Food Hydrocolloids 25 (2011) 251256

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Food Hydrocolloids
journal homepage: www.elsevier.com/locate/foodhyd

Chemical, physical and biological properties of alginates and their

biomedical implications
Kurt I. Draget*, Catherine Taylor
Norwegian Biopolymer Laboratory NOBIPOL, Department of Biotechnology, Norwegian University of Science and Technology (NTNU), N-7491 Trondheim, Norway

a r t i c l e i n f o a b s t r a c t

Article history: Alginates are binary, linear copolymers of (1 / 4) linked -D-mannuronic acid (M) and a-L-guluronic
Received 10 June 2009 acid (G) residues of widely different composition and sequence. The monomers do not occur randomly
Accepted 12 October 2009 but rather in a block-like fashion, where the G-blocks are responsible for the specic ion binding and
hence also the gelling properties of alginates. Alginates have for decades been used as medical devices in
Keywords: various products, and research has been conducted on alginate gel beads as entrapment devices for the
Alginate
transplantation of e.g. insulin producing cells. Until recently, no pharmaceutical activity of the alginate
Physicochemical properties
molecule itself had been claimed. The fact that alginates high in mannuronate residues are able to induce
Encapsulation
Oligoguluronate cytokine production and may stimulate Toll-like receptors has changed this picture. Furthermore, it has
Mucin interaction quite recently also been shown that oligoguluronates are able to transiently modify mucin network
Biomedicine structures to such an extent that it opens up possibilities for the treatment of pathological respiratory
diseases as well as a general increased drug bioavailability due to increased mucosal uptake. This review
presents a summary of the physicochemical properties of alginates and their entry into biotechnology
and biomedicine.
2009 Elsevier Ltd. All rights reserved.

1. Introduction 2. Physicochemical properties

Alginates occur both as structural components in marine brown
algae (Phaeophyceae) as well as capsular polysaccharides in some
bacteria (Draget, Moe, Skjk-Brk, & Smidsrd, 2006). Commercial
alginates are at present still exclusively extracted from algal sources
although production by microbial fermentation is technically
feasible. Industrial applications of alginates, based on their gelling,
viscosifying and stabilizing properties, account for the quantita-
tively most important uses of alginates. In comparison, emerging
and knowledge demanding speciality applications within biotech-
nology and medicine are based on biological effects of the alginate
molecule, of alginate molecular building blocks, or alginates
unique, gentle and almost temperature independent sol/gel tran-
sition in the presence of multivalent cations (e.g. Ca2), which
makes alginate highly suitable as an immobilization matrix for
biocatalysts such as living cells. Advanced research within these
areas is promoting a further detailed understanding of structure
function relationships of the alginate molecule.
* Corresponding author.
E-mail address: kurt.draget@biotech.ntnu.no (K.I. Draget).
Alginates constitute a family of linear binary copolymers, con-
sisting of (1 / 4) linked b-D-mannuronic acid (M) and a-L-gulur-
onic acid (G) residues (see Fig. 1a and b). Chemical composition and
sequence may vary widely between algae species and even
between different parts of the algae and the time of year when it is
harvested. Alginate with a very high content of guluronic acid,
which is of importance for the mechanical properties of the algi-
nate gel, can be prepared from special algal tissues such as the outer
cortex of old stipes of Laminaria hyperborea. Alginates with more
extreme compositions containing up to 100% mannuronate can be
isolated from bacteria (Valla, Ertesvg, & Skjk-Brk, 1996). Algi-
nates may also be sequentially modied by post-polymerisation
enzymatic modication applying mannuronan C-5 epimerasesfrom
Azotobacter vinelandii (Ertesvg et al., 1995), which convert M to G
within the polymer chain. A. vinelandii encodes a family of 7 exo-
cellular iso-enzymes with the capacity to epimerise alginates into
a wide range of polymer sequences ranging from very long G-locks
via short G-blocks to polyalternating alginates. Alginates with
tailored physical and chemical properties can thus be made.
As early as in the 1960s, alginate were determined to be a true
block copolymer with no regular repeating unit; i.e. the alginate
molecule consisted of M-blocks, G-blocks and stretches of blocks of
a predominantly alternating structure (MG-blocks; see also Fig. 1c)

0268-005X/$ see front matter 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.foodhyd.2009.10.007
252 K.I. Draget, C. Taylor / Food Hydrocolloids 25 (2011) 251256
Fig. 1. Structural characteristics of alginates: (a) alginate monomers, (b) chain
conformation, (c) block distribution.
(Haug, Larsen, & Smidsrd, 1967). The distribution of the monomers
along the polymer chain can therefore not be described by Ber-
noullian statistics, implying that knowledge of the monomeric
composition is not sufcient to determine the sequential structure
of alginates. This sequential structure also leads to the occurrence
of all four possible glycosidic linkages within the alginate molecule.
The diaxial linkage in G-blocks results in a large hindered rotation
around the glycosidic linkage, which combined with the poly-
electrolyte nature of the alginate molecule, may account for its stiff
and extended nature.
The most important feature of alginates physical properties is
the selective binding of multivalent cations, which is the basis for
gel formation, and the fact that the sol/gel transition of alginates is
not particularly inuenced by temperature. Selective binding of
certain alkaline earth metals ions (e.g. strong and cooperative
binding of Ca2 relative to Mg2) increases markedly with
increasing content of a-L-guluronate residues in the chains. Poly-
mannuronate blocks and alternating blocks are almost without
selectivity (Smidsrd, 1973). Some chelation of multivalent cations
obviously takes place as a result of structural features in the
G-blocks, with the so-called egg-box model (Grant, Morris, Rees,
Smith, & Thom, 1973) being an initial attempt at explaining the
phenomen. More recent small-angle X-ray scattering studies on
alginate gels suggest lateral association of G-blocks far beyond
a dimerization with increasing [Ca2] and G-content of the alginate
(Stokke, Draget, Yuguchi, Urakawa, and Kajiwara, 2000).
3. Alginate gels and their properties
A direct mixing of alginate and multivalent cations rarely
produces homogeneous gels due to the very rapid and irreversible
binding of such ions. A controlled introduction of cross-linking ions
is possible by the two fundamental methods for preparing an
alginate gel: the diffusion method and the internal setting method
(Smidsrd & Draget, 1996). The diffusion setting technique, which is
the only method to be described in this paper, is characterized by
allowing a cross-linking ion (e.g. Ca2) to diffuse from a large outer
reservoir into an alginate solution (Fig. 2). Diffusion setting is
characterized by rapid gelling kinetics, and is indeed utilized for
immobilization purposes where each droplet of an e.g. Na-alginate
solution makes one single gel bead containing and entrapping the
suspended cells (Smidsrd & Skjk-Brk, 1990). Alginates may also
gel following a third and ion-independent way in that they form
acid gels at pH values below the pKa values of the uronic residues
Alginate Cell
solution suspension
Mix
Calcium
chloride
Fig. 2. Alginate beads with encapsulated cells manufactured by the diffusion setting
method.
(Draget, Skjk-Brk, & Smidsrd, 1994) providing mechanical
properties comparable to their ionically cross-linked counterpart.
With the exception of some pharmaceutical uses, the number of
applications of acid gels is rather limited to date.
Alginate monomer composition and sequence have a profound
effect on the nal properties of calcium alginate gels since selective
binding of ions is a pre-requisite for gel formation. Fig. 3 shows gel
strength as a function of the average length of G-blocks larger than
one unit (NG>1). Marked effects on gel strength are observed when
NG>1 changes from 5 to 15, which coincides with typical G-block
lengths found in commercially available alginates.
Alginate gels made by the diffusion setting method often exhibit
an inhomogeneous distribution of alginate where the highest
concentration is found at the surface and gradually decreasing
towards the center of the gel. Extreme alginate distributions have
been reported (Skjk-Brk, Grasdalen, & Smidsrd, 1989) with
virtually zero concentration in the center of the bead. Diffusion of
gelling ions into the bead will create a sharp gelling zone, where the
activity of alginate will equal zero leading to soluble alginate
molecules diffusing towards this zero activity region from the
internal, non-gelled part of the gelling body (Mikkelsen & Elgster,
1995). Such controllable inhomogeneous alginate distribution may
be used, at least in part, to modify the porosity of the nal gel and
hence also control the diffusivity of chemical components into and
out of the alginate bead.
Fig. 3. Mechanical properties of alginate gels as function of average G-block length.
 K.I. Draget, C. Taylor / Food Hydrocolloids 25 (2011) 251256
4. Traditional biomedical alginate applications
Alginates have for many years been used as devices in various
human health applications, such as excipients in drug delivery
(DDS), wound dressings, as dental impression materials and in
some formulations preventing gastric reux. One advantage of
using alginates in oral tablet formulation is their property of
preserving a solid-like attribute (gel) also at gastric (acid) condi-
tions due to the formation of an alginic acid gel. This property
allows for the protection of delicate compounds against the acid
inuence of gastric juice, both by preventing convection ow and
by acting as a buffering agent in the stomach when tablets are
manufactured using Na- or Ca-alginate.
Alginate-based raft-forming formulations are also used for the
treatment of heartburn and gastric reux (Chateld, 1999), e.g.
Gaviscon. When in contact with the gastric content, these formu-
lations will build a physical raft on top of the stomach preventing
gastric reux into the esophagus, and they provide symptom relief
within minutes. Anti-reux formulations like Gaviscon are also
considered as being reasonably safe with little or no adverse effects
as they are also prescribed against heartburn during pregnancy
(Lindow, Regnell, Sykes, & Little, 2003).
Non-woven alginate ber wound dressings (e.g. Sorbsan, Sea-
sorb and Kaltostat) have been used for decades in management of
epidermal and dermal wounds. It can for example be mentioned
that applying Ca-alginate dressings appears to be an appropriate
topical treatment of diabetic foot lesions with respect to both
healing and tolerance (Lalau et al., 2002). It can not be ruled out
that the alginate molecule itself has a positive effect on wound
healing, but it has also be pointed out that Ca2 ions, which play an
important role in the normal homeostasis of mammalian skin
serving as a modulator in keratinocyte proliferation and differen-
tiation, may be released form Ca-alginate bers promoting early
stage wound healing (Lansdown, 2002).
5. Potential biomedical and pharmaceutical alginate
applications
Over the last couple of decades, new knowledge about the
impact of chemical composition and sequential arrangement of
alginate on biological systems points towards more advanced
biomedical devices as well as pharmaceutical properties of alginate
in its own right.
5.1. Therapeutic cell entrapment
Entrapment of living cells within Ca-alginate spheres is a well-
established technique (Smidsrd & Skjk-Brk, 1990), and can be
carried out in a single step process under very mild conditions. A
cell suspension is mixed with a (osmolytically balanced) sodium
alginate solution, the mixture dripped into a solution containing
Ca2 and the droplets instantaneously form gel-spheres entrapping
the cells in a three-dimensional lattice (Fig. 2). A most exciting
prospect for alginate immobilized cells is their potential use in cell
transplantation, where the main purpose of the gel is to act as
a barrier between the transplant and the immune system of the
host. Cell lines that have been suggested for such transplantation
include parathyroid cells for the treatment of hypocalcemia and
dopamine producing adrenal chromafn cells for treatment of
Parkinsons disease (Kuhtreiber, Lanz, and Chick, 1999).
One example that has been subject to a substantial amount of
research is insulin producing cells for the treatment of Type I dia-
betes. Alginate/poly-L-lysine capsules containing pancreatic Langer-
hans islets have been shown to reverse diabetes in large animals and
have also been clinically tested in humans (Soon-Shiong et al., 1994).
253
5.1.1. Desired physicalchemical properties of alginates used for cell
entrapment
The alginate bead matrix to be used for immobilization and
transplantation should in general be characterized by (Orive et al.,
2004):
 High mechanical and chemical stability
 Controllable swelling properties
 Low content of toxic, pyrogenic and immunogenic contaminants
 Dened pore size and a narrow pore size distribution.
This may, at least in part, be obtained by selection and puri-
cation of alginates, controlling gelling ions and gelling kinetics,
interaction with other polymers and possibly also chemical and
enzymatic modication of alginates. The mechanical and swelling
properties of the gel beads depend strongly on the monomeric
composition, block-structure, and molecular weight of the alginate
(Martinsen, Skjk-Brk, & Smidsrd, 1989). High mechanical
stability can be achieved by using alginate with a high content
(>70%) of a-L-guluronic acid, and NG>1 of about 15. Ba2 can, by
replacing some of the calcium ions, also contribute to improved
mechanical and swelling stability of the alginate beads. Alginates
also form strong complexes with polycations (Thu, Bruheim,
Espevik, Smidsrd, & Skjk-Brk, 1996). These complexes do not
dissolve in the presence of calcium chelators or non-gelling cations,
and can thus be used both to stabilize the gel and to reduce/control
gel porosity. In general, the pores of the alginate gels are so large
that small molecules exhibit diffusion characteristics close to what
is observed in water, and even large proteins (Mw > 3  105 Da) will
diffuse out of an alginate bead depending on their molecular size
(Tanaka, Matsumura, & Veliky, 1984). Some kind of porosity
modication, by e.g. complex coacervation with polycations,
therefore becomes imperative to prevent diffusion of antibodies
through the capsule membrane.
5.2. Immunogenic properties of alginates
A biological effect of alginate was initially hinted at in the rst
animal transplantation trials of encapsulated Langerhans islets for
diabetes control. Overgrowth of alginate capsules by phagocytes
and broblasts, resembling a foreign body/inammatory reaction,
was reported (Soon-Shiong et al., 1991). In bioassays, induction of
tumor necrosis factor (TNF) and interleukin 1 (IL-1) showed that
the inducibility depended upon the content of mannuronate in the
alginate sample (Soon-Shiong et al., 1994). This result directly
explains the observed capsule overgrowth; mannuronate-rich
fragments, which do not take part in the gel network, will leach out
of the capsules and directly trigger an immune response (Stokke,
Smidsrd, Zanetti, Strand, & Skjk-Brk, 1993). This observed
immunologic response can, at least partly, be linked to b-(1 / 4)
glycosidic linkages since also other homopolymeric di-equatorial
polyuronates, like D-glucuronic acid (C6-oxidised cellulose), also
exhibit this feature (Espevik & Skjk-Brk, 1996). The immunologic
potential of poly-mannuronate has also been registered in several
in vivo animal models (Skjk-Brk, Flo, Halaas, & Espevik, 2000).
5.2.1. Proposed mode of action for the immunogenic response of
high-M alginates
The signaling cascade leading to the immunological response
and proinammatory cytokine induction of mannuronate-rich
alginates seems to involve pattern recognition receptors (PPRs),
especially toll-like receptors TLR4 or TLR 2 together with CD 14
(Espevik, Rokstad, Kulsen, Strand, & Skjk-Brk, 2009). Although
the exact epitope of the alginate molecule responsible for TLR
activation is not established, it is a striking feature that neither
254 K.I. Draget, C. Taylor / Food Hydrocolloids 25 (2011) 251256
100% M alginate nor alginates containing G-blocks initiate this
activation. Some fraction, typically 0.050.30, of single G residues
seems to be a pre-requisite within a high MW alginate for an
immunological response to occur. This fact suggests that the
epitope may require a certain degree of chain exibility within
a certain length of an alternating MG sequence (Espevik et al.,
2009).
Some questions have been raised regarding whether this algi-
nate induced immunological response could be due to a general
biocompatibility issue, i.e. that contamination with proteins or LPS
could account for the observed effects. This is especially important
in the case of LPS from Gram negative bacteria since they both bind
to CD 14. Under any circumstances, it is highly important to apply
highly efcient purication methods, but one fact that teaches
away from an alginate immunological response due to contami-
nation of LPS is that this response is more or less lost by an enzy-
matic depolymerisation of the alginate. Upon coupling the resulting
high-M fragments to particles, the immunological response is
restored and often enhanced (Berntzen et al., 1998).
5.3. Alginate oligoelectrolytes as a mucin polymer network modier
It has been known for some time that oligoguluronates are able
to modify both gelling kinetics as well as the apparent equilibrium
properties of alginate gels (Draget & Smidsrd, 2006). Quite
recently, it has also been shown that such G-blocks are able to
transiently modify mucin network structures. Such effects may
provide a basis for the treatment of pathological respiratory
conditions as well as for a general manipulation of mucosal surfaces
for e.g. drug delivery systems (Taylor, Draget, & Smidsrd, 2007).
5.3.1. Oligoguluronates as modiers of cystic brosis mucus
In patients diagnosed with cystic brosis, the most common
lethal genetic disease amongst Caucasians, the general pathological
picture is described by a thick intractable mucus in multiple organs
of which the lungs are the most problematic accounting for well
over 90% of the mortality (Welsh, Ramsey, Accurso, & Cutting,
2001). Mucus rheology plays a major role in the mucociliary
clearance of the lungs, but in the case of cystic brosis the highly
viscous mucus combined with a hyperinammatory state leads to
malfunctioning of the mucociliary clearance. In addition to the
normal mucins a number of non-mucin macromolecular compo-
nents, such as DNA, actin and bacterial polysaccharides, appear at
high levels in CF mucus and are suspected to make a substantial
contribution to the viscoelastic properties. For example, high
30
20
G* Pa
10
0 0
0.001 0.01 0.1 1 10
Frequency Hz
Fig. 4. Mechanical spectra of partially puried fresh pig gastric mucus (PGM, 6), in the
presence of high molecular weight alginate (HMW, ,) and nally the PGM/HMW
alginate blend in the presence of oligoguluronates (>).
molecular weight alginate such as produced by Pseudomonas aer-
uginosa, a most common inammatory microorganism in the CF
lung, interacts with mucin in a synergistic manner and this inter-
action bears the ngerprint of being of an electrostatic nature
(Taylor, Pearson, Draget, Dettmar, & Smidsrd, 2004).
The possibility of applying low molecular weight oligoelec-
trolytes to normalize the rheology of mucus by a shielding off of
the interaction sites between mucin and other macromolecular
components therefore became pertinent. The general idea behind
this approach was that these types of interactions, which lead to
increased mucus mechanical properties, could be eliminated
through electrostatic competitive inhibition by charged oligo-
mers too small to create intermolecular cross-links. G-blocks,
typically degree of polymerization 1020, were chosen as an
appropriate candidate for this purpose as they are known to be
non-immunogenic (Otterlei et al., 1991).
Fig. 4 shows the mechanical spectra of a model mucus alone
(partially puried pig gastric mucus, PGM), in combination with
a high molecular weigh alginate and nally of a mixed PGM/HMW
alginate in the presence of G-blocks. It is clearly seen that the
mechanical properties of the mucus network increases profoundly
in the presence of HMW alginate. After G-blocks have been added
to this system, however, the mechanical properties are reduced to
the extent that the complex dynamic modulus (G*) is lower than
that for the pure PGM over the entire frequency region investi-
gated. This effect of G-blocks on pure PGM model systems has been
conrmed in other non-published studies implying that such
oligoelectrolytes may be applied in improving mucosal drug
delivery systems.
Fig. 5 shows the typical effect on mucus rheology of adding
G-blocks, and the equivalent amount of NaCl, to sputum from a CF
patients diagnosed positive for P. aeruginosa. It can be seen that
even though there is a slight reducing effect of adding NaCl to CF
sputum, again hinting at least some degree of electrostatic stabi-
lization of the CF sputum, the effect of G-blocks is substantially
greater. It also seems like average DP 10 is more efcient than DP
20, but this may be due to the DP 20 sample had a fraction (about
10%) comprising molecules large enough to create intermolecular
cross-links.
In Fig. 6, the complex viscosity from 4 different samples of CF
sputum is compared with respect to the effect of saline and oligo-
guluronates. As can be seen, and as expected, the rheology of CF
mucus is highly variable reected in the large scattering of h*
25
G* [Pa]
20
sputum
15
sputum + NaCl
10
sputum + G blocks Dp 20
5
sputum + G blocks Dp 10
0
10 20 30 40 50 60
Time [min]
Fig. 5. The initial mechanical response of an ex vivo sputum sample from a CF patient
after pre-shear (60 s at 20 s1) in the presence of oligoguluronates of different average
size, and in the presence of NaCl corresponding to the increase in ionic strength
imposed by the oligoguluronates.
 K.I. Draget, C. Taylor / Food Hydrocolloids 25 (2011) 251256 255

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