Advances in chitosan-based hydrogels: Evolution from covalently crosslinked systems to ionotropically crosslinked superabsorbents

Highlights

• This review discusses the recent advances & evolution of chitosan-based hydrogels.

• Distinctions into 3 gen. Are made based on crosslinks, stability, strength & toxicity.

• I gen. Comprises chemical & metal-coordinate crosslinks, which lack biocompatibility.

• II gen. Comprises physically crosslinks, which lack strength, but are biocompatible.

• III gen. Comprises dense physical crosslinks which contribute to strength & stability.

Abstract

Among the various physical forms of chitosan, viz. films, fibres, nanoparticles, gels, sponges, solution, etc., gels hold the most commercial importance. They are widely used in many areas, ranging from biomedicine to agriculture. This review discusses the recent advances in the chitosan-based hydrogels while highlighting its evolution from covalently crosslinked systems to ionotropically crosslinked super-absorbents. Distinctions into first, second and third generations of chitosan-based hydrogels are drawn based on the nature of crosslinks, environmental stability, mechanical strength and toxicity. While the first generation comprises chemically and metal-coordination crosslinked hydrogels, which were among the earliest to be identified, the second generation comprises of those physically crosslinked. Although the latter lack strength and stability, they are biocompatible in nature. The third generation, on the other hand, comprises of dense physical crosslinks that contribute to the strength and stability, without compromising on the biocompatibility.

Introduction

Hydrogels are three-dimensional macromolecular, hydrophilic networks, swollen in water or any other biological fluids [1]. For a material to be called a hydrogel, the storage modulus should dominate the loss modulus by at least an order of magnitude and the material should retain at least 10 wt% of the water or biological fluids [2]. These hydrogels find widespread applications in various fields, ranging from biomedicine to agriculture. Although several naturally occurring gel-forming materials have been known for many centuries, serious developments began only after the early 1960s, when the first synthetic hydrogel based on crosslinked poly(2-hydroxyethyl methacrylate) was developed. [3]. Generally, these macromolecular networks are made by crosslinking polymers. Often, groups such as -NH₂, –COOH, –OH, -CONH₂, -CONH- and -SO₃H on the crosslinked polymer chain contribute to the hydrophilicity of the network [2].

Based on the origin of the polymers, the hydrogels thereof are broadly classified into natural and synthetic [4]. While the natural hydrogels are made up of polysaccharides (e.g. starch, chitosan, alginates, hyaluronic acid, agarose, etc.), proteins (e.g. collagen, gelatin, etc.) or mucilages (e.g. gum acacia, guar gum, psyllium seed husks' mucilage, flax seeds mucilage, etc.), the synthetic ones are based on synthetic polymers such as poly(hydroxyethyl methacrylate), poly(acrylamide), poly(acrylic acid-co-acrylamide), poly(vinyl alcohol), poly(ethylene glycol) diacrylate, etc. Natural hydrogels are, in general, non-toxic in nature and find extensive use in biomedicine and tissue engineering. However, they are limited in their application, owing to their inferior mechanical properties, and batch-to-batch inconsistencies in their properties. These limitations are overcome by synthetic hydrogels. Although synthetic gels have better mechanical properties, stability, and batch-to-batch homogeneity, they are limited by biocompatibility and biodegradability. Hydrogels are also categorized into chemical, physical and metal-coordinate hydrogels, based on the nature of crosslinks [4]. Chemical hydrogels involve crosslinking of two or more polymers by covalent bonding while physical hydrogels involve crosslinking of polymers by physical forces such as H-bonding, electrostatic interactions or hydrophobic forces. Metal-coordinate hydrogels, on the other hand, involve crosslinks comprising metal-ligand coordination bonds. Likewise, classifications based on the ionic charge (cationic, anionic and neutral) and composition (homopolymeric, copolymeric and interpenetrating) are also common [2,5]. The classification of hydrogels, on the basis of the source, nature of crosslinks, composition and ionic charge are presented in Fig. 1.

Biopolymers, in general, offer good properties and are available in abundance, whilst being biodegradable. Chitin is one such biopolymer, widely referred to as the “cellulose of the sea” [6]. Second only to cellulose in abundance, it is extracted from the exoskeleton of crustaceans such as crabs, prawns, lobsters, etc. and the cell-wall of few fungi [[7], [8], [9]]. Chemically, it is a polymer of N-acetyl D-glucosamine, with fewer units [10] of D-glucosamine (not more than 50%). The extensive intra and intermolecular H-bonding in chitin, prevent thermal transitions and solubility of the biopolymer in organic solvents, limiting the applications of this biomaterial [11]. However, when deacetylated to a degree greater than 50%, the copolymer becomes soluble in mildly acidic solutions (pH less than or equal to 6.5) [12]. This polymer, containing more than 50% of D-glucosamine fraction, is referred to as chitosan. Apart from being biocompatible, biodegradable and mechanically strong, the amine groups on chitosan make it haemostatic, antibacterial, antifungal, anticholesteremic and mucoadhesive in nature [13]. The chemical structures of chitin and chitosan are presented in Fig. 2.

Due to its ability to be processed in solution form and the presence of amine and hydroxyl reactive “handles”, which allow easy modification, chitosan is widely used in many applications, unlike its acetylated counterpart. Having wound-healing and haemostatic properties, it has been used in biomedical sutures and bandages [11]. Also being bioresorbable and biocompatible, whilst having good mechanical properties, it has been used for making scaffolds for tissue engineering [14]. It is also used in cosmetics due to its biocompatibility, ability to hold moisture, whilst being non-allergenic and non-toxic in nature [10]. Being a polycation in its acidic solution, chitosan has also been used to flocculate or coagulate negatively-charged organic and inorganic impurities from wastewater. It has also been extensively studied to adsorb heavy metal ions from wastewater resources [15]. In the pharmaceutical domain, crosslinked chitosan particles and hydrogels have been used as targeted drug carriers, capable of controlled drug release [16,17]. Apart from usage as drug carriers, chitosan has also been suggested for use as an Active Pharmaceutical Ingredient (API) for the treatment of ulcers [18]. In agriculture, chitosan has been used as protective coatings for seeds and as foliar treatment agents, due to its antimicrobial nature [19]. Much research has also been done on using chitosan hydrogels in agriculture for the sustained release of water [10,20]. Clearly, hydrogels of chitosan hold the most commercial importance [21], among all other physical forms. This review sheds light on the three generations of chitosan-based hydrogels, distinguished on the basis of nature of crosslinks, environmental stability, mechanical strength and toxicity of the crosslinked systems.

Applications of chitosan in various fields have been continuously, on the rise. This is reflected from the exponential increase in the number of patent applications published, relating to chitosan, in the preceding years. One aim of this review is to shed light on such most recent advances in the field of chitosan and more particularly in regard to chitosan-based hydrogels. In addition, given the widespread application of chitosan-based hydrogels in fields like biomedicine, agriculture and cosmetics, it becomes important to draw distinctions on the basis of nature of crosslinks (and thereby toxicity), mechanical and environmental–strength and stability, in light of which, this review become important. Furthermore, this review also dedicates much-needed attention to ionotropic, chitosan-based superabsorbents and how it has evolved from non-absorbing covalently crosslinked systems. The number of patent applications published yearly, relating to chitosan, is presented in Fig. 3.