu, Torres, Troncoso, Min-Lin, & Boccaccini, 2006; while maintaining the gelling properties. Due to the slow
Rinaudo, 2008). Furthermore, similar to alginate as listed in degradation rate of alginate, partial periodate oxidation
Table 2, layer-by-layer or multilayer coating techniques have has been reported to accelerate the biodegradation rate of
been developed to prepare chitosan-based polyelectrolyte the oxidized alginate and this has found application in
complexes with 2D and 3D structures such as freestanding tissue engineering (Bouhadir et al., 2001; Rinaudo, 2008).
films, capsules, and porous scaffolds. Hyaluronic acid, algi- For example, partially periodate oxidized injectable algi-
nate, chondroitin sulfate, and hydroxyapatite have also been nate hydrogels have been developed to provide a suitable
applied with chitosan to prepare multilayer-structured bio- delivery vehicle for stem cells to engineer adipose tissue
materials based on the layer-by-layer technique for tissue- (Kim et al., 2012). Actually, such selective oxidation is a
engineering applications (Miranda, Silva, Reis, & Mano, 2011; classical pre-modification method due to the obtained
Rinaudo, 2008; Santo, Gomes, Mano, & Reis, 2012; Schneider, new reactive groups with larger rotational freedom. Var-
Richert, Francius, Voegel, & Picart, 2007; Silva et al., 2013a; ious graft copolymerizations or reductive amination can
Silva et al., 2013b). be further carried out based on such pre-modified inter-
mediate product as shown in Fig. 5 (Yang et al. 2011). For
4.6. Alginate example, low-molar-mass polyethylene glycol (mono-car-
boxyl terminated), a highly biocompatible polymer, was
Seaweed polysaccharides from the marine plants represent grafted onto a sodium alginate, which was first modified
the most abundant polysaccharides in the sea, and alginate is by inserting a given amount of amine functionalities. The
one of the most widely explored seaweed polysaccharides retained gelation characteristics and increased biocom-
(Wang, Wang, & Guan, 2012). It’s a linear block copolymer patibility and pore dimension of the alginate-PEG copoly-
which composed of β-(1-4)-linked D-mannuronic acid (M mers are requirements for gel entrapment devices and
block) and α-L-guluronic acid (G block) units arranged with microencapsulation techniques (Laurienzo, Malinconico,
varying proportion of GG, MG, and GM blocks (Fig. 5) (d’Ayala Motta, & Vicinanza, 2005). By controlling the degree of
et al., 2008; Khan & Ahmad, 2013; Rehm, 2009). In the tissue- alginate oxidation, a crosslinked bio-adhesive alginate-
engineering and cell immobilization fields, the use of alginate PEG system with controllable mechanical properties, swel-
for cartilage regeneration is well known due to its gelling and ling, and degradation rates have been developed (Jeon,
stabilizing properties, in which the G-blocks serve to intro- Samorezov, & Alsberg, 2014). The oxidized alginate itself is
duce a steric hindrance and to provide folded and rigid also promising material with improved biodegradability
structural conformation (Khan & Ahmad, 2013; Rinaudo, due to the presence of more reactive groups, which
Fig. 5 – Chemical modification of alginate (adapted from d’Ayala et al., 2008; Yang et al., 2011).
contribute to faster degradation when applied in a con- & McShane, 2013). In this approach, a variety of functional
trolled drug delivery system (Yang et al., 2011). materials including sensing element, bioactive agents, and
Ugi reaction has been applied to modify the alginate to form various types of nanoparticles may be encapsulated. A similar
a bis-amine (Fig. 5). Amidation reaction (Fig. 5) has been applied multilayer self-assembly approach by coating or depositing
to form amide linkage between amine bearing molecules (e.g. with oppositely charged polyelectrolytes bearing complemen-
EDC, NHS, 2-chloro-1-methylpyridinium iodide (CMPI), etc.) and tary amine and acetoacetate reactive groups has also been
the carboxylate moieties on the alginate (Yang et al., 2011). used to strengthen the alginate microcapsules by internally
Grafted alginate copolymers have recently been developed and externally cross-linked networks, which could become
for biomedical applications. An alginate-based pH- and temp- resistant to chemical and mechanical stress while remaining
erature-responsive hydrogel was synthesized by grafting of poly cyto-compatible. The resulting microcapsules are promising
(N-isopropylacrylamide) to the alginate backbone using EDC/ materials for cell encapsulation in cell-based therapies
NHS as coupling agents (Kim, Lee, Kim, & Lee, 2002). The (Mazumder, Burke, Shen, Potter, & Stover, 2009; Mazumder,
product might be useful in a rapid stimuli-responsive drug Shen, Burke, Potter, & Stover, 2008; Srivastava & McShane,
delivery system or as a biomimetic actuator in biomedical 2005). Moreover, multilayers could also be built from negatively
fields. Similarly, grafting of N-isopropylacrylamide onto sodium charged alginate and positively charged chitosan in acid
alginate with microwave radiation in aqueous environment conditions and be used for cell adhesion in tissue engineering
was carried out to prepare novel pH- and temperature- applications (Silva et al., 2013a). Other polyelectrolytes such as
responsive beads for colon-specific drug delivery (Isiklan & proteins (β-lactoglobulin or gelatin), poly(L-lysin), and poly(L-
Kucukbalci, 2012). ornithine) may also be utilized to form such multilayer
In addition to the conventional chemical modification structures (Rinaudo, 2008).
approaches to tailor the alginate derivatives, a self-assembly
approach has been explored to develop functional multilayer 4.7. Hyaluronic acid
alginate capsules with core-shell structure, which are useful in
biomedical applications such as drug delivery, bionanoreac- For diverse biological applications, further chemical modifica-
tors, nanofiltration, and biosensors (Srivastava & McShane, tion of HA to introduce desirable properties (e.g. the hydro-
2005; Zhu, Srivastava, & McShane, 2005). Partial protonation of phobicity and biological activity of resultant materials) is often
the carboxylate groups in alginate chains followed by the necessary. In HA, there are three targeting sites per repeating
cross-linking reaction with cross-linker 2,20 -(ethylenedioxy)- unit available for chemical modifications: carboxylic acid
bis(ethylamine) yielded a pH-dependent structure, which could groups; primary and secondary hydroxyl groups; N-acetyl
change between a coreshell to a hollow structure depending on groups. Generally, chemical modifications targeting carboxylic
the pH change of the medium (Cao et al., 2005). Layer-by-layer groups include amidation, Ugi condensation, and esterification
self-assembly has been used to prepare microporous alginate (Table 2). Carboxylic groups of HA can react either as elec-
hydrogels containing a variety of encapsulates (Roberts, Ritter, trophiles or nucleophiles to form esters (Cumpstey, 2013).
Esterifications of HA by alkylation using akyl halides (chlor- obtaining data from numerous analytical approaches, each of
ides, iodides, and bromides), by using diazomethane, and by which gives some structural information, and the assimilation/
using epoxides have been intensively studied and reviewed integration of these data into a chemical structure that rigor-
previously (Schanté, Zuber, Herlin, & Vandamme, 2011). For ously and uniquely fits all the available structural information
example, benzyl ester formation has been used to increase the (Kamerling & Boons, 2007). Thus, several different analytical
hydrophobic properties of HA for production of different strategies should be taken for analysis to reach final and
commercial biocompatibable and biodegradable materials accurate conclusions of the polysaccharide structure. Nowa-
(HYAFFs) (Benedetti et al., 1993). days, the improvements in analytic techniques such as nuclear
Functionalization targeted at the carboxylic group is similar magnetic resonance (NMR) spectroscopy, high-pressure liquid
as that of the alginate and the TEMPO oxidized cellulose chromatograph (HPLC), capillary electrophoresis (CE), and mass
modification as described above (Fig. 1 and Fig. 5). Recently spectrometry (MS), together with the development of suitable
Wang, Oommen, Yan, and Varghese (2013) reported a mild and microchemical degradation and derivatization protocols, and
efficient strategy for aldehyde modification of HA by conjugat- the incorporation of exo- and endo-glycosidase digestions, are
ing the amino-glycerol moiety onto the carboxylate residue of all greatly contributing to the structural analysis of polysac-
HA, which allowed selective cleavage of pendent diol groups charides. Different methodologies available for structural eluci-
without opening of the sugar ring structure of HA during dation of polysaccharides have been previously summarized by
periodate oxidation. This site-selective aldehyde modification Kamerling and Boons (2007).
could minimize the change of the native structure of HA and For building the detailed structure of polysaccharides, the
preserve its unique physiochemical and biochemical proper- primary structural analysis should be carried out to under-
ties. The aldehyde-bearing HA was developed to tailor extra- stand the nature and number of the monosaccharides build-
cellular matrix injectable hydrogel for growth factor release. ing blocks. This is generally done by hydrolysis and
Chemical modifications of HA on the hydroxyl groups (both methanolysis followed by gas chromatograph and liquid
primary and secondary) mainly include etherification, ester- chromatograph analysis. The absolute configuration (D or L)
ification, hemiacetal crosslinking, carbamate formation, and of the monosaccharides can be determined by separation of
selective oxidation (Khan & Ahmad, 2013; Schanté et al., 2011). enantiomers using gas-liquid chromatograph directly on a
Modification of the N-acetylglucosamine is difficult to chiral stationary phase, or on a nonchiral stationary phase
carry out directly, thus deacetylation is often taken to recover after conversion of the enantiomers into diastereomers using
the reactive amino groups which are able to conduct amida- chiral reagent. Linkages between monosaccharides and
tion or reductive amidation with aldehydes. branch pattern can be analyzed by firstly using methylation
When developing HA derivatives for medical and pharma- analysis, which involves methylation of the free hydroxyl
ceutical applications, HA derivatives are categorized as “mono- groups, hydrolysis of the methylated glycan, and reduction
lithic”, which are “terminally modified” forms of HA that do with NaBH4 or NaBD4 and acetylation with acetic anhydride
not form new chemical bonds in the presence of added cells or in pyridine, followed by gas-liquid chromatograph separation
molecules, and “living” which can form new covalent bonds in in combination with mass spectrometric profiling. The fol-
the presence of cells, tissues, and small or large molecules lowing monosaccharides identification can be done by using
(Prestwich & Kuo, 2008). Living HA crosslinked hydrogels (e.g. different mass spectrometry and NMR spectroscopy. Some-
crosslinked with poly(ethylene glycol) diacrylate) act as an times, modification or degradation (e.g. smith degradation,
extracellular matrix and permit incorporation of cells and a uronic acid reduction or degradation, enzymatic and/or par-
wide variety of small molecules, large molecules, nanoparti- tial acid/alkaline hydrolysis, acetolysis, labeling with radio-
cles, and microparticles, which have broad applications, e.g. active or fluorophoric compounds etc.) of polysaccharides are
targeting specific and long-acting delivery, wound repair, drug beneficial for constructing the ultimate structures (Kamerling
evaluation, stem cell niche engineering, and regenerative & Boons, 2007; Varki, 2009).
medicine (Oh et al., 2010; Prestwich, 2007, 2011). The introduction of soft-ionization techniques in mass
spectrometry provides new possibilities for the analysis of
polysaccharides. Fast-atom-bombardment MS (FAB MS),
5. Structural analysis matrix-assisted laser-desorption-ionization time-of-flight MS
(MALDI TOF MS), and electrospray ionization MS (ESI MS) have
Generally, bioactivities of polysaccharides are highly dependent become key techniques for identification and molecular mass
on their structural features. For example, the anticoagulant profiling of polysaccharides present in complex mixtures. Tan-
activity of seaweed fucans was shown to depend on their molar dem mass (MS/MS) or even MSn spectrometry can give more
mass, the extent of sulfation, and the distribution of sulfate detailed structural information including sugar constituents,
groups in the repeating units (Jiao, Yu, Zhang, & Ewart, 2011). sequence and interresidue linkage positions, and some informa-
Thus, accurately determining and establishing structure–function on stereochemistry (Mischnick, 2012). To reduce the com-
tion relationship is the prerequisite and fundament for their plexity of the analyte, isolation and profiling of analyte mixtures
applications. Structures of polysaccharides, especially those of and even isobaric analytes can be achieved by coupling techni-
heteropolysaccharides or hemicelluloses are complicated by the ques. For example, conjunction of mass analyzers with different
presence of different monosaccharides used as building blocks, isolation methods, such as reverse-phase, normalphase (NP),
which are usually isobaric stereoisomers, variations in porous graphitized carbon, size exclusion, ion exchange, or high
sequence, linkage, branching, and distribution of side chains performance anion-exchange, liquid chromatographic (LC) or
(Bauer, 2012). Structural elucidation of polysaccharides involves capillary electrophoretic separation methods are all possible
(Maslen, Goubet, Adam, Dupree, & Stephens, 2007; Ungewiß cell types are seeded for in vitro or in vivo culture and
et al., 2005). evaluation (Wan & Tai, 2013). Design of 3D chitin/chitosan
However, due to the structural complexity of polysacchar- hydrogel and sponge scaffolds, or 2D scaffolds and free-stand
ides, no single analytical method alone is able to give the films to support cartilage regeneration, to chemically interact
detailed structural information. Collecting structural informa- with apatite for bone and tendon regeneration, to encapsulate
tion from different available techniques such as ultraviolet stem cells and support their growth and differentiation for
(UV)/visible (vis) and infrared (IR) absorption spectroscopies, different stem cell therapy, and their utility in regenerative
NMR and MS is of significance for accurate elucidation of medicine have been recently reported and reviewed elsewhere
polysaccharide fine structures. (Croisier & Jérôme, 2013; Lu et al., 2012; Lu et al., 2012; Suh &
Matthew, 2000; Wu & Hochedlinger, 2011). Moreover, compo-
sites of chitosan with hydroxyapatite and grafted chitosan
6. Biomedical applications with carbon nanotubes have been developed as potential
materials for artificial bone and bone regeneration in tissue
Polysaccharides and their derivatives hold advantages over engineering (Venkatesan & Kim, 2010). Other polysaccharide-
the synthetic polymers, because they are non-toxic, biode- based materials, such as, hyaluronic acid, starch, and cellu-
gradable, biocompatible, and less expensive compared to their lose, have also been explored for bone, cartilage, and/or skin
synthetic counterparts. All these merits endow polysacchar- tissue engineering applications (Rinaudo, 2008).
ides and their derivatives a broad spectrum of applications in
different areas, such as in biomedical or pharmaceutical, food, 6.2. Wound healing and wound dressing
and cosmetic applications. Nowadays, polysaccharides play
important roles in traditional disease control and health care Due to their inherent biocompatibility, low toxicity, and phar-
(such as those originating from herbs and dietary fibers as maceutical biomedical activity, various polysaccharides, such as
reviewed above), meanwhile many new application areas are chitin, chitosan, cellulose, hyaluronan, and alginate, have been
also explored such as in tissue engineering, in drug delivery, in widely used to prepare wound healing materials (Barud Hda
wound treatment (both internal and external), in cancer et al., 2013; Czaja, Krystynowicz, Bielecki, & Brown, 2006; Czaja,
prevention, diagnosis, and therapy, and in treatment of Young, Kawecki, & Brown, 2007; Hrynyk, Martins-Green, Barron,
bacterial and viral diseases as already mentioned in the & Neufeld, 2012). For example, hyaluronan, a major extracellular
previous section for each polysaccharide and their derivatives component with unique hygroscopic, rheological, and viscoelas-
following functionalization (Khan & Ahmad, 2013; Lindblad, tic properties, has been extensively developed for tissue repair
Sjöberg, Albertsson, & Hartman, 2007; Sandra, 2009). Thus, purposes due to its physicochemical properties and specific
here in this section we emphasize the development of bioac- interactions with cells and extracellular matrix. It is generally
tive polysaccharides for such biomedical applications as tissue accepted that hyaluronan plays multifaceted roles in the media-
engineering, wound dressing/healing, and drug delivery appli- tion of the tissue repair process and is involved in all the stages
cations, which are the three major topics of the most recent of wound healing, i.e. inflammation, granulation tissue forma-
research activities. tion, reepithelialization, and remodeling. Derivatives of hyalur-
onan, such as cross-linked, esterified or other chemically
6.1. Tissue engineering modified products have also been developed for tissue repair
or wound healing purposes (Anilkumar et al., 2011; Chen &
Exploitation of polysaccharides and their derivatives for Abatangelo, 1999). Notably, wound healing-promoting activity of
tissue engineering applications, such as biological signaling, the materials is also important in the designing of materials for
cell adhesion, cell proliferation, cell differentiation, cell tissue engineering.
responsive degradation, and re-modeling, is attracting a great All-natural composite wound dressing films prepared by
deal of interest in medical research for guiding and promot- dispersion and encapsulation of essential oils (elicriso italic,
ing new tissue regeneration or to define the shape and chamomile blue, cinnamon, lavender, tea tree, peppermint,
structure of cell growth (Khan & Ahmad, 2013). A variety of eucalyptus, lemongrass, and lemon oils) in sodium alginate
polysaccharides, such as alginate, chitin, chitosan, hyaluro- matrices have been reported to show remarkable antimicro-
nic acid, cellulose, chondroitin sulfate, starch and their bial and antifungal properties and may find application as
derivatives, have been developed as biomaterials for tissue disposable wound dressings (Liakos et al., 2013). Chitosan/silk
engineering applications as reviewed above and previously fibroin blending membranes crosslinked with dialdehyde
elsewhere (Oliveira & Reis, 2011). Application of polysacchar- alginate have been developed for wound dressing and the
ides as scaffolds in tissue engineering needs to fulfill the membranes were found to promote the cell attachment and
requirements like biocompatibility and nontoxicity, biode- proliferation, which suggests a promising candidate for
gradability with controllable degradation rate, appropriate wound healing applications (Gu, Xie, Huang, Li, & Yu, 2013).
porosity, and structural integrity (Khan & Ahmad, 2013). Blending aqueous dispersions of sodium alginate and povi-
Chitin and chitosan possess the requisite properties to act done iodine (PVPI) complex was prepared as freestanding
as scaffolds for tissue engineering, with respect to their NaAlg films or as Ca2þ-cross-linked alginate beads. These
degradability, immunogenicity, and mechanical strength, and products were demonstrated to show antibacterial and anti-
therefore have been developed for tissue engineering applica- fungal activity and controlled release of PVPI into open
tions in the form of 3D hydrogels or porous sponges, fibrous wounds when the composite films and beads were brought
scaffolds or free-standing films, within which the appropriate into direct contact with water or with moist media (Liakos
et al., 2013). This proved that they could be suitable for and capsule diluents (Marchessault et al., 2006). Numerous
therapeutic applications such as wound dressings. In situ cellulose derivatives such as methyl cellulose, hydroxyethyl
injectable nano-composite hydrogels composed of curcumin, cellulose, hydroxypropyl cellulose, and hydroxylpropylmethyl
N,O-carboxymethyl chitosan, and oxidized alginate as a novel cellulose, which often possess specific respond or even better
wound dressing was successfully developed for dermal physicochemical properties than cellulose have been applied
wound repair application (Li et al., 2012b). In vitro release, in pharmaceutical applications (Francis, Piredda, & Winnik,
in vivo wound healing, and histological studies all sugges- 2006; Jain et al., 2014; Li & Mei, 2006; Marchessault et al., 2006).
ted that the developed nano-curcumin/N,O-carboxymethyl For example, phthalated hydroxypropylmethyl cellulose has
chitosan/oxidized alginate hydrogel as a promising wound excellent pH-dependent solubility, namely, stability in acidic
dressing might have a potential application in the wound conditions (at stomach) but soluble in mildly acidic to slightly
healing. Silver nanoparticles containing polyvinyl pyrrolidone alkaline solution and, therefore, has been developed for con-
and alginate hydrogels were synthesized using gamma radia- trolled intestinal targeting drug release systems (Kim, Park,
tion and showed the ability of preventing fluid accumulation Cheong, & Kim, 2003; Xu, Gao, Xu, Wu, & Sun, 2009). Recently,
in exudating wound (Singh & Singh, 2012). The incorpora- drug delivery systems based on nanocellulose which including
tion of nanosilver particles provided a strong antimicrobial cellulose nanocrystals (CNCs), nanofibrilated cellulose (NFC),
effect and therefore made such polyvinyl pyrrolidone/algi- and bacterial cellulose (BC) have been explored extensively
nate hydrogels suitable for use as wound dressing. Except (Plackett, Letchford, JacksonJohn, & Burt, 2014). For example,
the alginate and its various derivatives, other natural poly- antimicrobials (doxorubicin hydrochloride and tetracycline
saccharides such as cellulose, chitin, chitosan, and hyaluro- hydrochloride) binding to and release from CNCs have been
nic acid have also been explored for wound dressing or tested based on the ionically crosslinking delivery system, in
wound healing applications (Anisha, Biswas, Chennazhi, & which negatively charged sulfate groups on the CNCs form
Jayakumar, 2013; Kondo, Niiyama, Yu, & Kuroyanagi, 2011; reversible ionic crosslinking with the positively charged drugs
Matsumoto & Kuroyanagi, 2010). (Jackson et al., 2011). Similarly, NFC film networks have been
studied to entrap drugs and used for long lasting drug release,
6.3. Drug delivery and controlled release for example the entrapped poorly water soluble drugs in the
NFC film networks can sustainably release over weeks (e.g.
Polysaccharides hold their promising potential in drug deliv- indomethacin, 1–2 weeks) or even monthes (e.g. beclametha-
ery and controlled release applications due to their advan- sone dipropionate and itraconazole, 3 monthes) (Kolakovic,
tages such as biocompatibility, low immunogenicity, and Peltonen, Laukkanen, Hirvonen, & Laaksonen, 2012). Highly
minimal cytotoxicity. Numerous polysaccharide-based drug porous nanocellulose aerogels (ε¼ 90–99%) with large surface
delivery systems have been developed for specific targeting areas (Sa ¼ 70–680 m2/g) prepared by freeze-drying may provide
delivery or controlling release, for protection of drugs from new possiblilities for enhancing drug bioavailability and drug
premature degradation, for improving intracellular penetra- loading capacity (García-González et al., 2011). For example
tion and transporation, for enhancing stability and bioavail- aerogels of BC (Valo et al., 2013) or NFC (Valo et al., 2011) have
ability of drugs, or for the delivery of biomolecules such as been studied for stabilizing and release of insoluble drugs
genes, antigens, and small interfering RNA (Csaba, Koping- within nanoparticle formulations in a controlled manner.
Hoggard, & Alonso, 2009; Mao, Sun, & Kissel, 2010; Mizrahy & Exploring the use of chitin or chitosan as biomolecular
Peer, 2012; Valo et al., 2011). These delivery systems are delivery vector is of increasing interest in drug delivery for
generally prepared in the form of 3-D cross-linking network therapeutic application, such as genes (Csaba et al., 2009),
(covalently or ionically crosslinking), the polyelectrolyte antigens (Chen, Huang, Lai, & Ling, 2013), small interfering
structures (polyelectrolyste complexes or layer-by-layer RNA carrier (siRNA) (Mao, Sun, & Kissel, 2010), and cells and
assembly), self-assembly, and the polysaccharides-drug con- proteins (Shelke, James, Laurencin, & Kumbar, 2014). Applica-
jugate (Mizrahy & Peer, 2012). The release of the entrapped tion of chitosan-based siRNA carrier for efficient delivery of
drugs or certain molecules can be triggered by the change of siRNA in vivo has shown great promise as a therapeutic tool for
pH, ions, electrical or magnetic field, light, temperature, redox gene expression implicated disease (Ragelle, Vandermeulen, &
potential, or certain molecules (Alvarez-Lorenzo, Blanco- Preat, 2013). For example the chitosan (Ji et al., 2009) has been
Fernandez, Puga, & Concheiro, 2013). Cellulose, chitin or directly used to prepare chitosan/siRNA nanoparticles which
chitosan, and alginate, representing the three most abundant showed knockdown human colorectal cancer gene expression.
polysaccharide types, are discussed more in detail below. Alternative, Katas and Alpar (2006) found that the chitosan/
Pharmaceutical utilization of cellulose and its derivatives siRNA nanoparticles which were prepared by ionic gelation
range from excipients through carriers and protecting agents with sodium tripolyphosphate showed much higher target
to active substances themselves. Oral drug delivery is one of gene silencing effect due to the higher binding and loading
those applications, in which the polysaccharide excipients are efficiency. Tahara, Yamamoto, Hirashima, and Kawashima
used to increase the solubility and bioavailability of the active (2010) proved that the chitosan coating of the nanocapsules
drugs, to achieve a certain release profile from the final can protect the encapsulated siRNA from the degradation by
formulation, and to enhance the stability of the final drug nucleases meanwhile avoid the burst release of siRNA.
products (Marchessault, Ravenelle, & Zhu, 2006; Reddy, Extended delivery of encapsulated antigens or intradermal
Mohan, Satla, & Gaikwad, 2011). Nowadays, cellulose (e.g. vaccines to the skin via a chitosan microneedle transdermal
microcrystalline cellulose) and starch (e.g. corn and rice starch) delivery system has been reported to provide sustained
are widely used as glidants, tablet disintegrants and binders, immune stimulation (Chen, Huang, Lai & Ling, 2013).
Cross-linking of alginate with di- and tri-valent ions (Ca, Ba, with high specificity; therefore, combining enzymatic and che-
Sr, Al) to form the reversible “egg-box” array has been exploited mical approaches may offer an excellent alternative to engineer
to prepare pH-responsive network for intestinal target drug the properties of polysaccharides in a controlled manner. Proper
delivery (Alvarez-Lorenzo et al., 2013). Such pH-responsive is isolation and purification of the chemically functionalized or
based on the limited swelling in the acidic environment (pH 1.2) natively bioactive polysaccharides is of crucial importance for
in stomach and erosion of the network in the neutral environ- applications in the biomedical area, as there is a need to avoid
ment (pH 7–7.4) in intestine. However, such pH sensitivity can the undesirable side reactions of by-products, remainants of
also result in the stability problem of the delivery system solvents and impurits in the products, and thus to enable the
(Mizrahy & Peer, 2012). Alternatively, various alginate and safe, reproducible and accurate dosage for experimental or
hyaluronic acid (semi-) interpenetrating polymer networks therapeutic applications. Accumulating data from different mod-
((semi-)IPNs) have been developed for the application in drug ern structural analysis techniques, such as ultraviolet and infra-
delivery systems as reviewed by Matricardi, Di Meo, Coviello, red absorption spectroscopic, mass spectrometry, nuclear
Hennink, and Alhaique (2013). In addition to the pH-responsive magnetic resonance spectroscopy, and some hyphenated
network, the temperature-responsive alginate (semi-)IPNs approaches (HPLC–MS, HPLC–NMR, HPLC–DAD–MS–NMR, HPLC–
delivery system has been explored by incorporation of poly(N- TOF–MSn, etc.) may enable a clear determination of structural
isopropylacrylamide); by physically or chemically crosslinking features of the functionalized polysaccharides. The successful
via the addition of Ca2þ and N,N0 -methylenebisacrylamide outcome of exploitation of polysaccharides in biomedical appli-
respectively; and by photopolymerization via incorporation of cations will require multidisciplinary expertise in plant biology,
photoinitiator, such as 2-hydroxy-1-[4-(2-hydroxyethoxy)phe- organic chemistry, material science and engineering, medical,
nyl]-2-methyl-1-propanone (Matricardi et al., 2013). health care and beyond.
Several other polysaccharides such as pectin, chitin, chit-
osan, guar gum, xanthan gum, gellan gum, dextran, and
chondroitin have also been developed for drug delivery or Acknowledgements
controlled drug release, which were reviewed in the functio-
nalization of polysaccharides section in this paper and some- Jun Liu would like to acknowledge the financial support of the
where else by others (Liu, Jiao, Wang, Zhou, & Zhang, 2008; China Scholarship Council. This work is part of the activities
Luo & Wang, 2013; Morris, Kok, Harding, & Adams, 2010; in the Graduate School of Chemical Engineering and also of
Pachuau & Mazumder, 2013; Reddy et al., 2011; Tonnesen & the activities in the Åbo Akademi University Process Chem-
Karlsen, 2002; Zhang et al., 2013b). istry Centre.
r e f e r e n c e s
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A Review of Bioactive Plant Polysaccharides: Biological Activities, Functionalization, and Biomedical Applications

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Bioactive Carbohydrates and Dietary Fibre 5 (2015) 31–61

Available online at www.sciencedirect.com

A review of bioactive plant polysaccharides:

Jun Liun, Stefan Willför, Chunlin Xun,1

art i cle i nfo ab st rac t

Functionalization properties of polysaccharides, particularly from wood species, in previously unperceived

1. Introduction biomolecules, e.g. proteins, polynucleotides, lipids, lignin, and

Table 1 – A brief summary of bioactive polysaccharides from different sources.

Type Name Composition Sources Physiological effects Ref.

Type Name Composition Sources Physiological effects Ref.

of backbone or ramiﬁed regions.

Type Name Composition Sources Physiological effects Ref.

β- Lichenan: β-(1-3 Lichens, Cetraria islandica/ Immunomodulating Omarsdottir,

Generally, (bioactive) polysaccharides are present together with 4. Functionalization of polysaccharides

Table 2 – Summary of polysaccharide modiﬁcation and applications of the functionalized derivatives.

Polysaccharides Modiﬁcation Description of reactions or Potential applications Ref.

Cellulose Etheriﬁcation Methyl-/carboxymethyl-/ Pharmacy Kalia, Kaith, and Inderjeet

Polysaccharides Modiﬁcation Description of reactions or Potential applications Ref.

Prepared by reaction of starch Used as superdisintegrant and

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