Elsevier

Biomaterials

Volume 33, Issue 11, April 2012, Pages 3279-3305
Biomaterials

Review
Alginate derivatization: A review of chemistry, properties and applications

https://doi.org/10.1016/j.biomaterials.2012.01.007Get rights and content

Abstract

Alginates have become an extremely important family of polysaccharides because of their utility in preparing hydrogels at mild pH and temperature conditions, suitable for sensitive biomolecules like proteins and nucleic acids, and even for living cells such as islets of Langerhans. In addition, the complex monosaccharide sequences of alginates, and our growing ability to create controlled sequences by the action of isolated epimerases upon the alginate precursor poly(mannuronic acid), create remarkable opportunities for understanding the relationship of properties to sequence in natural alginates (control of monosaccharide sequence being perhaps the greatest synthetic challenge in polysaccharide chemistry). There is however a trend in recent years to create “value-added” alginates, by performing derivatization reactions on the polysaccharide backbone. For example, chemical derivatization may enable alginates to achieve enhanced hydroxyapatite (HAP) nucleation and growth, heparin-like anticoagulation properties, improved cell–surface interactions, degradability, or tuning of the hydrophobic-hydrophilic balance for optimum drug release. The creation of synthetic derivatives therefore has the potential to empower the next generation of applications for alginates. Herein we review progress towards controlled synthesis of alginate derivatives, and the properties and applications of these derivatives.

Introduction

Alginates are unbranched polysaccharides consisting of 1→4 linked β-d-mannuronic acid (M) and its C-5 epimer α-l-guluronic acid (G). The natural copolymer is an important component of algae such as kelp, and is also an exopolysaccharide of bacteria including Pseudomonas aeruginosa. It is comprised of sequences of M (M-blocks) and G (G-blocks) residues interspersed with MG sequences (MG-blocks). While it is possible to obtain alginates from both algal and bacterial sources, commercially available alginates currently come only from algae. The copolymer composition, sequence and molecular weights vary with the source and species that produce the copolymer. Due to the abundance of algae in water bodies, there is a large amount of alginate material present in nature. Industrial alginate production is approximately 30,000 metric tons annually, and is estimated to comprise less than 10% of the biosynthesized alginate material [1]. Therefore there is significant additional potential to design sustainable biomaterials based on alginates. The combination of chemical and biochemical techniques provides considerable potential for creating modified alginic acid derivatives with control over monosaccharide sequence and nature, location and quantity of substituents. This in turn enables the tailoring of alginate derivative properties such as solubility, hydrophobicity, affinity for specific proteins, and many others. Such modifications are complicated by key alginic acid properties including solubility, pH sensitivity, and complexity (which can make both synthetic control and analysis difficult). Both the promise and the difficulty of alginate modification have attracted much effort towards controlled derivatization.

The significance of alginates as natural polysaccharides in biomedicine can hardly be overstated. Alginates are currently used as wound dressing materials for the treatment of acute or chronic wounds [2]. They also play a crucial part in the progression of cystic fibrosis, wherein bacterial biofilms formed from alginate gels are secreted by P. aeruginosa [3]. More importantly, the use of alginate crosslinking to make hydrogels for cell encapsulation has proved to be most advantageous for biomedical applications [4], [5], [6]. Worthy of mention is the role played by alginates gels in encapsulating islets of Langerhans for diabetes treatment [7]. Chemical modification of alginates is used as a tool to attain one of two ends – (A) enhance existing properties (example: improvement of ionic gel strength by additional covalent crosslinking, increase hydrophobicity of the backbone, improve biodegradation, or achieve greater HAP nucleation and growth), or (B) introduce completely new properties otherwise not existing in unmodified alginates (example: afford anticoagulant properties, provide chemical/biochemical anchors to interact with cell surfaces or bestow temperature dependent characteristics such as lower critical solution temperature). In short, alginate derivatization is the most convenient way to achieve both inherent property enhancement and new property introduction. We herein review the chemical routes to such modifications, and the resulting properties achieved.

Section snippets

Biosynthesis of alginates

Recent progress in biosynthesis of bacterial alginates has been reviewed in several excellent articles [8], [9], [10], [11]. Alginate biosynthesis (Fig. 1) involves the oxidation of a carbon source to acetyl-CoA, which enters the TCA cycle to be converted to fructose-6-phosphate via gluconeogenesis. Fructose-6-phosphate then undergoes a series of biosynthetic transformations to be eventually converted to GDP-mannuronic acid, which acts as a precursor to alginate synthesis. In general, the

Alginate modification

The derivatization and design strategies for alginates depend on three important parameters: solubility, reactivity and characterization (Fig. 8). (A) Solubility: alginates may be dissolved in aqueous, organic or mixed aqueous-organic media for derivatization. The choice of solvent system can dictate the type of reagents that may be used for modification. In addition, the degree of alginate solubility in the solvent system can impact derivative substitution pattern. (B) Reactivity: alginates

Conclusions and prospects

Advances in the biochemistry of the complex alginate polysaccharides have provided opportunities to control monosaccharide sequence that are unique in polysaccharide chemistry [131]. This provides insight into the structure-property relationships of alginates that can illuminate its important natural functions, for example in structural gels in kelp and in protective bacterial films made by P. aeruginosa (which play a critical part in the progression of cystic fibrosis [3]). The developing

Acknowledgements

We gratefully acknowledge support for SNP from USDA NIFA grant number 2010-34489-20784, and from the Sustainable Engineered Materials Institute at Virginia Tech, the Institute for Critical Technology and Applied Science for facility support, and the Macromolecules and Interfaces Institute for educational support.

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