Polyelectrolyte Complexes Based on Chitosan and Natural Polymers

For many years chitosan has been the subject of interest for its use in different medical fields due to its appealing properties such as biocompatibility, biodegradability, low toxicity and relatively low production cost from abundant natural sources. Chitosan is positively charged at low pH values, so it is spontaneously associated with negatively charged polyions in solution to form polyelectrolyte complexes. These chitosan based polyelectrolyte complexes exhibit favourable physicochemical properties with preservation of chitosan’s biocompatible characteristics. These chitosan based complexes are a good candidate for excipient materials for the design of different types of dosage forms. The aim of this review is to describe polyelectrolyte complexes of chitosan with selected natural polyanions and also to indicate some of the factors that influence the formation and stability of these formed complexes.


INTRODUCTION
Chitosan is a combination of a series of polymers that are deacetylated derivatives of chitin,a natural polysaccharide,and presents different degrees of deacetylation and molecular weights.It consists of deacetylated units of β-1,4-linked glucosamine and acetylated units of N-acetyl-D-glusoamine (Figure 1).Chitosan presents typical degrees of deacetylation between 70 and 95% and molecular weights between 10 and 1,000 kDa [1,2] .It was reported that highly refined grades of chitosan have been used in pharmaceutical formulations as a release-controlling agent [3].
It was shown that the cationic amino groups on the C2 position of the repeating glucopyranose units of chitosan can interact electrostatically with the anionic groups (usually carboxylic acid groups) of other polyions to form polyelectrolyte complexes.Many different polyanions from natural origin (e.g.pectin, alginate, carrageenan, xanthan gum, carboxymethyl cellulose, chondroitin sulphate, dextran sulphate, hyaluronic acid) or synthetic origin (e.g., poly (acrylic acid)), polyphosphoric acid, poly (L-lactide) have been used to form polyelectrolyte complexes with chitosan in order to provide the required physicochemical properties for the design of specific pharmaceutical formulations [4].
Thoughout the years chitosan complexes have been used in a wide range of pharmaceutical applications such as complexes formed between chitosan and anionic polymers for use as biosensors, scaffolds in tissue engineering, for wastewater treatment and for drug delivery in different forms [5,6].
Most of the investigated and studied polycomplexes that involve chitosan are those formed with other polysaccharides, which are divided into natural polysaccharides (including phytopolysaccharides, zoopolysaccharides and microorganism polysaccharides) and synthetic polysaccharides [7] Figure 1.Chemical structure of chitosan consisting of N-acetyl-D-glucosamine and glucosamine units.

RESEARCH METHODS
Natural polymers are widely used in the regenerative field of medicine, for wounds and burns dressing because of their unique properties such as biocompatibility, biodegradability and similarity to macromolecules recognized by the human body.
The selection of the natural polymers in this review was based on the complexing capacity with chitosan.The structural characteristics are presented, as well as the therapeutical effects and data on the biodegradability of these complexes in comparation with data from ohter reseaches and specialty literature.

RESULTS AND DISCUSSIONS
Polyelectrolyte Complexes between Chitosan and Natural Polymers 1.
In order to form a polyelectrolyte complex, the negatively charged carboxylic acid groups of manuronic and guluronic acid units in alginate interact electrostatically with the positively charged amino groups of chitosan.
Due to the biodegradability and biocompatibility of the polyelectrolyte complex formed between these two polymers, alginate is one of the most studied anionic polyelectrolytes in complexation with chitosan.This polyelectrolyte complex is mechanically stronger at lower pH values where chitosan dissolves [10].A study on the biodegradation of chitosan-alginate polyelectrolyte complexes showed that while chitosan alone, with a low degree of deacetylation, was effectively degraded by lysozymes, the effect of these enzymes on the polyelectrolyte complex was negligible.The ability of the polyelectrolyte complex of lysozyme absorbtion was high, but enzymatic degradation was hindered by the strong interaction between the chitosan and alginate polymeric chains.
Since it was demosntrated that the rate of biodegradation may be regulated by changing the polymer ratio, it indicates that this particular polyelectrolyte complex has a high potential in tissue engineering for scaffolds and support materials [11].
Chitosan-alginate polyelectrolyte complex fibers showed promising results for controlling the release of charged molecules and exhibited high encapsulation efficiencies of these molecules [12].

Chitosan-carrageenan polyelectrolyte complex
Carrageenan is the generic name for a family of high molecular weight sulphated polysaccharides obtained from certain species of red seaweeds.There are three basic types of carrageenan, namely kappa (κ), iota (ι) and lambda (λ) carrageenan (Figure 3) [13,14].Recent reports have shown that the nature or type of carrageenan considerably influence the characteristics of the polyelectrolyte complex that is formed with chitosan.The mechanical strength of polyelectrolyte complex gels formed between chitosan and different carrageenans were in the order λ-> ι-> κ-carrageenan.The gels obtained for ι-and κcarrageenan were temperature sensitive because of the helix-coil conformational transitions in their molecules [15].

Chitosan-pectin polyelectrolyte complex
Pectin is a linear polysaccharide composed of α-1,4-linked D-galacturonic acid units, however, this linear structure is interrupted with highly branched regions in the polymer chain (Figure 4).The composition of the pectin molecule varies from source to source, e.g.pectin from citrus fruit contains less neutral sugars and has a smaller molecular size than pectin from apples [16,17].A homogenous solution is obtained when acidic chitosan and pectin solutions are mixed without any ionic interactions between the two polymers.At a value of pH of 5.5 the electrostatic interactions between the 104 negatively charged carboxylic acid groups of pectin and the positively charged amino groups of chitosan can occurre.Furthermore, by adjusting the pH of this mixture a polyelectrolyte complex could be obtained.As expected, the extent of this interaction depended on the pH of the surrounding medium which determined the extent of ionization of the polymers [6].

Chitosan-xanthan gum polyelectrolyte complex
Xanthan gum is an exopolysaccharide secreted from Xanthomonas campestris.
It is produced by bacterial fermentation of streptococcus species or by extraction processes from rooster combs, umbilical cords, synovial fluids or vitreous humour for commercial purposes.Hyaluronic acid has many applications in the medical field beeing used in ophthalmic surgery, arthritis treatment, in tissue engineering, a component of scaffolds for wound healing and implant devices [2,20,21].Recent studies have shown that the polyelectrolyte complex between chitosan and hyaluronic acid protected hyaluronic acid against enzymatic hydrolysis, but only at pH values different from the optimal pH of the enzyme.The results from this studies revealed that the chitosan-hyaluronic acid polyelectrolyte complex unfortunately had less cell proliferation and wound healing effects compared to chitosan alone [22].

Chitosan-gelatine polyelectrolyte complex
Gelatine is a heterogeneous mixture of protein fractions consisting of single or multi-stranded polypeptides (Figure 7).The process of obtaining gelatine is by partial hydrolysis of animal collagen derived from skin, white connective tissues and bones.There are two tipes og gelatine: type A and type B. Type A gelatine is derived from pig skin by using acid hydrolysis and type B gelatine is obtained by alkaline hydrolysis of cattle hides and bones [23].
It was shown that the polyelectrolyte complex between chitosan and gelatine can only occur at a pH value above 4.7 and below 6.2.Above this value the net charge on gelatine type B is negative.A pH value of 4.7 represents the isoelectric point of gelatin.Above a pH value of 6.2 chitosan start to precipitate out of solution.[24].
Natural polymers are involved in the repair of damaged tissues and in skin regeneration by Inducing and stimulating the wound healing process.Biomaterial hydrogels are engaged in the pharmaceutical and biomedical area, due to their threedimensional cross-linked polymeric networks that are soaked with water or biological fluids, and are used especially for wound management, tissue engineering, drug delivery, and organ transplant.Hydrogels containing crosslinked natural polymers and polyelectrolyte complexes can be used for wounds and burns dressing.

CONCLUSION
Polyelectrolyte complexes combine unique physico-chemical properties of different polymers with the advantage of retaining high biocompatibility.It is therefore not surprising that polyelectrolyte complexes are gaining importance in modern pharmaceutical technology.In the management of wounds and burns dressings play an important role.The use of threedimensional polymeric scaffolds for cell targeting is already a common strategy for tissue engineering.Recent studies upon the properties of natural polymers (biocompatibility and biodegradability) will lead to a substantial development of novel types of wound dressings and to outstanding applications for regenerative medicine.
In the present, the most promising materials for wounds and burns dressing are still based on natural polymers such as polysaccharides (alginates, chitin, chitosan), proteoglycans and proteins (collagen, gelatin, fibrin, keratin, silk fibroin, eggshell membrane).

Figure 5 .
Figure 5.Chemical structure of xanthan gum