Bioactivity and Applications of Polysaccharides from Marine Microalgae

  • Maria Filomena de Jesus Raposo
  • Alcina Maria Miranda Bernardo de Morais
  • Rui Manuel Santos Costa de MoraisEmail author
Living reference work entry


Marine microorganisms have been under research for the last decades, as sources of different biocompounds, each with various applications. Polysaccharides (PSs) are among these chemicals being produced and released by marine microalgae. These are very heterogeneous, including cyanobacteria and eukaryotic microalgae from several divisions/phyla, each of which with different characteristics. The PSs, sulfated or not, that they produce have already proved to be promising agents in various fields, such as food, feed, pharmaceutical, and biomedical. They can also be applied in wastewater and/or soil treatment and in some engineering areas, as naval engineering.

After a brief introduction on the general types of biopolymers produced by marine microalgae and cyanobacteria, this chapter starts by presenting the species of these microorganisms and the types of PSs they produce, as well as the respective chemical composition; goes into the production of PSs and the effect of specific compounds; and focuses on the physicochemical properties of these PSs and their composition and structure, approaching the rheological properties relevant for their functions and behavior. The bioactivity of PSs and their applications are, next, presented, including therapeutic applications based on their antiviral and antibacterial activities, antioxidant properties, anti-inflammatory and immunomodulatory characteristics, antitumoral activity, and antilipidemic and antiglycemic properties, among others. The potential use of PSs from marine microalgae as it is or incorporated in health foods is also considered. The mechanisms behind their antiviral and antibacterial activities are explained. Toxicological and safety issues are also disclosed, and there is a brief mention of the bioavailability of PSs from microalgae. The chapter ends by listing some preclinical studies with this type of polymers.


Marine microalgae Polysaccharides Sulfate (exo)polysaccharides Health foods Bioactivity-Antioxidant Antiviral Antitumoral Immunomodulators Toxicity 





Calcium spirulan




The molar concentration of a drug that produces 50 % of the maximum possible response for that drug


In vitro or in vivo dose of drug that produces 50 % of its maximum response or effect










Galacturonic acid


Glucuronic acid




The molar concentration of a drug which produces 50 % of its maximum possible inhibition


In vitro or in vivo dose of a drug that causes 50 % of the maximum possible inhibition for that drug




Molecular weight


Sodium spirulan


Nitric oxide






Sulfated exopolysaccharide


Sulfated polysaccharide



1 Introduction

Polysaccharides (PSs) and oligosaccharides can be synthesized by microorganisms; some of them are even secreted out into the environment (or culture medium), from which they are easily extracted. PS s have been studied for a long time due to their characteristics, especially their conformation, which is reflected in their chemical behavior and, therefore, in their wide range of applications. However, the knowledge on their complete composition and structure is still taking the first steps, and despite the applications that might appear after a solid understanding of their structure and conformation, these applications could even be extended to the medicine field. As a matter of fact, there is some difficulty on studying these polymer chains because of the diversity and distribution of simple sugars (mono-, di-, and oligosaccharides) along the PSs chains and whether these chains are linear or ramified. Therefore, the analysis of the PSs structures and, consequently, their applications is a real challenging task. Thus, the analysis of these polymer chains has been limited to oligosaccharides obtained by hydrolysis of high molecular polymers and to X-ray diffraction studies of PSs gels (Eteshola et al. 1998).

Among the PSs produced by microalgae and cyanobacteria (thereafter referred to as microalgae), especially marine species, only the sPS from Gyrodinium impudicum is a homopolymer of gal (Yim et al. 2007) and perhaps a cell wall PS from Chlorella vulgaris, a β-(1,3)-glucan (Nomoto et al. 1983), composed of d- glc; the PS s from all the other marine unicellular algae are heteropolymers, mostly constituted of xyl, gal, and glc in different proportions, but some other neutral sugars can also be constituents of the PS, as it is the case of rham, man, or fuc, and also some methyl sugars (Table 1). But in spite of this similarity in monosaccharide composition, the types of sugar themselves and the glycosidic bonds between each molecule are two of the characteristics that establish all the differences between the properties of PSs found in microalgae. Either the composition of monosaccharides and their distribution or the percentage in sulfate and uronic acids greatly determines the rheological behavior of the PSs, whose aqueous solutions can be highly viscous, as it happens with the EPSs from the marine red microalgae, or they may not present any apparent viscosity, as it is the case of the glucuronorhamnan from C. vulgaris.
Table 1

Marine species of microalgae producing PSs



Type of polysaccharide

Main neutral sugars



Cylindrotheca closterium

Navicula salinarum

Phaeodactylum tricornutum

Haslea ostrearia

Nitzschia closterium

Skeletonema costatum

Chaetoceros sp.

Amphora sp.









xyl, glc, man, rham

glc, xyl, gal, man

glc, man, xyl, rham

Staats et al. 1999; Pletikapic et al. 2011

Staats et al. 1999

Guzman et al. 2003; Ford and Percival 1965a, b

Rincé et al. 1999

Penna et al. 1999

Chen et al. 2011

Chlorella stigmatophora

C. autotrophica

C. vulgaris

Dunaliella salina

Ankistrodesmus angustus

Botryococcus braunii









glc, xyl, fuc

rham, gal, arab



gal, glc, xyl, fru

gal, fuc, glc, rham

Guzman et al. 2003

Guzmán-Murillo and Ascenci 2000

Ogawa et al. 1997, 1999; Nomoto et al. 1983

Mishra et al. 2011

Chen et al., 2011

Allard et al. 1987

Allard and Casadeval 1990

Tetraselmis sp.




Guzmán-Murillo and Ascencio 2000

Isochrysis sp.




Guzmán-Murillo and Ascencio 2000

Porphyridium sp.



xyl, gal, glc

Geresh and Arad 1991; Dubinsky et al. 1990; Arad 1988

P. cruentum

P. purpureum

Rhodella reticulata

R. maculata





xyl, gal, glc,


xyl, rham

3-O-methyl- rham


xyl, gal, glc


Garcia et al. 1996; Kieras 1972; Raposo et al. 2014; Gloaguen et al. 2004; Geresh et al. 2002a; Dubinsky et al. 1992

Radonic et al. 2010

Geresh and Arad 1991; Dubinsky et al. 1992

Evans et al. 1974; Fareed and Percival 1977

Cochlodinium polykrikoides

Gyrodinium impudicum




man, gal, glc


Hasui et al. 1995

Yim et al. 2007


Aphanothece halophytica



glc, fuc, man, arab

Li et al. 2001

Arthrospira platensis

Anabaena, Gloeothece, Nostoc Aphanocapsa, Phormidium, Synechocystis, Cyanothece





gal, xyl, glc, fru

rham, fuc, glc


Radonic et al. 2010; Hayashi et al. 1996b; Martinez et al. 2005

Hayashi et al. 1996b; Senni et al. 2011; Lee et al. 2000

Senni et al. 2011

Adapted from Raposo et al. (2013)

2 Marine Sources

In the last decades the interest in products that have a marine origin, mainly seaweeds and microalgae, and also in the compounds they produce is growing rapidly. Nevertheless, microalgae have an advantage over macroalgae: they are easy to grow and manipulate, and harvesting does not depend on the climate or season. Marine microalgae do not need much for culturing: a simple medium of seawater, with a source of nitrogen, phosphate, iron, magnesium, and some minor salts, is the only requirement to produce them. Their culture can be easily controlled and, hence, the properties and physicochemical characteristics of the biocompounds they produce, such as the polysaccharides, can be maintained all over different cultures.

2.1 Marine Unicellular Algae Producing PSs

Some marine/brackish species are already produced commercially, as it is the case of Arthrospira (Spirulina) platensis, Dunaliella salina, Isochrysis galbana, Nannochloropsis salina, Phaeodactylum tricornutum, and Porphyridium cruentum (Fig. 1), either for their biomass and/or extracts or the compounds they produce. In addition, many other species are known to produce and secrete out PSs into the culture medium (Table 1), EPSs, which can be, or not, sulfated polysaccharides (sPSs) these EPSs show properties that go from application as antiviral agents to inclusion in health foods. But these marine microalgae are so diverse (Table 1) that it seems useful to locate their taxonomic positions and present some of their characteristics.
Fig. 1

Some of the microalgae cited in this chapter: I, Botryococcus braunii; II, Chlorella vulgaris; III, Dunaliella salina; IV, Isochrysis galbana; V, Phaeodactylum tricornutum; VI, Porphyridium cruentum; VII, Arthrospira platensis

All diatoms belong to the class Bacillariophyceae, which includes organisms with round cells (Centrophycidae) and organisms with elongated cells (Pennatophycidae). Chaetoceros and Skeletonema belong to the first group; Amphora, Cylindrotheca, Haslea, Navicula, Nitzschia, and Phaeodactylum (Fig. 1-V) are included in the second group. The main characteristic of these unicellular organisms is the presence of a silicate ornamented two-piece frustule surrounding the protoplast. Their brownish color comes from the large quantities of xanthophylls (fucoxanthin, diatoxanthin, diadinoxanthin, neoxanthin), but they also possess chlorophylls a and c and α- and β-carotenes. Their main reserves are lipids, leucosin (or chrysolaminarin, a β-(1,3)-linked and β-(1,6)-linked glucose polymer) being the second main reserve.

Isochrysis (Fig. 1-IV) is a flagellated organism belonging to the class Prymnesiophyceae (or Haptophyceae). These golden-colored unicellular algae also have chlorophylls a and c, β-carotene, and xantophylls fucoxanthin, diatoxanthin, diadinoxanthin, and echinenone. They usually present two flagella and one smooth haptonema (hence the name of the class). Their main reserve compound is leucosin. Prymnesiophyceae and Bacillariophyceae are two classes of the phylum Chromophyta.

Another diverse group of algae is phylum Chlorophyta. As it happens with the plants, the microalgae members of Chlorophyta are green in color due to the high quantities of chlorophylls a and b. But α- and β-carotene and xantophylls (neoxanthin, lutein, violaxanthin, and zeaxanthin) are also present. Their reserve is mainly starch. This is a very diverse group, including macro- and microalgae. Only two classes are referred to in this chapter: Prasinophyceae, to which Tetraselmis belongs, and Chlorophyceae, the latter includes Chlorella (Fig. 1-II), Ankistrodesmus, and Botryococcus braunii (Fig. 1-I), all of them being Chlorococcales.

Porphyridium and Rhodella are two genera from the phylum Rhodophyta. This is the group that includes red macro- and microalgae. The main photosynthetic pigments are chlorophylls a and d, but their red color is associated mostly to the phycobiliproteins phycocyanin, allophycocyanin, and phycoerythrin. Lutein is the main xanthophyll. Porphyridium belongs to the class Porphyridiophyceae, order Porphyridiales, and family Porphyridiaceae; Rhodella is included in the class Rhodellophyceae, order Rhodellales, and family Rhodellaceae. However, there are still some organisms with different scientific names, such as Dixionella grisea, Rhodella reticulata, and Porphyridium purpureum and P. cruentum (Fig. 1-VI).

Both Cochlodinium and Gyrodinium are dinoflagellates that belong to the phylum Pyrrophyta, class Dinophyceae, and order Gymnodiniales. The pigments that characterize dinoflagellates are chlorophylls a and c2, β-carotene, and xantophylls piridinine, dinoxanthin, diadinoxanthin, diatoxanthin, and neodinoxanthin; fucocyanin is the main pigment responsible for the brownish color of pyrrophytes; starch and lipidic droplets are the main reserve substances. Dinoflagellates are very particular organisms, many of them produce highly toxic compounds (dinotoxins), the most known being saxitoxins and gonyautoxins (paralytic shellfish toxins or PST), two groups of carbamate alkaloid neurotoxins, brevetoxins (another group of neurotoxic shellfish toxins or NST), and the diarrheic shellfish toxin okadaic acid (Camacho et al. 2007; Wang 2008). These toxins affect all marine organisms’ and also humans’ lifes as seafood consumers. The red toxic tides are due to a high accumulation (or bloom) of flagellated dinophyceae, the red color coming from the remarkable accumulation of carotene.

Cyanophyta is a group of prokaryotic organisms that is most of the times studied along with microalgae (eukaryotic organisms). Cyanophytes are unicellular, solitary, or colonial organisms. This phylum includes a class, Cyanophyceae, with either filamentous or nonfilamentous structures, distinction of subclasses being based on hormogonia formation. Aphanocapsa, Aphanothece, Cyanothece, Gloeothece, and Synechocystis do not form hormogonia and, therefore, they are included in the subclass Coccogonophycidae, order Chroococcales; Anabaena, Arthrospira (Fig. 1-VII), Nostoc, and Phormidium belong to the subclass Hormogonophycidae, order Nostocales/Oscillatoriales, whose filaments are not ramified or, if they present branches, these are false. Only one chlorophyll (chlorophyll a) and phycocyanin are their main pigments, but they also contain carotenes and phycoerythrin (Table 2).
Table 2

Percentage of sulfate, protein, and uronic acids in polysaccharides from different marine microalgae


Sulfate (%)

Protein (%)

Uronic acids (%)



Porphyridium sp.




Geresh and Arad 1991; Sun 2010; Arad et al. 1985, Gloaguen et al. 2004; Raposo et al. 2014

Rhodella sp.




Geresh and Arad 1991; Badel et al. 2011a

B. braunii



Fernandes et al. 1989

C. stigmatophora




Guzman et al. 2003

C. vulgaris


Ogawa et al. 1999

P. tricornutum




Guzman et al. 2003

C. closterium




Staats et al. 1999

N. salinarum




Staats et al. 1999

C. polykrikoides



(a) presence

Hasui et al. 1995

G. impudicum




Yim et al. 2007


A. platensis




Lee et al. 2000; Trabelsi et al. 2009





Hayashi et al. 1996b; Lee et al. 1998, 2000

A. halophytica


Li et al. 2001

Adapted from Raposo et al. (2013)

2.2 Production of the Polysaccharides : Influence of Specific Compounds

The production of EPSs and their composition depend on the algal species; on the strain; on the composition and nutrient status of the culture medium, namely, the N source (Banerjee et al. 2002), the N/P ratio, and the deficiency in silicon (for diatoms); and on the culture growth phase. Some microalgae produce large amounts of EPSs during the stationary phase, but some others increase the yield and continue to release even during the exponential phase of growth (Ramus and Robins 1975), when synthesis of biocompounds is more active, or even during both the growth phases, depending on the culture conditions (Penna et al. 1999).

Glyoxylate is one of the compounds that can positively influence the production of EPSs (Bergman 1986). In A. cylindrica, C. capsulata, and Scenedesmus obliquus, the addition of glyoxylate to the culture medium enhanced the yield of EPSs. One explanation could be the metabolization of glyoxylate into serine via glycine, a process associated to photorespiration. Glyoxylate, thus, induced some changes in the metabolism of carbon, increasing its relative yield and, therefore, increasing intracellular PSs and the release of soluble EPSs (Bergman 1986; De Philippis et al. 1996; Liu et al. 2010). However, in some microalgae, the PS is secreted out into the culture medium only when N metabolism is not affected. As a matter of fact, after being exposed for a short period to glyoxylate, the concentration of EPSs produced by C. capsulata increased by 43 % (De Pilippis et al. 1996). Nevertheless, nitrogen starvation had also proved to induce an overproduction of carbohydrates, via an alternative pathway, with the consequent release of PSs, not only in other cyanobacteria but also in microalgae (de Phillipis et al. 1993; Arad et al. 1992). In addition to glyoxylate, some other substances can interfere with the production and release of PSs. For example, an increase of EPS can be induced by a magnesium shortage (de Phillipis et al. 1991; Raposo et al. 2014) or by higher ion concentrations (Raposo et al. 2014), depending on the culture medium and species of microalga. The ratio N/P and a deficiency in silicon also influence the production and release of PSs – while a high ratio N/P induces an increase in the EPS from N. closterium, S. costatum and Chaetoceros produce high quantities of EPS under low N/P ratios (Penna et al. 1999).

3 Biochemical Composition and Physical Properties

Carbohydrates represent the major group of compounds synthesized by microalgae and include some of the substances under research for the last decades because of their physicochemical and biological properties and promising applications, even in medicine. But it is well known that the biological activities of PSs are closely related to the chemical composition and structure of the polymers, these factors being also the reason for their physicochemical behavior. Some of the characteristics that must be taken into account are their molecular weight, as large molecules are difficult to transfer across membranes in order to carry out their specific functions, and their sulfate and uronic acid content (or other constituents that can give the polymers their anionic and acidic properties), as these components seem to have great influence on their biological activity and applications. The number of monosaccharides, the type of linkages and distribution in the molecule, the conformation and type of chains (linear or ramified), and the existence of some other chemical groups (such as amino acids, proteins, or nucleic acids) that can be (non)covalently linked to the PS chains are other features that are worthy to be evaluated, along with the rheological properties and resistance to digestion, either acidic or enzymatic.

The composition of the PSs may differ due to the method used for the extraction and hydrolysis. Sometimes a single strong step of acidic hydrolysis is used; some other times the sugar profile is obtained by means of a multistep hydrolysis associated to an ion exchange fractionation (Dubinsky et al. 1992). The fractionation and centrifugation can help to obtain different polymers, which can be separated from the initial PS, as they have different sedimentation coefficients (Kieras and Chapman 1976). In Porphyridium, for example, one of the fractions obtained by the elution with urea showed to be xylan, xyl and glcAc being the main constituents (75 % and 13 %, respectively) (Geresh et al. 1992). In R. reticulata, a similar fraction was obtained by the same technique, xyl and glcAc also being the predominant constituents (Dubinsky et al. 1992). Cleavage of the PS molecule can also be attained by enzymatic action by PS-lyases (EC4.2.2.-) and PS-hydrolases (EC3.2.1.-), endo-and exoenzymes, but the process can be time-consuming (Badel et al. 2011b) due to all the techniques that have to be employed. These researchers, however, developed a new promising method by adapting the Biofilm Ring Test® (or BRT®) technique used to degrade the PS. They applied the BRT in microplate assays and associated the BRT® to the biofilm index (BFI), which corrects some of the discrepancies between images of the former technique, before and after the magnetic treatment of particles (Badel et al. 2011b).

3.1 Structure

Within the group of PSs, not only the intracellular and the cell wall PSs but also and mainly the exo- or extracellular polysaccharides (EPS) will be focused in this work. Among all these polymers, only the sPS of G. impudicum is a homopolymer of gal (Yim et al. 2007), a galactan, and perhaps the cell wall PS of C. vulgaris, a β-(1,3)-glucan, composed of glc; the EPSs from all the other marine microalgae are heteropolymers of gal, xyl, and glc in different proportions. Other sugars can also be constituents of the PSs, such as rham, fuc, fru, and some unusual methyl sugars. The types of glycosidic linkages are described only for some of the PSs produced by microalgae. This is the case of the EPS from A. halophytica – most of the linkages are 1,3-type (1,3-linked glc, 1,3-linked fuc, 1,3-linked arab, 1,3-linked glcAc), but 1-linked glc and 1-linked glcAc (Fig. 2a) can also be found, as well as 1,2,4-linked man and 1,3,6-linked man (Li et al. 2001). In the CaSp of A. platensis, the linkages and monosaccharides of the backbone structure are usually 1,3-linked rham and 1,2-linked 3-O-methyl-rham (acofriose) (Lee et al. 1998). 2,3-di-O-methyl-rham and 3-O-methyl-xyl are the monosaccharides in the nonreducing end. Besides d- xyl, d- glc, and l- and d- gal, the main neutral sugars, the EPS from P. cruentum has also small amounts of 3-O-methyl-xyl, 3-O- and 4-O-methyl-gal, and 2-O-methyl-glcAc (Percival and Foyle 1979). This type of monosaccharide is also part of the glucurono-rhamnoglycan, or glucuronorhamnan (White and Barber 1972; Ogawa et al. 1999) of Chlorella, as 2-O-methyl-l-rham and 3-O-methyl-l-rham (or acofriose) (Ogawa et al. 1997); these methylated rham sugars seem to appear only in some green algae. 2-O-methyl-l-rham was firstly reported by Ogawa et al. (1997) to be part of the PS of Chlorella, but, in fact, it was also identified in A. platensis (Collins and Munasinghe 1987). Despite seeming to be a characteristic of Chlorella (Ogawa et al. 1997), 3-O-methyl-l-rham was also identified in B. braunii and A. platensis (Lee et al. 1998; Collins and Munasinghe 1987). B. braunii also present other less common methyl sugars: 3-O-methyl-fuc and 6-O-methyl-hexose besides fuc (Banerjee et al. 2002). Besides rham (52.3 %), the main neutral sugar, and other minor monosaccharides (fuc, glc, arab), CaSp, another PS of A. platensis, presents small amounts of 2,3-di-O-methyl-rham and 3-O-methyl-xyl (Lee et al. 1998). The positions of sulfate in the exocellular glycan of P. cruentum were identified (Archibald et al. 1981) in the glc and gal residues, as d-galactopyranose 6-sulfate, d-glucopyranose 6-sulfate, and d-galactopyranose 3-sulfate.
Fig. 2

Some of the components already identified for the PSs produced by marine microalgae: (a) d-glucuronic acid; (b) d-galacturonic acid (; accessed on 07-04-14); (c) glucuronyl-rham (or glucuronosyl-(1,4)-l-rham), (d) 3-O-α-d-glucopyranuronosyl-l-gal, and (e) O-d-glucopyranosyl-(1,3)-O-d-mannopyranose are aldobiuronic acids found in the acidic PSs produced by microalgae (c and e; d adapted from and; accessed on 07-04-14); (f) α-d-glucuronosyl-α-l-rhamnosyl-α-l-rham, an acidic trisaccharide found in Chlorella (Ogawa et al. 1999); (g) oligosaccharides I and II from Porphyridium (Gloaguen et al. 2004); (h) models 1 or 2 for the possible acidic repeating unit in polysaccharide II, from Porphyridium sp., according to Geresh et al. (2009); R = H, SO2O, terminal gal or terminal xyl, m = 2 or 3

If the composition of monosaccharides is indicated for most of the PSs by several researchers, further information for higher levels of organization of the polymers is scarce and only for a couple of microalgae. Only some di- and oligosaccharides are described, some of them are characteristic for the microalgae from which the PS was obtained. White and Barber (1972) and Ogawa et al. (1998, 1999) advanced in the structure of the glucuronorhamnan of Chlorella with the identification of the disaccharide 3-O-α-d-glucopyranuronosyl-l-rhamnopyranose (or glucoronosyl-rham) (Ogawa et al. 1998) (Fig. 2c) and the acidic trisaccharide α-d-glucopyranuronosyl-(1→3)-α-l-rhamnopyranosyl-(1→2)-α-l-rhamnopyranose (or glucoronosyl-rhamnosyl-rham, C18H30O15, Ogawa et al. 1999) (Fig. 2f), whose molecular weight was found to be 73 kDa, and with the determination of the respective structures. Besides the aldobiuronic acid 3-O-(α-d-glucopyranosyluronic acid)-l-galactopyranose (Fig. 2d), two different heterosaccharides were found to be part of the structure of the EPS from P. cruentum. These two oligosaccharides were identified after digestion of the EPS (Pignolet et al. 2013), whose complete structure was established by Gloaguen et al. (2004) (Fig. 2g, h), who also found the monosaccharide composition and distribution, their absolute configuration in the molecules, and that the oligosaccharide 1 was part of the oligosaccharide 2. Hence, they found the unusual presence of both l-and d- gal isomers in the EPS from P. cruentum, a common characteristic of the red algae PS, besides having confirmed the presence of the aldobiuronic acid. EPS from P. cruentum can, eventually, present two other aldobiuronic acids (3-O-(2-O-methyl-α-d-glucopyranosyluronic acid)-d-galactopyranose and (3-O-(2-O-methyl-α-d-glucopyranosyluronic acid)-d-glucopyranose) (Heany-Kieras and Chapman 1976), but signals of OMe groups should be confirmed (Geresh et al. 1990). This acid-type was also found in other species of Porphyridium and in Rhodella reticulata (Geresh et al. 1990). However, a lot of work is still necessary in order to determine whether these oligosaccharides are repeating building blocks of the EPS and whether there is any kind of alternate distribution. Another microalga, whose sPSs (CaSp and NaSp) have an aldobiuronic acid-type disaccharide, the O-hexunorosyl-rham, and O-rhamnosyl-acofriose, another disaccharide, is A. platensis. But as far as we know, the “hexose” is still waiting to be identified. Further, Lee et al. (2000) referred the structure as consisting alternately of a uronic acid and a rham. The O-rhamnosyl-acofriose, O-rhamnosyl-(3-O-methyl-rham), is the other repeating di-unit identified as being part of CaSp and NaSp (Lee et al. 2000; Kaji et al. 2004) constituted by alternating molecules of rham and acofriose (Lee et al. 2000). Besides these disaccharide units, an oligosaccharide is also part of the CaSp – the trisaccharide O-rhamnosyl-acofriosyl-rham (Lee et al. 2000). A tetrasaccharide was also identified: it is composed of two units of an aldobiuronic acid; in other words, two uronic acids alternating with two rham monosaccharides make up that tetrasaccharide. The di-unit uronic acid-rham can eventually be repeated some more times along the CaSp glycan, forming some more repeated units of the aldobiuronic acid-type disaccharide (Lee et al. 2000).

Despite being almost “forgotten,” some knowledge on the structure of the PS produced by P. tricornutum came into light some decades ago (Ford and Percival 1965a, b). At that time, these researchers found that the PS from this diatom is a hetero-, ramified polymer, one of the products obtained by acid hydrolysis being a sulfated glucuronomannan, composed of β-(1,3)-linked man. The aldotriuronic acid O-d-glucopyranosyluronic acid-(1,3)-O-d-mannopyranosyl-(1,2)-O-d-mannopyranose (Fig. 2e) was found to be a constituent of the side chains. As a matter of fact, an aldobiuronic acid was also identified as being O-d-glucopyranosyluronic acid-(1,3)-d-mannopyranose. Another derived product, a glucan, seems to be the other constituent of the crude PS, comprising of β-(1,3)-linked glc units.

3.2 Rheology

In order to fully understand the several uses and applications of (E)PSs, the physicochemical characteristics must be taken into account. Rheological properties and the molecular weight are some of the most important parameters as they seem to be relevant to their functions and behavior.

Most PSs, especially EPSs, are polymers of high molecular weight (220–2.9 × 103 kDa; Kaji et al. 2004; Hayashi et al. 1996b; Hasui et al. 1995; Li et al. 2001; Pignolet et al. 2013; Mishra et al. 2011), negatively charged (anionic) and sulfated. Sulfated half-ester groups and uronic acids (mostly glcAc and galAc), along with the carboxyl groups, are responsible for the acidic and anionic characteristic of PSs.

Unfortunately, information on the rheological properties and behavior is scarce and described only for A. platensis and a couple of red marine unicellular algae.

Qualitatively, solutions of sPSs from red microalgae, such as Porphyridium and Rhodella, are characterized by their pseudoplastic properties (Sun 2010; Geresh and Arad 1991) and thixotropic characteristics (i.e., exhibit a stable form at rest but become more fluid when under some agitation) (Eteshola et al. 1998) these characteristics can be evaluated quantitatively by their viscosity, elasticity, shear rate, shear strain, and shear stress ( It is well known that hydrocolloid solutions of sPSs produced by red microalgae and the cyanobacterium A. platensis present a non-Newtonian behavior, as their viscosity depends negatively on the shear strain rate, i.e., decreases with the increase of this last parameter (Raposo et al. 2014; Geresh et al. 2000, 2002a; Eteshola et al. 1998; Badel et al. 2011a; Ginzberg et al. 2008), thus showing to be a pseudoplastic compound (Geresh and Arad 1991) with a strong shear-thinning behavior (Eteshola et al. 1998). However, Sun et al. (2009b) showed that fragments of EPSs from Porphyridium have a different rheological behavior, depending on the degree of degradation, sometimes exhibiting even the typical characteristics of Newtonian fluids. In addition, elasticity, viscosity, and intrinsic viscosity decrease when high temperatures (˃90 °C) are applied in the drying process of the EPS, as these high temperatures cause significant modifications in the conformation of the polymer chains (Ginzberg et al. 2008). Another reason supporting the idea of EPS from Porphyridium having weak-gel characteristics is the fact that the elasticity (G’) values are higher than the viscosity (G”) ones (Raposo et al. 2014) after small deforming oscillatory forces are applied to the EPS, which was previously dried at temperatures below 140 °C (Geresh et al. 2002a; Ginzberg et al. 2008). These properties prevailed also when the polysaccharide was obtained from cultures grown under different concentrations of sulfate (Raposo et al. 2014). The decrease in viscosity with the application of higher shear rates was suggested to be related to the dissociation of the strong hydrogen bonds that exist between polymer chains (Ginzberg et al. 2008). In this study, Ginzberg and coworkers described well the influence of several factors on conformational modifications and also highlighted the effects caused by drying on the interactions between the polymer and its non-covalently linked glycoprotein. Raposo et al. (2014) also found that the viscosity of the EPS from P. cruentum decreases with the increase of MgSO4 concentration in the culture medium. The reason for this behavior can be associated with the decrease in the dimensions of the chains as a result of the intrachain electrostatic repulsions. An explanation of the similar behavior of the EPS was given by Eteshola et al. (1998) when NaCl, at different concentrations, was added to the aqueous solutions of EPSs. Another mechanism that can explain the gel-forming characteristic of polymers might be associated with hydrophobic and ionic forces, as it was referred for the anionic colloids of Amphora, P. tricornutum (diatoms), and Ankistrodesmus (chlorophyte) (Chen et al. 2011). Hence, some of these extracellular polymers behave as fluid-dynamic polymers, as it is the case of the EPS from Porphyridium, giving place to highly viscous solutions at very low concentrations, in a wide range of pH and temperatures, showing rheological properties similar to the ones of industrial PSs (Arad and Levy-Ontman 2010; Patel et al. 2013). Viscosity indexes, or the degree of polymerization, also seem to be closely associated with the culture growth temperature, since solutions with similar concentrations of the polymer presented higher viscosities when the cultures had been grown at the optimum temperature (Lupi et al. 1991). Therefore, growth of the culture at the optimum temperature might induce polymers with a higher polymerization degree.

Further, Eteshola and coworkers (1998) presented a fairly complete study on the rheology of the EPS produced by the red microalgae, including X-ray diffraction techniques, referring as well the viscoelastic properties of the EPS by using dynamic mechanical spectra. They observed, as well, an increase in the G’ modulus for temperatures above 60 °C, suggesting that heat promoted polymer self-association in an aqueous solution.

However, as far as we know, some PSs only jellify when dropped into FeCl3 solutions, and some others are not viscous at all. In fact, the somewhat turbid solutions of the glucuronorhamnan produced by C. vulgaris do not have the ability to form gels, and hence the solutions do not show any viscosity (Ogawa et al. 1999), and the calcium-rich PS produced by A. halophytica has the capacity to jellify when some drops of the EPS aqueous solution (1 % w/v) are put in contact with FeCl3 solutions (0.05 M), the jellified beads formed being stable for over 1 month (Li et al. 2001).

Furthermore, the rheological behavior of the EPS released by both C. capsulata and P. cruentum seems to be similar, the viscosity decreasing with the increase of the shear rate. Also, there were no significant differences between the EPS behaviors when the microalgae were subjected to different culture media (De Philippis et al. 1996; Raposo et al. 2014). This might indicate that the molecular weights of EPSs are stable, showing no major differences no matter the changes to the growth media and conditions, even under nutrient starvation (Gasljevic et al. 2008; Geresh and Arad 1991).

The high molecular weight is also an important requirement for the PSs to be good drag-reducing polymers, as polymers with higher molecular weights are usually more efficient as drag-reducing agents (Gasljevic et al. 2008). Therefore, EPSs from microalgae are promising candidates, as their PSs have similar, if not higher, molecular weights than industrial polymers, as xanthan gum, for example.

4 Bioactivity and Applications

Below is a list of some potential applications of the polysaccharides produced by microalgae:
  • Drugs or nutraceutical carriers in the pharmaceutical industry, to slow and control the release of the substances; for bacterial vaccines, to improve nonspecific immunity (Mishra et al. 2011);

  • Thickeners and gelling agents in food industries, to improve quality and texture (Mishra et al. 2011);

  • In soils and water treatment, to act as nutrient carriers to fertilize soils (Raposo and Morais 2011); to improve the aggregation of soils and sand particles (Paterson 1989; Sutherland et al. 1998), influencing the stability and cohesiveness of sediments and improving water holding capacity of soils (Mishra et al. 2011); to act as soil conditioners (Kroen and Rayburn 1984; Metting and Rayburn 1983) and to improve sludge settling and dewatering (Subramanian et al. 2010); to be used in wastewater treatment (Raposo et al. 2010), in detoxification acting as metal chelators due to the presence of uronic acids (Kaplan et al. 1987), and in bioremediation to remove toxic metals from polluted waters (Otero and Vincenzini, 2003); and to act as growth promoters for crops (Pignolet et al. 2013).

4.1 Therapeutical Applications

Antiviral, antibacterial, anti-inflammatory, immunomodulatory, antilipidemic, antiglycemic, anti-adhesive, antioxidant and free radical scavenging, and prevention and treatment of tumors are some of the therapeutical applications of PSs.

4.1.1 Antiviral Activity

Many studies have already highlighted that the polysaccharides released (or not) into the culture medium by some marine microalgae present antiviral bioactivity against different kinds of viruses, either mammalian or otherwise (Table 3); the interest increased after some experiments were conducted on HIV (Hayashi et al. 1996a; Hasui et al. 1995). Radonic et al. (2010) and Chen et al. (2010) have recently reviewed the antiviral effects of several sPS on different host cell lines. To date, PSs from Arthrospira and Porphyridium were the most studied anionic sulfonated polymers, exhibiting antiviral activity against a wide range of viruses, including Herpes simplex and Varicella zoster viruses (HSV AND VZV), human cytomegalovirus (HCMV), measles, mumps and Flu-A viruses, and vaccinia virus, a variola-related virus. In fact, the PS TK-V3 from A. platensis and EPS from P. purpureum proved to be active against Vaccinia and Ectromelia orthopoxvirus infection; in studies conducted with HEp-2 and Vero C1008 cells, the IC 50 is significantly lower (0.78 and 0.65 μg/ml, respectively) than the response to dextran sulfate (1.24 μg/ml). Despite being slightly toxic, PSs can be safely applied for in vivo experiments, as they were also effective in ovo, by decreasing the VACV replication (Radonic et al. 2010). Besides, the EPS from P. cruentum has also demonstrated a significant inhibition against Vesicular stomatitis virus proliferation on HEL cells (Raposo et al. 2014), the response being higher for the EPS isolated from the culture medium enriched with 104 mM in sulfate. As a matter of fact, the antiviral activity of the EPS from P. cruentum depends not only on the culture medium, algal strains, and cell lines used for testing but also on the methodology and the degree of sulfation and uronic acid content of the EPS (Raposo et al. 2014; Huleihel et al. 2001, 2002). These acidic compounds, along with the half-ester sulfate groups and the carboxyl groups of the polymer, contribute to their anionic characteristics, making the EPS of Porphyridium a good agent to be used against viruses (Raposo et al. 2014). CaSp, an intracellular polysaccharide produced by A. platensis, inhibited the replication of several viruses in vitro by inhibiting the penetration of the virus into the different host cells used (Hayashi et al. 1996a, b). The experiments conducted by Hayashi and coworkers (1996b) also confirmed the importance of sulfate groups on the antiviral activity of CaSp from A. platensis, activity proved by studying the effect of calcium-free-Spirulan and another compound derived from CaSp, without sulfate, on the replication of HSV-1 and on the cytotoxicity in HeLa cells, the latter compounds showing a higher toxicity and a significantly lower antiviral capacity. However, the molecular configuration due to the chelation of the calcium ion with the sulfate groups might have a crucial role in the antiviral properties, as no antiviral effect was verified when the calcium-free compound was used despite the presence of sulfate groups (Hayashi et al. 1996b). Other factors that are correlated to the inhibition of viral infection are the size of the molecules and the degree of sulfation (Ghosh et al. 2009); the composition of monosaccharides and the diversity of the linkage types also determine the specificity of sPSs and influence their functional properties. That is why tests for antiviral capacity should be carried out with a variety of virus and isolates, as wide as possible.
Table 3

Antiviral applications of EPS from marine microalgae (in Raposo et al. 2013)


Virus strain

Family/group of virus

Cell lines

EC50/ED50 (μg/mL)


A. platensis; A. maxima

Vaccinia virus VACV and VACV-GFP; ectromelia virus (ECTV); HSV-1, HSV-2, human cytomegalovirus (HCMV), measles virus, mumps virus, HIV-1, Flu-A

Orthopoxvirus/Poxviridae; Simplexvirus/Herpesviridae; Morbillivirus/Paramyxoviridae; Rubulavirus/Paramyxoviridae; Lentivirus/Retroviridae; Influenza virus/Orthomyxoviridae

HEp-2 and Vero C1008; HeLa, HEL, Vero, MDCK, MT-4 (HIV-1)

0.78; 69; 0.92–16.5; 8.3–41; 17–39; 23–92; 2.3–11.4; 9.4–230

Radonic et al. 2010; Hayashi et al. 1996a, b; Hernandez-Corona et al. 2002

Porphyridium sp.

Herpes simplex virus HSV-1 and HSV-2; varicella zoster virus (VZV); murine sarcoma virus (MuSV-124) and MuSV/MuLV (murine leukemia virus)

Simplexvirus/Herpesviridae; Varicellovirus/Herpesviridae; Gammaretrovirus/Retroviridae (type VI)


1–5 (in vivo, 100); 0.7; 10 and 5 (RT50)

Huleihel et al. 2001, 2002; Talyshinsky et al. 2002

P. cruentum

Hepatitis B virus (HBV); viral hemorrhagic septicemia virus (VHSV); African swine fever virus (ASFV), vaccinia virus (VACV), vesicular stomatitis virus (VSV)

Orthohepadnavirus/Hepadnaviridae; Novirhabdovirus/Rhabdoviridae; Asfarvirus/Asfarviridae; Orthopoxvirus/Poxviridae; Vesiculovirus/Rhabdoviridae


20, 200 (exocellular extracts); 12–56; 20–45

Huang et al. 2005; Fabregas et al. 1999; Raposo et al. 2014; Vieira and Morais 2008

P. purpureum

Vaccinia virus VACV and VACV-GFP, ectromelia virus (ECTV)


HEp-2, Vero C1008


Radonic et al. 2010

R. reticulata

Herpes simplex virus HSV-1 and HSV-2, varicella zoster virus (VZV), murine sarcoma virus (MuSV-124), and MuSV/MuLV (murine leukemia virus)

Simplexvirus/Herpesviridae; Varicellovirus/Herpesviridae; Gammaretrovirus/Retroviridae (type VI)


10–20; 8; 150 and 50 (RT50)

Huleihel et al. 2001; Talyshinsky et al. 2002

G. impudicum

Encephalomyocarditis virus; influenza A virus (Flu-A)

Cardiovirus/Picornaviridae; Orthomyxoviridae



Yim et al. 2004

C. polykrikoides

Flu-A and Flu-B, respiratory syncytial virus types A (RSV-A) and B (RSV-B), HIV-1, HSV-1, parainfluenza virus type 2 (PFluV-2)

Orthomyxoviridae; Pneumovirus/Paramyxoviridae; Retroviridae; Herpesviridae; Rubulavirus/Paramyxoviridae

MDCK, Hep-2, MT-4, HMV-2

0.45–1.1 and 7.1–8.3; 2.0–3.0 and 0.8; 1.7; 4.52–21.6; 0.8–25.3

Hasui et al. 1995

EC50/ED50 is the concentration/dose at which 50 % of the population exhibit a response after being exposed to a certain compound

Unlike what happens with most of sPSs, the PS from C. polykrikoides showed to be effective against influenza virus type B (Flu-B), among other different viruses, including that of HIV-1. This sulfated polymer that does not contain proteins, aminoacids, or nucleic acids showed an inhibitory effect higher than that of dextran sulfate on Flu-B and MSLV, with no cytotoxic effects against the different cell lines used for testing concentrations up to 100 μg/ml (Hasui et al. 1995).

The antiviral activity is probably the most studied quality exhibited by sulfated polysaccharides of marine microalgae, especially the one produced by Porphyridium. The mechanisms for this activity are not yet completely understood. As happens with heparin, the anionic nature of sPS makes it a good candidate to protect against viruses. Several mechanisms have been proposed. Hayashi and colleagues (1996a, b) noted that sPS inhibited infection by different viruses through inhibiting the penetration of viral particles into host cells. But other mechanisms can also be involved, such as the inhibition of attachment/adsorption, or even replication during the early phases of the virus cycle (Martinez et al. 2005; Kim et al. 2012), without any toxicity to the host cells (Hasui et al. 1995).

4.1.2 Antibacterial Activity

The PS from A. platensis has antibacterial properties, the activity depending on the solvent used to extract the polymer. While water and methanolic extracts showed antimicrobial properties on both Gram-positive and Gram-negative bacteria, methanolic EPS extracts show a wider capacity to inhibit the growth of bacteria than aqueous extracts. However, methanolic extracts presented only a bacteriostatic effect against the strain NCIMB8166 of Micrococcus luteus, needing an MBC/MIC ratio >4, i.e., the minimum inhibitory concentrations (MIC) of EPS is considerably lower than the concentration needed to kill the organisms (MBC, minimum bactericidal concentrations) (Challouf et al. 2011). Ethanolic and some other solvent extracts did not show any antimicrobial activity. In fact, the EPS did not exhibit any activity against E. coli (strain ATCC25922) and S. aureus (ATCC25923). A similar explanation can be applied to the results obtained by Raposo et al. (2014), who tested the antimicrobial activity of the EPS from P. cruentum and reported that their ethanolic extracts did not show a significant inhibition on the growth of bacteria E. coli and S. aureus. Perhaps the bioactive portions of the molecules have different affinities to the solvents used, being highly influenced by mutual interactions (Basedow et al. 1980), and ethanol might not be adequate for the extracts to maintain the antibacterial active principle/ingredient of the EPS. Nevertheless, the ethanolic extract of the EPS from P. cruentum showed some activity against S. enteritidis (Raposo et al. 2014).

4.1.3 Antioxidant Activity and Free Radical Scavenging

As photoautotrophs , microalgae are highly exposed to oxidative and radical stresses, therefore accumulating effective antioxidative scavenger complexes to protect their own cells from free radicals (Pulz and Gross 2004). Oxidation of lipids by reactive oxygen species (ROS), like hydroxyl radicals, hydrogen peroxide, and superoxide anion, can affect the safety of pharmaceuticals and also decrease the nutritional quality of foods. Sulfated PSs produced and secreted out by marine microalgae may act not only as dietary fiber (Dvir et al. 2009), but have also showed the capacity to prevent the accumulation and the activity of free radicals and reactive chemical species, therefore acting as a protective system against these oxidative and radical stress agents (Table 4).
Table 4

Applications, other than antiviral uses, of EPS from marine microalgae (in Raposo et al. 2013)



Cells/animals used for in vitro/in vivo studies



Health foods , nutraceutical, and functional foods


Dvir et al. 2000, 2009

Rhodella, Porphyridium

Antioxidant and free radical scavenging

3T3; mouse liver homogenates and erythrocyte hemolysates, sarcoma 180 cells/mice

Sun 2010; Chen et al. 2010; Tannin-Spitz et al. 2005; Sun et al. 2009b

Porphyridium, P. cruentum; R. reticulata

Antilipidemic, antiglycemic

Rats/mice, chickens

Dvir et al. 2009; Arad 1999; Ginzberg et al. 2000; Huang et al. 2006

Porphyridium, Chlorella stigmatophora, Phaeodactylum tricornutum

Anti-inflammatory and immunomodulatory

Polymorphonuclear leukocytes/human dermal microvascular endothelial cells, humans; rabbits and sheep (bone joints); mice macrophages/mice and rats

Guzman et al. 2003; Sun 2010; Matsui et al. 2003; Arad and Atar 2007

Porphyridium, R. reticulata, Gyrodinium impudicum, A. platensis

Prevention of tumor cell growth

FD early myeloid cell line, 24-1 and EL-4T-lymphoma cell lines; Graffi myeloid cells; rats

Senni et al. 2011; Geresh et al. 2002b; Gardeva et al. 2009; Shopen-Katz et al. 2000

Phaeodactylum, Tetraselmis


HeLa S3/sand bass culture cells

Guzmán-Murillo and Ascencio 2000; Dade et al. 1990


Biolubricant (for bone joints)


Arad and Atar 2007; Arad et al. 2006

Porphyridium, R. reticulata

Ion exchanger


Lupescu et al. 1991

P. cruentum, R. reticulata, R. maculata

Drag reducers


Gasljevic et al. 2008; Ramus et al. 1989

It was already demonstrated that the sPS from Porphyridium exhibited antioxidant activity against the autoxidation of linoleic acid and inhibited oxidative damage to 3T3 cells that might be caused by FeSO4 (Tannin-Spitz et al. 2005). These researchers also proved that the bioactivity was dose dependent, correlating positively with the sulfate content of the sPS, and mentioned the possibility of the glycoprotein to contribute to the antioxidant properties. They even suggested that the antioxidant activity of this polymer relied on its ability to act as a free radical scavenger. Despite the various applications suggested for the EPSs from different species/strains of marine microalgae, when the biological activity involves crossing the cellular membrane of cells, the high molecular weight of the polymers can be a drawback to pursue their properties. This feature was confirmed by Sun et al. (2009b). These researchers submitted the EPS from P. cruentum to microwave, and the EPS-derived products (6.55, 60.66, and 256.2 kDa) showed different levels of antioxidant activity, a lower molecular weight (6.55 kDa) being a requisite for a stronger activity either by scavenging hydroxyl, superoxide anion, and DPPH (1,1-diphenyl-2-picrylhydrazyl radical) free radicals or by inhibiting the (per)oxidation of lipids induced by FeSO4 and ascorbic acid, thus giving better protection to mouse cells and tissues against oxidative damage. They found that the antioxidant ability is dose dependent; the same is true in relation to the inhibition of oxidation damage of both liver cells and tissue. The free radical scavenging of some of the EPS fragments was significantly higher at the same, or even lower, concentration than that reported for vitamin C (Xing et al. 2005). But strangely, they found no scavenging activity and no inhibition of oxidative damage in cells and tissues for the crude high molecular sPS from Porphyridium cruentum (Sun et al. 2009b).

The sulfated exopolysaccharide from Rhodella reticulata also has antioxidant activity, the effects being dose dependent (Chen et al. 2010). Unlike what happened with the sPS from Porphyridium (Sun et al. 2009b), crude sPS from Rhodella exhibited higher antioxidant properties than the polysaccharide-modified samples, these demonstrating lower radical scavenging activity (Chen et al. 2010). These researchers found that all the different samples of sPS from R. reticulata had a stronger ability than α-tocopherol against superoxide anion radical scavenging, the crude polysaccharide being twice as strong as α-tocopherol.

Besides the antibacterial properties, the methanolic extracts of EPS from A. platensis also exhibit a moderate antioxidant capacity (TEAC=0.27 mg/mL) using Trolox, a common antioxidant substance, while the ethanolic extracts presented lower antioxidant activity (Challouf et al. 2011). According to Mendiola et al. (2007) and Sun et al. (2009b), uronic acid contents are directly related to the radical scavenging properties of PSs, but other factors also seem to have influence on the antioxidant capacity, namely, low molecular weights (Chen et al. 2008; Sun et al. 2009a), and the structure and conformation of the polymer (Tao et al. 2007). The antioxidant properties of these PSs might be exerted by improving the activity of antioxidant enzymes, scavenging free radicals, and/or inhibiting lipid (per)oxidation (Sun et al. 2009a).

4.1.4 Anti-inflammatory and Immunomodulatory Properties

Polysaccharides from marine microalgae, like Porphyridium, Phaeodactylum, and C. stigmatophora, had already demonstrated to have pharmacological properties, such as anti-inflammatory activity and as immunomodulatory agents (Table 4). The sPS from both C. stigmatophora and P. tricornutum demonstrated a significant anti-inflammatory activity against paw edema induced by carrageenan injected as a sterile saline solution (0.9 %), with IC 50 values of 2.25 and 2.92 mg/kg for C. stigmatophora and P. tricornutum, respectively, compared to the anti-inflammatory indomethacin, with an IC 50 of 8.50 mg/kg. The anti-inflammatory efficacy was tested in vivo, by intraperitoneally injecting the crude PS in female rats and mice, and in vitro, the phagocytic activity being evaluated in macrophages from mice (Guzman et al. 2003). The direct stimulatory effect of P. tricornutum on immune cells was evidenced by the positive phagocytic activity tested either in vitro or in vivo, and the activity of the extract of sPS from C. stigmatophora showed immunosuppressant effects (Guzman et al. 2003). As reported for the polysaccharide from Ulva rigida, a green seaweed (Leiro et al. 2007), the sPS p-KG03 from the marine dinoflagellate G. impudicum also activates the production of nitric oxide and immunostimulates the production of cytokines in macrophages (Bae et al. 2006). On the other hand, inhibition of leukocyte migration seems to be related to the anti-inflammatory activity of the polysaccharides (Matsui et al. 2003). As leukocyte movement to the site of injury contributes to additional cytokine release and to the production of nitric oxide, therapeutics has to be effective against this over-inflammation. In fact, the sPS from Porphyridium seems to be a good candidate for this role as it inhibited the movement and adhesion of polymorphonuclear leukocytes in vitro and inhibited the development of erythema in vivo as well (Matsui et al. 2003).

Besides inhibiting tissue oxidative damage, EPS from P. cruentum can be used to inhibit the biomembrane peroxidation as well (Sun et al. 2009b) and to enhance in vitro immunomodulatory activity (Sun et al. 2012). These researchers have also explained the mechanism/pathway that is most probably involved in the immune response enhancement by EPS from P. cruentum – the stimulation of macrophages. They found that low molecular fractions of EPS can stimulate the proliferation of macrophages and the production of NO (nitric oxide). NO is a signaling free radical gas molecule that can be synthesized by phagocytes (monocytes, macrophages, and neutrophils) and is involved in the human immune system response. When studying the effects of EPS-derived products, Sun (2010) showed that EPS from Porphyridium presented immunostimulating activity in mice with S180 tumors by increasing both spleen and thymus index and also spleen lymphocyte index. Sulfated PS-derived products, with lower molecular weight, can also improve the production of NO in mouse macrophages. In his Ph.D. Thesis, Sun referred to the fact that sulfate content has a positive correlation with the immunomodulatory system. Furthermore, Namikoshi (1996) noted that sPS can stimulate the immune system by triggering cells and humor stimulation. This shows the capacity of marine unicellular algae sPS to directly stimulate the immune system.

Spirulan is a GAG-like PS (Senni et al. 2011). This means that spirulan from A. platensis, for example, is recognized as having similar properties as glycosaminoglycans (GAG), present in all animals. GAGs are sulfated (or not) PSs composed of disaccharide repeating units, a uronic acid or a neutral monosaccharide, and an amino sugar (Senni et al. 2011) with anticoagulant properties, such as heparin and hyaluronic acid. By interacting with a vast range of proteins involved in many human body physiological and pathological responses, GAGs show several bioactivities associated either to inflammatory processes or to tissue repair (Gandhi and Mancera 2008; Mulloy and Linhardt 2001). Some sulfated GAGs can be covalently linked to proteins (proteoglycans); this is the case of the sPS from red marine unicellular algae Porphyridium, which has also some protein moieties non-covalently linked, but shows anti-inflammatory properties.

On the other hand, immunomodulators are response modifier biocompounds that present an enhancement or suppression of the immune responses, depending on a wide range of factors, such as dose, way, and time of administration, but also on the site of activity and the respective mechanism of action (Tzianabos 2000). β-(1,3)-Glucans, such as that of C. vulgaris (Nomoto et al. 1983), have already proved to exhibit several biological properties, including prevention of some infections and antitumor activity (Bleicher and Mackin 1995; Nomoto et al. 1983). These polymers stimulate the functional activity of macrophages (Burgaleta et al. 1978) and the proliferation of monocytes and macrophages, presenting also potent hematopoietic properties (Patchen and Lotzova 1980; Riggi and DiLuzio 1961).

4.1.5 Activity Against Tumors and Vascular Muscle Cell Proliferation

Sometimes, after suffering some kind of damage, vascular endothelial cells are not sufficiently repaired by their own cell type; there can be an invasion of platelets and/or macrophages or other blood cell types, which secrete cytokines and growth factors that can increase the proliferation of vascular smooth muscle cells, causing a hyperplasia of the arterial intimae. This atherosclerosis is one of the main causes of myocardium and cerebral infarction.

Some PSs that are used as anticoagulants have also some inhibitory activity against the proliferation of vascular smooth muscle cells. This is the case of heparin (Clowes and Clowes, 1987) and heparin sulfate (Kaji et al. 2004) and the sulfated fucoidan from some seaweeds (Vischer and Buddecke 1991). Nevertheless, spirulan (either Na- or Ca-) from A. platensis is a more potent inhibitor of cell proliferation, as it was demonstrated by Kaji and coworkers (2004) on bovine arterial smooth muscle cells. These researchers also demonstrated that it is not enough to be composed of sulfate for the PSs to show inhibitory activity against cell growth: while both NaSp and CaSp inhibited the proliferation of vascular smooth muscle cells, as it happened with heparin and heparin sulfate, the desulfated equivalent compounds did not show this effect. And, as depolymerized compounds (PS-derived products with lower molecular weights) of NaSp and CaSp maintained the inhibitory capacity against the proliferation of arterial smooth muscle cells, with MW ≥14,700, this suggests that spirulan (especially NaSp) is a particular polymer with a specific structural sequence and conformation maintained by the linkage of Na+ to the sulfate groups, keeping, therefore, that strong inhibitory activity (Kaji et al. 2004); the effect is dose and time dependent. Furthermore, depolymerized NaSp inhibited the growth of vascular smooth muscle cells without inhibiting the growth of vascular endothelial cells (Kaji et al. 2002, 2004).

Spirulan is also capable of inhibiting pulmonary metastasis in humans and to prevent the adhesion and proliferation of tumor cells (Senni et al. 2011).

Other sPSs have also antiproliferative activity in cancer cell lines (in vitro) and inhibitory activity against tumor growth (in vivo). The sPS p-KG03 from G. impudicum is one of these polymers that prevents and suppresses tumor cell growth either in vitro or in vivo by activating NO production and by stimulating the innate immune system, increasing the production of cytokines interleukin-1 (or IL-1), IL-6, and THF-α in macrophages (Bae et al. 2006; Namikoshi 1996; Yim et al. 2005). This PS has immunostimulating properties in vivo as well (Yim et al. 2005).

Another candidate with potential to be used as an antitumor agent is the β-(1,3)-glucan from C. vulgaris, besides being considered an active immunostimulator (Laroche and Michaud 2007). Low molecular weight fragments (6.53–1,002 kDa) of the sPS from P. cruentum are also good immunostimulators as they all inhibited in vivo S180 tumors implanted in the peritoneal cavity of mice models by inhibiting the tumor cell proliferation and the growth of the tumor, increasing the spleen and thymus indexes and the number of spleen lymphocytes as well, enhancing the immune system in this way (Sun et al. 2012). However, nonmodified or higher molecular weight fragments of the same sPS showed no inhibition of tumor cell growth (Geresh et al. 2002b; Sun 2010). Nonetheless, in a recent study, Gardeva et al. (2009) reported the strong antitumor activity exhibited by the polysaccharide of P. cruentum. This sulfated polymer strongly inhibited Graffi myeloid tumor proliferation in vitro and in vivo, the activity being dose dependent, and the survival time of hamsters was increased by 10–16 days. Gardeva and coworkers (2009) also suggested that the antitumor activity could be related to the immunostimulating properties of the polymer. Therefore, it can be concluded that the reinforcement of the immune system induced by the sPSs is probably the main mechanism against tumor growth and respective effects (Sun et al. 2012; Zhou et al. 2004). However, other mechanisms, such as changes in the biochemical characteristics of the cell membrane, inducing tumor cell differentiation and apoptosis, and regulation of the cell signaling pathways, can also be involved (Zhou et al. 2004). Besides these mechanisms, the antimetastatic properties may be associated to the capacity of blocking the interactions between cancer cells and the basement membrane or inhibiting the adhesion of tumor cells to the substrates.

In addition, some years ago, it has already been demonstrated that high molecular weight oversulfated EPSs from Porphyridium inhibited neoplastic mammalian cell growth and that the biomass of this marine microalga could prevent the proliferation of colon cancer in rats (Geresh et al. 2002b; Shopen-Katz et al. 2000).

4.1.6 Antilipidemic and Antiglycemic Properties

Sulfated PSs from seaweeds and marine animal origin are potent inhibitors of human pancreatic cholesterol esterase, an enzyme that promotes its absorption at the intestinal level (Laurienzo 2010). These inhibitory effects are enhanced by higher molecular weights and degree of sulfation, as well as by the presence of 3-sulfate in the monosugar molecule (Laurienzo 2010). And most of the PSs from marine microalgae are naturally and highly sulfated with high molecular weights, making them non-readily absorbable and thus enabling them to be used as anticholesterolemic agents.

However, this area of research has not been sufficiently explored in what concerns microalgae (Table 4). When Ginzberg and coworkers (2000) fed chickens with biomass containing EPS from Porphyridium, they verified that cholesterol decreased either in serum or egg yolk of chickens, the fatty acid profile was modified, and the carotenoid content in the egg yolk was improved as well. Furthermore, in rats fed with Porphyridium and R. reticulata biomass, which PSs contain dietary fibers, there was a decrease in serum cholesterol and triglycerides; hepatic cholesterol levels were also improved and the levels of VLDL considerably lowered with no toxic effects noticed in the animals (Dvir et al. 1995, 2000, 2009). Also, either the biomass of Rhodella or the sPSs from Porphyridium were able to lower the levels of insulin and/or glucose in diabetic rodents (Dvir et al. 1995; Huang et al. 2006), causing no modifications in the pancreatic island cells and no fibrosis or hemorrhagic necrosis in cells (Huang et al. 2006).

These experiments suggest the strong potential of sulfated polysaccharides from unicellular algae to be used as hypolipidemic and hypoglycemic agents, but they are also promising substances in reducing coronary heart disease due to their hypocholesterolemic effects (Dvir et al. 2000, 2009).

Mechanisms focusing on the role of dietary fibers in lowering cholesterol are not yet completely understood, but Oakenfull (2001) proposed that it could be related to the increase in the viscosity of intestinal contents, which have influence on nutrient absorption, micelle formation, and decreasing of lipid absorption. The decrease in serum cholesterol levels and the increase in bile excretion, caused by the disruption of the enteropathic circulation of bile acids, were suggested as another possible explanation (Glore et al. 1994; Marlett 2001).

4.2 Other Biological Activities

4.2.1 Anticoagulant and Antithrombotic

There are several studies on the anticoagulant properties of the PSs isolated from seaweeds, presented in a recent review by Wijesekara and coworkers (2011). Carrageenans, for example, are sPSs that show potent anticoagulant activity, inhibiting platelet aggregation as well, probably due to the antithrombotic capacity, which, in turn, is associated to a high sulfate content (Prajapati et al. 2014). However, there are only a few references to microalgae. On one hand, it was stated that the anticoagulant activity is associated to the high sulfate content of the PS, which is a characteristic of most of the PSs with marine microalgae origin. But, this feature could be an inconvenience when considering their use for the treatment of virus-induced diseases, for example, as an anti-inflammatory. On the other hand, Hasui and colleagues (1995) found no anticoagulant activity in the sPS of C. polykrikoides in spite of the high contents in sulfate of this PS. This suggests that the anticoagulant properties of polysaccharides may not only depend on the percentage of sulfate residues but rather on the distribution/position of sulfate groups and, probably, on the configuration of the polymer chains (Ginzberg et al. 2008; Pereira et al. (2002). Spirulan from A. platensis is one of the marine microalgae PS that strongly interferes with blood coagulation-fibrinolytic system and exhibits antithrombogenic properties (Hayakawa et al. 1996, 2000). Both NaSp and CaSp enhance the antithrombin activity of heparin cofactor II and the production of the tissue-type plasminogen activator in human fetal lung fibroblasts (Hayakawa et al. 1997), and, in addition, NaSp still enhances the secretion of urokinase-type plasminogen activator and inhibits the secretion of the plasminogen activator inhibitor type 1, sulfate being essential for these properties (Yamamoto et al. 2003). Therefore, spirulan is a promising antithrombotic agent in clot breakdown, but some care should be taken in relation to hemorrhagic strokes.

4.2.2 Biolubricant

This is one of the lesser known applications for sPSs, and very little has been published on this issue (Table 4). Nevertheless, the sEPS of Porphyridium has already shown good lubrication capacity due to its rheological properties (Arad and Weinstein 2003). Arad and coworkers (2006) have compared the lubricating properties of sPSs to the most used hydrogel lubricant, hyaluronic acid. They simulated efforts of joints, during both walking and running, and found a better quality of the EPS from Porphyridium. The explanation for these properties is associated to EPS rheological characteristics as they showed to be stable than most lubricants at higher temperatures, the viscosity of the latter decreasing along with a decrease of lubricity. A 1 % PS solution presented the best friction properties under high loads, and its viscosity did not suffer any significant change when incubated with hyaluronidase, with standing degradation by this enzyme (Arad et al. 2006). This experiment shows the potential of the sPS from Porphyridium to be an excellent candidate to substitute hyaluronic acid as a biolubricant. Another promising application could be as a substance to be part of a joint-lubricating solution, as it was demonstrated by injecting the EPS from Porphyridium into the joints of rabbits’ knees (Arad and Atar 2007), thus mitigating degenerative joint disorders caused by arthritis.

4.2.3 Anti-adhesive

Sulfated PSs from marine microalgae revealed the ability to block the adhesion of pathogenic microorganisms, suggesting the hypothesis to be used in anti-adhesive therapeutics. In fact, several sPSs presented a higher inhibition of the adherence of both Helicobacter pylori to HeLa S3 cell line and three fish pathogens to spotted sand bass gills, gut, and skin cultured cells (Guzmán-Murillo and Ascencio 2000) (Table 4).

Infection by microorganisms appears usually after binding to the cell membrane. Carbohydrates were already demonstrated as recognition sites for decades (Ofek et al. 1978), heparan sulfate glycosaminoglycan being one of those receptors in the host cells (Ascencio et al. 1993). These researchers suggested that this interaction could be associated to the net charge and molecular stereochemistry of the polymer.

4.3 Health Foods , Nutraceuticals, Functional Foods

Nowadays, the implications of specific diets on health assume a relevant role in developed countries, and the pursuit for equilibrated diets, supported by considerable epidemiological evidences, is a major issue for the scientific community and consumer in general, who more and more look for natural food products. In this context, microalgae have great potential to be used in food and feed preparation due to their rich composition, including high protein content with balanced amino acid pattern, carotenoids, fatty acids, vitamins, polysaccharides, sterols, phycobilins, and other biologically active compounds (Gouveia et al. 2008). The commercial production of microalgae for human nutrition is already in practice, and they find many applications either as nutritional supplements, for instance, in the form of tablets and pills, or as functional foods, incorporated in food products, such as pastas and cookies. The health-promoting effects associated with microalgal biomass are probably related to several effects due to their phytochemical constituents.

Some PSs from microalgae may by themselves be of interest for industrial and commercial applications. PSs can find applications in the food industry as emulsifying and gelling agents and as flocculant and hydrating agents, emulsifiers, stabilizers, and thickening agents, i.e., food additives (Bernal and Llamas 2012), like agar E406, alginates E400-404, and carrageenan E407. Because of the presence of peptide/protein moieties and deoxysugars, such as rhamnose and fucose, some PSs from marine cyanobacteria and unicellular algae show a significant hydrophobic behavior, conferring them emulsifying characteristics (Flaibani et al. 1989; Shepherd et al. 1995). In addition, some PSs include fucose as a constituent, this deoxysugar being of high value in the chemical synthesis of flavoring agents (Lupi et al. 1991). The sPS from marine microalgae could also be used as nutraceuticals due to their fiber content, their ability of acid binding and cation exchange, and their property of fecal bulking, and they are also good candidates as prebiotics (Ciferri 1983) and in some cases with a strong bioactive potential as hypolipidemic and hypoglycemic agents (Gonzalez de Rivera et al. 1993; Dvir et al. 2000, 2009) similar to polysaccharides from seaweeds (O’Sullivan et al. 2010). The PSs from microalgae alone or in combination with other compounds have also great potential to be used in edible films and coatings of foods other than carriers of flavors, colorants, spices, and nutraceuticals (Marceliano 2009). PSs from microalgae also have the potential to be used in low-fat or fat-free food products, as fat replacers in mayonnaises (Franco et al. 1998; Raymundo et al. 1998), and salad dressings and other food emulsions (Raymundo et al. 2005).

4.4 Other Applications

Another little known field of application is as drag reducers. Only a few studies were conducted in order to determine whether polysaccharides had the potential of drag-reducing ability (Ramus et al. 1989; Gasljevic et al. 2008), in order to extend their functionalities to engineering applications (Table 4), namely, naval engineering. It is known for some years that the efficiency of PSs drag-reducing properties is improved by the high molecular and linear structure of the polymers, associated with a strong resistance to mechanical degradation (Gasljevic et al. 2008). In fact, these researchers have already studied the potential of several marine microalgal PSs as drag reducers. P. cruentum and R. maculata were the ones whose polysaccharides showed the higher drag-reducing power at lower concentrations, followed by Schizochlamydella (former Chlorella) capsulata. However, the PSs of some of these microalgae proved to be more powerful than others. As a matter of fact, to have the same level of drag-reduction effectiveness, 25 % more PS of R. maculata is required in relation to P. cruentum and almost three times more than the polysaccharide of S. capsulata (Gasljevic et al. 2008). Thus, if applied to the hulls of the vessels, these high-molecular EPSs could reduce friction losses by reducing flow turbulence due to the elasticity of the polymers. Therefore, there could be a reduction in the fuel consumption and in the propelling power for a ship to achieve a certain velocity (Gasljevic et al. 2008).

Another promising and emerging application of microalgae might be associated to the production of nanofibers from the biomass of A. platensis to be used as extracellular matrices for the culture of stem cells in order to treat spinal cord injuries (Raposo et al. 2010).

Their gluing and adhesive capacities and also their strong cohesive and binding strength, allied to their nontoxic and nonirritating properties, make these bioadhesive PSs produced by marine microalgae good candidates as mucobioadhesives or glues for bone gluing and soft tissue closure after surgery, promising to be, in the near future, the substituents of metallic screws and traditional wound closure methods, respectively (Laurienzo 2010).

Other areas of application of the marine microalgal sPSs could be as diverse as cosmetics or as ion exchangers, due to their chemical composition, rheological characteristics, and ion affinity.

Finally, besides all these applications, the adhesion properties of the sPSs produced by microalgae seem to play an important role in either the locomotion of some algae (Wetherbee et al. 1998) or in the aggregation of soil and sand particles (Paterson 1989; Sutherland et al. 1998), influencing stability and cohesiveness of sediments.

5 Mechanisms of Action

5.1 Antibacterial Activity

Some researchers have found that some PSs have an inhibitory effect on some bacteria: the extract from Chaetomorpha aerea inhibited the growth of S. aureus (Pierre et al. 2011); EPS from P. cruentum inhibited the growth of S. enteritidis (Raposo et al. 2013); fucoidan from the brown seaweed Laminaria japonica inhibited E. coli (Li et al. 2010). This inhibitory effect might be explained by the anti-adhesive properties of sulfated exopolysaccharides of some microalgae against the adherence of microorganisms. Several sPSs inhibited the adherence of both Helicobacter pylori to HeLa S3 cell line and three fish pathogens to spotted sand bass gills, gut, and skin cultured cells (Guzman-Murillo and Ascensio 2000). PSs may compete with carbohydrates as recognition sites to which microorganisms can attach to, this mechanism having already been evidenced for other carbohydrates in cell surfaces (Ofek et al. 1978). Heparan sulfate glycosaminoglycan was identified as a receptor in host cells, this interaction having been associated with the net charge and molecular stereochemistry of the polymer (Ascencio et al. 1993).

However, the same PS may also not show activity against other bacteria (C. aerea extract against S. enteritidis, Pierre et al. 2011; P. cruentum extract against S. aureus, Raposo et al. 2014). The different reactions of various bacteria to the biological extracts of PSs could be due to the composition of the bacterial cell wall, to the absence of a specific structure in the bacteria, or also to the ability of the bacteria to change the chemical structure of the extract (Michael et al. 2002). The antibacterial activity may also be related to the antibiofilm formation ability of the EPS (Bernal and Llamas 2012) and, therefore, with the anti-adhesive properties. Most evidence suggests that these molecules act by modifying the physical properties of biotic surfaces (Rendueles and Ghigo 2012). Gram-negative E. coli and Gram-negative S. enteritidis present different cell surfaces that might explain the differences found between the correspondent inhibitions by the EPS (Raposo et al. 2014).

Rendueles and Ghigo (2012) suggest that PSs, as surfactant molecules, may modify the physical properties of the bacterial cell surfaces. PSs from microalgae might act in a similar way as E. coli exopolysaccharides, which can inhibit the autoaggregation via adhesins of bacterial cells (Valle et al. 2006; Rendueles et al. 2011). Polysaccharides, as sugar polymers, have also the capacity to act as inhibitors of lectin, which, being mainly located on the surface of bacteria cells, facilitate the attachment or adherence of bacteria to host cells by binding to the glycan substrates present on the surface of those host cells (Esko and Sharon 2009). PSs compete with the sugar-binding domain of lectins and inhibit the lectin-dependent adhesion of pathogens and biofilm formation, therefore reducing the occurrence of infection.

5.2 Antiviral Activity

Several mechanisms have already been proposed to explain the antiviral activity of EPSs, either involving the inhibition of the virus penetration into the host cells (Hayashi et al. 1996b), by competing with the glycoprotein attachment sites of the membrane/envelope of the viruses (Damonte et al. 2004; Radonic et al. 2010; Rashid et al. 2009), or relating to the replication during the early phases of the virus cycle (Martinez et al. 2005; Kim et al. 2012).

The general mechanism of the antiviral activity of most PS against enveloped viruses could be based on shielding off the positively charged sites in the viral envelope glycoprotein through ionic interactions between the anionic (mainly sulfate) groups in the polysaccharide and the basic amino acids of the glycoprotein (Damonte et al. 2004; Radonic et al. 2010; Rashid et al. 2009), in a similar way to what happens when a virus attaches to a cell through the cell surface heparan sulfate receptor (Witvrouw and De Clercq 1997). Therefore, the EPS could compete with the amino acids of the virus glycoprotein, blocking the viral adsorption process, in an identical way to what happens in relation to bacteria, already mentioned. There is evidence that carrageenan, a sulfated polysaccharide from a macroalgae, could directly bind to human papillomavirus capsid (Buck et al. 2006). The EPS from P. cruentum is a good candidate to protect against viruses (Raposo et al. 2013), since uronic acids, along with the half-ester sulfate groups and the carboxyl groups of the EPS, contribute to its anionic properties. Raposo et al. (2014) found that the EPS from a Spanish strain of P. cruentum revealed, in general, greater antiviral activity than the EPS from an Israeli strain, and this fact might be related to the higher degree of sulfation of the former, although they did not discard other factors.

6 Safety and Regulatory Aspects

The safety hazards of a PS as food or food ingredient is directly or indirectly associated to the microalgae which it was extracted or secreted from, respectively.

Some microalgae have been widely commercialized and used, mainly as nutritional supplements for humans and as animal feed additives, and some have the GRAS status being attributed by the FDA (Food and Drug Administration) of the USA (Table 5).
Table 5

Some food and feed applications of microalgae and safety aspects



Safety aspect



Safety aspect










Nitzschia dissipata






P. tricornutum



Chlamydomonas reinhardtii



Thalassiosira pseudonana


H. pluvialis



Odontella aurita










Monodus subterraneus












Parietochloris incisa








Crypthecodinium cohnii



P. cruentum



Adapted from Enzing et al. (2014)

NT no toxins known, GRAS generally recognized as safe

In the EU, several Chlorella species and A. platensis were on the market as food or food ingredient, and consumed to a significant degree, before 15 May 1997. Thus, in general, they are not subject to the Novel Food Regulation EC No. 258/97. However, in some EU Member States, specific legislation may restrict the placing of these products in the market, and it is recommended to check this issue with the national competent authorities.

Safety hazards related to algae may include allergens and toxins , heavy metals and pesticides, and pathogens (van der Spiegel et al. 2013). Allergenicity has been reported for the cyanobacteria Phormidium fragile and Nostoc muscorum (Sharma and Rai 2008) and the green algal genus Chlorella (Tiberg and Einarsson 1989). No toxins have been found in Arthrospira and Chlorella, but toxic microcystines were detected in other cyanobacteria (Kerkvliet 2001; Heussner et al. 2012). Extracts from Aphanizomenon flos-aquae, Spirulina, and Chlorella, or mixtures thereof, were cytotoxic (Heussner et al. 2012). Pheophorbides may be formed in Chlorella, which give rise to photosensitization in some humans (Kerkvliet 2001). A. platensis remarkably reduced the incidence of liver tumors and prevented DBN-induced hepatotoxicity in rats without causing any side effects or organ toxicity (Ismael et al. 2009). Microalgae may also accumulate heavy metals, depending on the conditions under which they are grown (Hung et al. 1996; Wong et al. 1996). The presence of pathogenic microorganisms is another crucial safety aspect that must be considered. If microalgae are cultivated in open tanks, this may result in microbiological contamination from birds, insects, or rodents (Kerkvliet 2001). These safety problems might be eliminated by growing the microalgae in closed bioreactors (Amara and Steinbuchel 2013).

PSs from microalgae might be a valuable material for a wide potential range of uses, including food, feed, and biomedical applications due, in general, to the absence of or to no known toxicity problems. Most toxicological data from the PSs from microalgae are driven from in vitro tests. Raposo et al. (2014) found no cytotoxic effects of the EPS from P. cruentum for the concentration (100 μg/mL) and cell lines tested. Other studies with Vero cells indicated that the cytotoxic effect only occurred for concentrations higher than 250 μg/mL, and some other in vivo assays indicated that this type of polysaccharide does not show any cytotoxic effect at 2 mg/mL (Huleihel et al. 2001).

The treatment of aortic endothelial smooth muscle cultured cells with depolymerized sodium spirulan (NaSP), an sPS obtained from a hot water extract of A. platensis, resulted in a significant inhibition of the proliferation of the arterial smooth muscle cells, therefore preventing atherosclerosis without exhibiting any toxic effects on the integrity of the vascular endothelial cell layers (Yamamoto et al. 2006). Some sPSs may interfere with blood coagulation and, therefore, have the potential to be used in some biomedical applications and not in another (Raposo et al. 2013).

It should be remarked that any PS extracted from microalgae/cyanobacteria and refined to be used as food is considered a new product and, thus, falls under the Novel Food Law of EU. For biomedical applications the novel biological products, in the USA, must comply with FDA Biologics Control Act (21 CFR 600 Biological Products General, Subpart A – General Provisions, Sec.600.3 Definitions) (Whiteside 2011). In the EU the term “biological product” was first published in the Directive 2003/63/EC, amending Annex I of the Directive 2001/83/EC (Noffz 2011). This implies that companies have to provide information on the safety of the food product (including results of animal testing) to the EFSA or FDA, before commercialization is authorized. For instance, carrageenans, which are polysaccharides from seaweeds, not from microalgae, are used as a food additive (E-407), have very low toxicity, and have been shown not to be teratogenic (Necas and Bartosikova 2013). However, the poligeenan, formerly referred to as degraded carrageenan, is not a food additive, exhibiting toxicological properties at high doses (Cohen and Ito 2002). Nilson and Wagner (1959) found no adverse effects on rats lifelong fed with kappa-/lambda-carrageenan from C. crispus or G. mamillosa at concentrations up to 25 %, while in two other unidentified strains of carrageenan, they found evidence of hepatic cirrhosis, but only at a concentration of 25 % and with no effect on mortality. Therefore, any PS from a novel source must be tested prior to be used in human applications.

7 Bioavailability and Metabolism

To our knowledge, there are no known bioavailability studies on the PSs from marine microalgae, the bioavailability of PSs from microalgae being yet to be studied on humans (Raposo et al. 2013). The EPS from P. cruentum is not hydrolyzed in the gastrointestinal tract; therefore, its bioavailability is null or very reduced (Arad et al. 1993). However, some knowledge may be withdrawn from studies carried out with polysaccharides from macroalgae, plants, or microorganisms of structures similar to the PSs from microalgae.

Sulfated PSs from seaweeds, such as fucoidan from brown seaweeds (Senthilkumar et al. 2013) and carrageenans, alginates, and porphyrans from red seaweeds, are known to have biological effects that could be useful in the prevention or reversal of metabolic syndrome (Holdt and Kraan 2011).

As discussed previously in point 4.3, PSs could act as prebiotics. In fact, these PSs cannot be digested by human endogeneous enzymes, belonging, therefore, to the dietary fibers (Baird et al. 1977). They are able to modify gastrointestinal hormone secretion, glycemia regulation, and lipid metabolism, preventing, in this way, obesity (Parnell and Reimer 2012). One of the physicochemical properties of PSs is the ability to be fermented by the human colonic microbiota, resulting in beneficial health effects (Mišurcová et al. 2012). Also, in vitro and in vivo animal studies highlighted anti-hyperlipidemic and anti-hyperglycemic activities of PSs from microalgae (Raposo et al. 2013).

8 Clinical Trials

Reporting to what was already mentioned in Sect. 4 on bioactivity and applications, PSs constitute a good source for potential development of novel food ingredients and biomaterials. However, the exploitation of the biomedical potential of these PSs will be a long and challenging road, as the regulatory context of medical devices and, in this case, advanced therapy medicinal products are very demanding. Also, the lack of industrial-scale extraction and purification of many of these molecules is an obstacle for their application development. In fact, any clinical application will demand for the implementation and validation of industrial manufacturing methods. Besides this issue, the natural provenience of PSs imposes a strict control of their purity, stability, and safety, which imply extensive and, above all, expensive studies (Silva et al. 2012).

In spite of all these considerations, a large number of preclinical essays have already been conducted with microalgae. Recently, extensive studies have been performed to evaluate the therapeutic benefits of microalgae on several disease conditions including hypercholesterolemia, hyperglycerolemia, cardiovascular diseases, inflammatory diseases, cancer, and viral infections. Some studies reported the antioxidant and/or anti-inflammatory activities of Spirulina or its extracts, containing PSs, in vitro and in vivo, suggesting that Spirulina may provide a beneficial effect in managing cardiovascular conditions (Deng and Chow 2010). Some of the preclinical trials of polysaccharides from marine microalgae that have been carried out are listed in Table 6.
Table 6

Preclinical trials of polysaccharides from marine microalgae (see also Table 4)

Microalgae species


Experimental model



Arthrospira sp.


Several models

Hypolipidemic, antioxidant, and anti-inflammatory activities

Deng and Chow 2010

A. platensis


Raw macrophages

Synthesis of TNF-α

Parages et al. 2012

Spirulina sp.

Spirulan-like substance

Several types of cell cultures

Antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus (HSV-1), human herpes virus type 6 (HHV-6), human immunodeficiency virus type 1 (HIV-1), non-susceptibility of Epstein-Barr virus (EBV), and human influenza A virus (A/WSN/33)

Rechter et al. 2006

N. flagelliforme


Vero, HEL, MDCK, and HeLa cells

Antiviral activity against HSV-1 (HF), HSV-2 (UW-268), HCMV (Towne), influenza (NWS)

Kenji et al. 2005

C. pyrenoidosa; C. ellipsoidea

Polysaccharide complex

Natural killer cells

Immunostimulating properties, inhibition of the proliferation of Listeria monocytogenes and Candida albicans

Barrow and Shahidi 2008

C. ellipsoidea


Reticuloendothelial system in rats

Stimulate phagocytic activity of the reticuloendothelial system

Kojima et al. 1974

P. cruentum

(EPSs) degraded by Hermetic microwave and H2O2 under ultrasonic waves

Mouse tumor model, peritoneal macrophage activation, splenocyte proliferation assay

Antitumor and immunomodulatory activities of different molecular weight

Sun et al. 2012

Porphyridium sp.


NIH/3T3 cells

Antiviral activity against retrovirus MuSV-124 and MuSV/MuLV

Talyshinsky et al. 2002

P. aerugineum

P. cruentum


Confluent cultures of human erythroleukemia cell line (HEL)

Antiviral activity against HSV type 1 (HSV-1; strain KOS), HSV type 1 (HSV-1; strain TK-KOS ACVr) and type 2 (HSV-2; strain G), vaccinia virus, and vesicular stomatitis virus

Raposo et al. 2014

With respect to clinical essays and applications in the market, the area of cosmetics is one of the few known. An EPS from a cyanobacterium was reported to be effective in skin aging (Loing et al. 2011). There is a recent US patent defending the use of sPSs in cosmetics. Indeed, microalgae extracts, mainly from Arthrospira and Chlorella (Stolz and Obermayer 2005; Spolaore et al. 2006), are incorporated in many face and skin care products (e.g., antiaging cream, refreshing or regenerating care products, emollient, and anti-irritant in peelers), sun protection, and hair care products (Martins et al. 2014). Alguard™ is a purified sPS from P. cruentum that is used in cosmetics worldwide as antiaging, anti-inflammatory, anti-irritant, skin maintenance, UVB damage prevention, soothing and healing creams, and lip balms. Also a mixture of PSs from microalgae makes part of the composition of a commercial product called Algenist™ antiaging skin care formulas in the form of alguronic acid.

There is a patent (WO 2007066340 A1, Arad and Atar 2007) defending the use of a material composed of algal polysaccharides for viscosupplementation in the treatment of degenerative joint disorders related to joint lubrication, preferably osteoarthritis, rheumatoid arthritis, gout, trauma, and age-related degeneration.

9 Conclusion

Microalgae are easy to grow organisms, and, in comparison with seaweeds, their culture conditions are easily controlled in closed systems, thus avoiding safety hazards. The chemical composition and structure and the rheological behavior of the polysaccharides they produce are relatively stable no matter the period/phase of harvest. However, the polysaccharides synthetized and/or released by marine microalgae can be so heterogeneous and structurally different that research on these compounds can be a very challenging task.

Polysaccharides may be regarded as key ingredients for the production of bio-based materials in life sciences (e.g., food, cosmetics, medical devices, pharmaceutics). The biological source and biodegradability of these biopolymers, coupled to the large variety of chemical functionalities they encompass, make them promising compounds. Despite having showed several interesting properties, including for human nutrition and health, their use in humans and clinical trials and bioapplications are yet to be explored, one of the reasons being the high molecular weights of the polymers. It would be an interesting issue to explore its use orally and therapeutically in human subjects, considering their anti-inflammatory, hypoglycemic, and anticoagulant/antithrombotic activities. However, the toxicity and bioavailability of such compounds are yet to be studied on humans. Although there are a large number of products on the market with biomass or extracts from microalgae, there are very few commercial products from polysaccharides isolated and purified on the market, but the outlook for such products is considered of major importance. Only a few patent applications on microalgae polysaccharides exist. However, the properties of polysaccharide-based products indicate great potential in the food and biomedical sectors.

Other areas of interest, due to their biochemical characteristics and rheological behavior, could be in engineering fields, such as naval (as drag-reducing agents), in food science/engineering, or in biomedical applications, as joint biolubricants and in arthritis treatment.

The extensive use of marine microalgae polysaccharides in these fields, however, would require a reliable supply of raw materials to guarantee the affordable price, sufficient purity, and constant high quality of these bioproducts. In addition, the possibility of obtaining polysaccharides in high quantities from modern microalgae biorefineries might be a competitive advantage with other sources.



This work was supported by National Funds from FCT through project PEst-OE/EQB/LA0016/2013.


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Maria Filomena de Jesus Raposo
    • 1
  • Alcina Maria Miranda Bernardo de Morais
    • 1
  • Rui Manuel Santos Costa de Morais
    • 1
    Email author
  1. 1.CBQF - Centro de Biotecnologia e Química Fina – Laboratório Associado, Escola Superior de BiotecnologiaUniversidade Católica Portuguesa/PortoPortoPortugal

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