Role of crosslinkers in advancing chitosan-based biocomposite scaffolds for bone tissue engineering: A comprehensive review

Bone tissue engineering (BTE) aims to repair and regenerate damaged bone tissue by combining cells, scaffolds, and signaling molecules. Various macromolecules, including natural polymers like chitosan (CS), collagen, hyaluronic acid, and alginate, as well as synthetic polymers such as polyethylene glycol and polylactic acid, are used in scaffold fabrication. Among these, CS holds significant potential in BTE due to its biocompatibility, biodegradability, and other features. The inherent mechanical weaknesses of CS-based scaffolds require the implementation of crosslinking strategies to improve their stability and overall performance. Physical crosslinkers like ultra-violet irradiation and freeze-thaw cycles are biocompatible but offer limited mechanical strength. Chemical crosslinkers like glutaraldehyde significantly improve mechanical strength, but they may induce cytotoxicity. We briefly outline here the critical role of physical and chemical crosslinkers in improving the physicochemical properties, mechanical strength, biocompatibility, and biological functions of CS-based scaffolds, including effective bone regeneration. The influence of crosslinking on the CS-based scaffolds' bioactivity, including the controlled release of bioactive molecules, is also discussed. A thorough understanding of crosslinker chemistry and application in CS-based scaffolds is essential for advancing bone regeneration therapies.