Progress on green crosslinking of polysaccharide hydrogels for drug delivery and tissue engineering applications

Natural polysaccharides are being studied for their biocompatibility, biodegradability, low toxicity, and low cost in the fabrication of various hydrogel devices. However, due to their insufficient physicochemical and mechanical qualities, polysaccharide hydrogels alone are not acceptable for biological applications. Various synthetic crosslinkers have been tested to overcome the drawbacks of standalone polysaccharide hydrogels; however, the presence of toxic residual crosslinkers, the generation of toxic by-products following biodegradation, and the requirement of toxic organic solvents for processing pose challenges in achieving the desired non-toxic biomaterials. Natural crosslinkers such as citric acid, tannic acid, vanillin, gallic acid, ferulic acid, proanthocyanidins, phytic acid, squaric acid, and epigallocatechin have been used to generate polysaccharide-based hydrogels in recent years. Various polysaccharides, including cellulose, alginate, pectin, hyaluronic acid, and chitosan, have been hydrogelized and investigated for their potential in drug delivery and tissue engineering applications using natural crosslinkers. We attempted to provide an overview of the synthesis of polysaccharide-based hydrogel systems (films, complex nanoparticles, microspheres, and porous scaffolds) based on green crosslinkers, as well as a description of the mechanism of crosslinking and properties with a special emphasis on drug delivery, and tissue engineering applications.