10.

10 Alginates: Properties and Applications

G Skjk-Brk and KI Draget, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
2012 Elsevier B.V. All rights reserved.

10.10.1 Introduction 213

10.10.2 Sources and Production 213
10.10.3 Chemical Composition and Conformation 213
10.10.4 Properties 214
10.10.4.1 Selective Ion Binding and Gel Formation 214
10.10.4.2 Gel Properties 214
10.10.4.3 Biological Properties of the Alginate Molecule 215
10.10.5 Tailoring of Alginates by In Vitro Modification 216
10.10.6 Technical Applications 216
10.10.7 Applications of Alginates in Medicine and Biotechnology 217
10.10.7.1 Traditional Uses 217
10.10.7.2 New and Potential Uses 218
10.10.8 Conclusions 218
References 218

10.10.1 Introduction or by enzymatic modification in vitro using mannuronan

C5-epimerases from Azotobacter vinelandii5 (see below).
Alginates occur both as a structural component in marine The extraction of alginate from algal material is schemati
brown algae (Phaeophyceae) and as capsular polysaccharides cally illustrated in Figure 1. Since alginate is insoluble within
in some bacteria, but all commercial alginates are at present the algae with a counterion composition determined by the
extracted from algal sources only. Microbial fermentation and ion-exchange equilibrium with seawater, the first step in algi
postpolymerization of alginates will be of the utmost impor nate production is an ion exchange with protons by extracting
tance in high-tech specialty applications within pharmacy and the milled algal tissue with mineral acid. Next, the alginic
biotechnology. Quantitatively important industrial applica acid is brought into solution by neutralization with alkali.
tions of alginates include their ability to retain water and their Na-alginate (most common), and potassium and ammonium
gelling, viscosifying, and stabilizing properties. Applications salts are manufactured. The only derivative of alginates today
within biotechnology and medicine are mainly based on their having a commercial value is the propylene glycol alginate
unique, gentle, and almost temperature-independent solgel (PGA). This product is processed by an esterification of alginate
transition in the presence of multivalent cations (e.g., Ca2+), with propylene oxide. PGA is used in beers and salad dressings
which makes alginates highly suitable as an immobilization due to its higher solubility at low pH.
matrix for living cells. Advanced research within these areas
now functions as a locomotive for a further detailed under
standing of structurefunction relationships.
10.10.3 Chemical Composition and Conformation

Alginates are a family of unbranched binary copolymers, con

sisting of (1 4)-linked -D-mannuronic acid (M) and
10.10.2 Sources and Production
-L-guluronic acid (G) residues (see Figures 2(a) and 2(b)) of
widely varying composition and sequence. In the 1960s, it was
Commercial alginates are mainly produced from Laminaria
revealed that alginate was a true block copolymer when it was
hyperborea, Macrocystis pyrifera, Laminaria digitata, Ascophyllum
separated into three fractions by partial acid hydrolysis,2,69
nodosum, Laminaria japonica, Ecklonia maxima, Lessonia nigres
giving two fractions containing almost homopolymeric
cens, Durvillaea antarctica, and Sargassum spp. Table 1 gives
molecules of G and M (G- and M-blocks) while the third
some sequential parameters (determined by high-field nuclear
fraction consisting of a large number of MG dimer residues
magnetic resonance (NMR) spectroscopy) for samples of these
(MG-blocks; see Figure 2(c)). Furthermore, as there are no
types of alginates. The composition and sequential structure regular repeating units in alginates,1012 the distribution of
may, however, vary according to seasonal and growth condi the monomers along the polymer chain cannot be described
tions.2,3 Alginates with more extreme compositions containing by Bernoullian statistics. Knowledge of the monomeric com
up to 100% mannuronate can be isolated from bacteria.4 position is hence not sufficient to determine either the
Alginate with a very high content of guluronic acid, being of sequential structure or the properties of alginates. The main
importance for the mechanical properties of the alginate gel difference at the molecular level between algal and bacterial
(see below), can be prepared from special algal tissues such as alginates is the presence of O-acetyl groups at C2 or/and C3 in
the outer cortex of old stipes of L. hyperborea (see Table 1) the bacterial alginates.13

Polymer Science: A Comprehensive Reference, Volume 10 doi:10.1016/B978-0-444-53349-4.00261-2 213

214 Carbohydrate-Based Polymer Building Blocks & Biopolymers | Alginates: Properties and Applications

Table 1 Monomer composition and sequential parameters of algal glycosidic linkages: diequatorial (MM), diaxial
alginates (GG), equatorial-axial (MG), and axial-equatorial (GM) (see
Figure 2(b)). The diaxial linkage in G-blocks results in a large
Source FG FM FGG FMM FGM,MG hindered rotation around the glycosidic linkage, which may
account for the stiff and extended nature of the alginate
Laminaria japonica 0.35 0.65 0.18 0.48 0.17
chain.15 The electrostatic repulsion between the charged groups
Laminaria digitata 0.41 0.59 0.25 0.43 0.16
on the polymer chain will also increase the chain extension and
Laminaria 0.55 0.45 0.38 0.28 0.17
hyperborea, blade hence also the intrinsic viscosity.
Laminaria 0.68 0.32 0.56 0.20 0.12
hyperborea, stipe
Laminaria 0.75 0.25 0.66 0.16 0.09 10.10.4 Properties
hyperborea, outer
10.10.4.1 Selective Ion Binding and Gel Formation
cortex
Lessonia nigrescensa 0.38 0.62 0.19 0.43 0.19 The basis for the gelling properties of alginates is their
Ecklonia maxima 0.45 0.55 0.22 0.32 0.32 specific ion-binding characteristics.2,4,1719 Selective binding
Macrocystis pyrifera 0.39 0.61 0.16 0.38 0.23 of certain alkaline earth metals ions (e.g., strong and coopera
Durvillaea antarctica 0.29 0.71 0.15 0.57 0.14 tive binding of Ca2+ relative to Mg2+) increases markedly with
Ascophyllum 0.10 0.90 0.04 0.84 0.06 increasing content of -L-guluronate residues in the chains.
nodosum, fruiting Polymannuronate blocks and alternating blocks are almost
body without selectivity. Structural features in the G-blocks account
Ascophyllum 0.36 0.64 0.16 0.44 0.20 for this high selective binding. This phenomenon was first
nodosum, old explained by the so-called egg-box model.20 More accurate
tissue steric arrangements have been suggested,21,22 but the simple
a
Data provided by Bjrn Larsen.

egg-box model still persists (Figure 3), being principally cor

Adapted from Moe, S.; Draget, K. I.; Skjk-Brk, G.; et al. In Food Polysaccharides;
rect and giving an intuitive understanding of the ion-binding
Stephen, A., Ed.; Marcel Dekker: New York, 1995; pp 245287.1
properties of alginates. The original intermolecular dimeriza
tion of alginate molecules in the egg-box model seems to be
questionable, as data from small-angle X-ray scattering on
alginate gels suggest lateral association far beyond a pure
Ca, Mg, and Sr-alginate
in algal particles
dimerization with increasing [Ca2+] and G-content of the algi
nate.23 Higher order junction zones are also supported by the
Pre-extraction fact that purified G-blocks (typically degree of polymerization
HCl (DP) = 20) are able to act as gelling modulators when mixed
with high-molecular-weight (Mw) alginates.24
A direct mixing of alginate and multivalent cations rarely
Alginic acid produces homogeneous gels due to a very rapid and irreversible
binding. A controlled introduction of cross-linking ions is made
Wash, filtration possible by the diffusion method and the internal setting method.
Neutralization Na2CO3 or NaOH In the diffusion method, a cross-linking ion (e.g., Ca2+) diffuses
from a large outer reservoir into an alginate solution
(Figure 4(a)). Diffusion setting is characterized by rapid gelling
kinetics, and is utilized for immobilization purposes since each
Sodium alginate droplet of alginate solution makes one single gel bead containing
the entrapped (bio-) active agent.25 In the case of internal setting,
Precipitation Ca2+ HCl the Ca2+ ions are released in a controlled manner from an inert
calcium source within the alginate solution (Figure 4(b)).
Ca-alginate Alginic acid Controlled release is obtained by a change in pH, by a limited
HCl solubility of the calcium salt source, and/or by the presence of
Na2CO3 chelating agents. With internal setting, tailoring of an alginate
Alginic acid

gelling systems toward a given manufacturing process is possible

Na2CO3

due to controlled gelling kinetics.26

Sodium alginate Sodium alginate Alginates may also form acid gels at pH values below the
pKa values of the uronic residues (3.5). With the exception of
Figure 1 Schematic representation of manufacturing of alginate from some pharmaceutical uses (see below), the number of applica
algal tissue. tions is limited.

X-ray diffraction studies of mannuronate- and

10.10.4.2 Gel Properties
guluronate-rich alginates showed that the guluronate residues
in homopolymeric blocks were in the 1C4 conformation,14 while Most gelling polysaccharides depend on temperature for a sol
the mannuronate residues had the 4C1 conformation15,16 gel transition, whereas alginate gels are cold setting (more or
(see Figure 2(a)). Hence, alginate contains all four possible less independent of temperature). Gelling kinetics can,
 Carbohydrate-Based Polymer Building Blocks & Biopolymers | Alginates: Properties and Applications 215

(a) COO
O OH O
COO OH
OH OH OH OH
HO HO

-D-Mannuronate (M) -L-Guluronate (G)

(b)
OOC OH OOC OOC
HO
O O O HO O
OH HO O OH
O OOC O
O HO O
OH
O O
OOC
OH OH
G G M M G

(c) MMMMGMGGGGGMGMGGGGGGGGMMGMGMGGM

M-block G-block G-block MG-block

Figure 2 Structural characteristics of alginates: (a) alginate monomers; (b) chain conformation; and (c) block distribution.

from the non-gelled part of the gelling body toward the zero
activity region.27,28 Presence of non-gelling ions (e.g., Na+) will
affect the stability of the gels. Alginate gels will start to swell
markedly when the ratio between non-gelling and gelling ions
becomes too high, and that the observed destabilization
increases with decreasing FG.29
O Alginic acid gels are more of an equilibrium nature than
O ionically cross-linked alginate gels.30 Figure 5 shows the elastic
Ca2+ OH moduli of acid gels made from alginates with different chemi
O O
cal composition together with expected values for ionically
OH O cross-linked gels. It can be seen that acid gels resemble ionic
O gels in that high contents of guluronate (long stretches of
OH
G-blocks) give the strongest gels. But polymannuronate
O
sequences support alginic acid gel formation, whereas
OH O
poly-alternating sequences seem to perturb this transition.
O The obvious demand for homopolymeric sequences in acid
Figure 3 Binding of divalent cations between homopolymeric blocks of gel formation suggests cooperative processes to be involved
-L-guluronate residues (the egg-box model), and a suggested binding just as in the case of ionic gels.30
site in a GG sequence.

10.10.4.3 Biological Properties of the Alginate Molecule

however, be strongly modified by a change in temperature, but Through a series of papers, it has been demonstrated that the
a solgel transition will always occur if gelling is favored (e.g., alginate molecule itself may have effects on biological systems.
by the presence of cross-linking ions). When set at different A biological effect of alginate was observed in the first animal
temperatures, the properties of the final gel most likely will transplantation trials of encapsulated Langerhans islets for dia
change due to the nonequilibrium nature of alginate gels.18 betes control. Overgrowth of alginate capsules by phagocytes
Alginate monomer composition and sequence will have a pro and fibroblasts, resembling a foreign body inflammatory reac
found impact on the final properties of calcium alginate gels. tion, was reported.31 In bioassays, induction of tumor necrosis
A gel made by the diffusion setting method will often factor (TNF) and interleukin-1 (IL-1) showed that the induci
exhibit an inhomogeneous alginate distribution, with the high bility depended upon the content of mannuronate in the
est concentration at the surface and gradually decreasing alginate sample.32 This result directly explains the observed
toward the center of the gel. Extreme alginate distributions capsule overgrowth; mannuronate-rich fragments, which do
have been reported27 with a 5-fold increase at the surface (as not participate in the gel network, will leach out of the capsules
calculated from the nominal concentration), and virtually zero and directly trigger an immune response.33 This observed
concentration in the center. This can be explained by the fact immunological response can, at least partly, be linked to
that a sharp gelling zone moves from the surface toward the (1 4) glycosidic linkages since other homopolymeric die
center of the gel. The activity of alginate (and of the gelling ion) quatorial polyuronates, such as D-glucuronic acid (C6-oxidized
will equal zero in this zone, and alginate molecules will diffuse cellulose), also exhibit this feature.34
216 Carbohydrate-Based Polymer Building Blocks & Biopolymers | Alginates: Properties and Applications

(a) Diffusion setting

10.00
Na-
Alginate

Eapp (kPa)
CaCl2
Ca2+

Ca2+

Na- GEL
Ca2+ Alginate 1.00
0.00 0.20 0.40 0.60 0.80
Ca2+ Fraction of guluronic acid residues
Figure 5 Apparent equilibrium moduli of alginic acid gels as function of
Ca2+ guluronic acid content (data points) compared to expected moduli for
Ca2+ cross-linked alginate gels (dashed line).
Gelling zone

(b) Internal gelation interesting properties. In this respect, it is to be mentioned

that, besides the remarkable increase in syneresis displayed by
the AlgE4-treated samples, a much higher stability of the gel is
H+ directly correlated with the presence of long alternating
sequences. The evidence of gel formation by a polymer com
GDL
Alginate CaCO3 posed of strictly alternating sequences suggests a direct
CO2 involvement of MG-blocks in the formation of both mixed
HCO3 H+
Ca2+ GG/MG- and MG/MG-junctions.39 Generally, gels made from
H2O enzyme-modified alginate were found to be more elastic and
compact, less permeable, and extremely stable under
physiological conditions, hence offering significant advantages
over native alginates.40 The ability to tailor alginate
macro-properties has a great impact on the wide use of alginate
Figure 4 Gelling of alginate by the diffusion method (immobilization in industry and medicine.
technique) and the internal setting method using CaCO3/
D-glucono--lactone (GDL).

10.10.6 Technical Applications

10.10.5 Tailoring of Alginates by In Vitro Modification
The single largest market for alginate is in textile printing,
The discovery of the mannuronan C5-epimerases suggests a where alginate serves as a thickener of the printing paste.
rapid movement of alginate into the specialty polymers rather Since the textile printing process is water based, the thickener
than staying a commodity. Alginate with a high content of must be water soluble and not react with the dyes or other
guluronic acid can be prepared by in vitro enzymatic modifica component of the printing paste or the textile fibers. The lack of
tion using these epimerases from A. vinelandii.3538 A. vinelandii primary hydroxyl groups in alginates and the high negative
encodes a family of seven exocellular isoenzymes with the charge density make it inert to most colorants used in textile
capacity to epimerize all sorts of alginates and other printing. Moreover, the high water solubility also facilitates the
mannuronate-containing polymers as shown in Figure 6, wash-off. Another important technical application is in sizing/
where the mode of action of AlgE4 (giving alternating intro coating of paper in which the film-forming properties of algi
duction of G) is presented. nates are exploited to generate smooth surfaces, improving the
The production of new tailor-made alginates by the penetration control and increasing oil and grease resistance.
C5-epimerases allows an extremely efficient tuning of both Alginates are also used in the manufacturing of high-quality
composition and physicochemical properties of the polysac welding rods, where their use gives the required body, easy
charide. In particular, the epimerase AlgE4, which enables the extrusion, and green bond strength to the coating at the
conversion of M-blocks into alternating sequences in a proces stage when the rods are extruded. The result is homogeneous
sive mode of action, has provided new alginates with welding rods with improved welding performance.41
 Carbohydrate-Based Polymer Building Blocks & Biopolymers | Alginates: Properties and Applications 217

HOOC HOOC
OH O OH O
HO O HO O
O HO O HO O
O O
HOOC OH HOOC OH
-D-ManpA
M M M M

C5-Epimerase AlgE4

HOOC
HO
O O
OH
O
HOOC OH HOOC
O
HO
O O
M OH
O
OH HOOC OH
O
G
O
M
OH -L-GulpA
G
Figure 6 Mannuronan C5-epimerase AlgE4; mode of action.

10.10.7 Applications of Alginates in Medicine impressions of the nose prior to rhinoplasty,50 as molds for
and Biotechnology measuring wound volumes,51 and as molds for the manufac
ture of polycarbonate face masks for the treatment of
10.10.7.1 Traditional Uses hypertrophic scars.52
Alginate-based raft-forming formulations have for 40 years
For decades, alginates have been used as devices in various
been used in the treatment of heartburn and gastric reflux.53
human health applications: in drug delivery systems (DDSs),

The most famous antireflux brand is Gaviscon, where alginate

traditional wound dressings, as a dental impression material,

is administered in a soluble form. Upon contact with the gastric

and in some formulations preventing gastric reflux. For a sum-

content, it will build a physical raft on top of the stomach

mary of the use of alginates in oral DDS, please see Reference

42. In DDS, the main advantage of alginates is their property of preventing gastric reflux into the esophagus, providing symp
preserving a solid-like attribute (gel) under two different con tom relief within minutes.54 These formulations are considered
ditions (cross-linked with ions and the alginic acid gel). reasonably safe with little or no adverse effects, as they are also
Delicate compounds may hence be protected against the acid prescribed to infants55 and against heartburn during
influence of gastric juice, both by preventing convection flow pregnancy.
56
and by acting as a buffering agent in the stomach. Oral admin- In dressings for the management of dermal wounds, algi

istration of colon-targeted drugs based on alginates as excipient nates have been used successfully for decades (e.g., Sorbsan,

has been successfully obtained in tablets containing viable Seasorb, and Kaltostat). Applying Ca-alginate dressings appears

lactic acid bacteria43 and colon-specific delivery of bee venom to be an appropriate topical treatment of diabetic foot lesions

peptide by applying alginate gel beads containing liposomes.44 with respect to both healing and tolerance,57 and Ca-alginate
Alginate/chitosan microcapsules have also been studied as dressings can preferably also be used in postsurgical wounds
possible systems for controlled delayed release of orally admi- being allowed to heal by second intention.58 It has been
nistered drugs. Positive results have been reported, for example, pointed out that Ca2+ ions, playing an important role in the
for acid-labile water-soluble mistletoe lectins for potential can- normal homeostasis of mammalian skin by serving as a mod
cer therapy45 and for controlled release of tramadol HCl.46 ulator in keratinocyte proliferation and differentiation, could
DDS for controlled release of drugs for the treatment of sys- be released from Ca-alginate fibers promoting early-stage
temic hypertension in order to obtain a reduced administration wound healing.59 Some studies have been undertaken to
frequency is another important area. Here, alginates have been study such dressings to try to distinguish between effects of
used as an excipient for verapamil.47,48 alginates and the effects of endotoxins on immunological
As dental impression material (e.g., Jeltrate), alginates have responses.60,61 Most wound dressings made from natural bio
been used for several decades.49 It is based on a dry mix of materials will contain endotoxins, which in substantial
alginate and gelling agents, which will set within minutes upon amounts will give cytotoxic effects on proliferation of fibro
the addition of water. These materials have also been suggested blasts, but immunological effects from the alginate itself seem
for use as a device for such diverse applications as taking to be present in some products. But it is doubtful if the classical
218 Carbohydrate-Based Polymer Building Blocks & Biopolymers | Alginates: Properties and Applications

alginate wound dressings contain immunologically active algi pore size; and a narrow pore size distribution. This may be
nate in reasonable quantities (not readily available as of yet). In obtained, at least in part, by
the future, new and improved alginate wound dressings will
selection and purification of alginates,
probably be seen.62,63
selection of gelling ions and control of the gelling kinetics,
combination with other polymers, and
chemical and enzymatic modification of alginates.
10.10.7.2 New and Potential Uses
Biopolymers, in general, also find use as hydrogel scaffolds
Ca-alginate spheres have become the most widely immobiliza
in tissue engineering.67,68 Polymer scaffolds are used as
tion vehicle of living cells.25 Carried out in a single-step process
space-filling agents, as delivery agents for bioactive molecules,
under very mild conditions, this method is compatible with
and as three-dimensional structures organizing cells to direct
most cells. A cell suspension is mixed with a Na-alginate the formation of a desired tissue. By resembling the extracellu
solution and the mixture dripped into a gelling bath containing lar matrix (ECM) of many tissues, by being processed under
multivalent cations (usually Ca2+). Each single droplet mild conditions and that they may be delivered in a minimally
instantaneously forms a gel sphere entrapping the cells in a invasive manner, gels made of natural biopolymers are an
three-dimensional lattice. There are numerous possible uses for appealing scaffold material.68Alginate gels also have potential
such systems in industry, medicine, and agriculture, ranging as (ECM) for tissue engineering. Although alginate entrapment
from production of ethanol by yeast, monoclonal antibodies is a very gentle technique for immobilizing living cells, many
by hybridoma cells to mass production of artificial seed by cells need specific interaction with the matrix for their prolif
entrapment of plant embryos.25 eration and viability. Such anchoring-dependent behavior is
Immobilized cells for transplantation purposes represent a common for most mammalian cells; however, the alginate
very exciting and prosperous application. The main purpose of network itself is noninteracting. Various ligands have been
the gel is to act as a barrier between the transplant and the coupled to alginate polymers to improve cellmatrix interac
immune system of the host. Multiple cell types have been tion.69 A problem with chemically modified alginates is that
suggested for this type of therapy, including parathyroid cells substitution is not restricted to the M-residues (M units) but
for treating of hypocalcemia and dopamine producing adrenal also takes place in the G-residues (G units) in the G-blocks
chromaffin cells for the treatment of Parkinsons disease.64 reducing the amount of available G-residues, thus impairing
Most interest has been focused around insulin-producing cells the cooperative binding of calcium and decreasing rate of gel
for the treatment of Type I diabetes. Alginate/poly-L-lysine formation, which results in weak gel formation and uncontrol
capsules containing pancreatic Langerhans islets have been lable swelling behavior. This can be solved by chemoenzymatic
shown to reverse diabetes in large animals and have also strategy as shown in Reference 70.
been clinically tested in humans.65 Table 2 lists some
potential biomedical application of alginate-encapsulated
cells. Ultrapure alginate qualities, being low in pyrogens and
easily sterile filtered, are now commercially available for this
10.10.8 Conclusions
purpose.
Alginates have for decades been used in technical applications,
Optimization of the alginate bead matrix to be used for
as well as a device in medicine and biotechnology, on an
immobilization and transplantation of highly different cell
empirical and semiempirical basis. New knowledge within
systems will have to be optimized in each case. For a general
different areas of alginate physicochemical and biological
recent review on the challenges and perspectives of cell micro
properties, such as the biological properties of the alginate
encapsulation, please see Reference 66. Alginate gel beads
molecule itself, on controlling alginate capsules, as well as the
should ideally be characterized by high mechanical and chemi
possibility of tailoring alginate molecules with the mannuro
cal stability; controllable swelling properties; low content of
nan C5-epimerases, suggests that an increased number of
toxic, pyrogenic, and immunogenic contaminants; defined
tailored alginate products will see the light of day in the near
future.
Table 2 Some potential biomedical applications of
alginate-encapsulated cells
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220 Carbohydrate-Based Polymer Building Blocks & Biopolymers | Alginates: Properties and Applications

Biographical Sketches
Gudmund Skjk-Brk is a professor in biochemistry at the Institute of Biotechnology, NTNU in Trondheim and director of
a multidisciplinary research group the Norwegian Biopolymer Laboratory (NOBIPOL). He received his Dr.techn. degree
from the Norwegian Institute of Technology (NTH), Trondheim in 1988 for his study on biosynthesis and structure
function correlations in alginates. Since then, his work has been devoted to basic and applied research on alginate and other
polysaccharides. Alginate is still his favorite molecule, and he is currently focused on polysaccharide sequencing using
alginate as model system.

Kurt Ingar Draget obtained his PhD in 1990 from the University of Trondheim where he worked on the use of alginates in
plant cell and tissue culture. He has worked ever since within the field of physicochemical properties of biological
macromolecules, such as alginates, chitosans, and gelatins from various sources, as well as carrageenans, in the intercept
between fundamental properties and applications with a special focus on biomedicine. Recently, he has also taken great
interest in biological oligomers and how they can be used to modify macromolecular network structures, both during
formation and equilibrium properties.