Harnessing Cross-Linked Cysteine Scaffolds for Soft Tissue Engineering Applications

Biomaterials are either cross-linked ionically, chemically, or physically, or they can be functionalized with amino acids to overcome inherent biocompatibility and stability limitations. Hydrogels for scaffold fabrication have been effectively utilized to promote tissue integration and cellular processes for soft tissue regeneration. Despite significant progress, poor remodeling limitations persist, hence the need for cross-linkers with dynamic adaptability, native tissue mimicry, and controllable degradation. The aim of this review is to highlight cysteine's capability and potential to cross-link biomaterials using thiol chemistry while discussing the different cross-linking strategies to aid in the fabrication of robust hydrogel inks and bioinks. Furthermore, cysteine's limitations and research scarcity in soft tissue scaffolds are highlighted for its chemical significance and potential role. The review examines cysteine's thiol reactions, including disulfide bonds, thiol-ene, thiol-yne, and Michael additions, and cross-linking ability, with a specialized focus on adipose tissue regeneration. The fabrication methods reviewed include 3D bioprinting, electrospinning, films, and nanostructured scaffolds, with a primary focus on 3D bioprinting of hydrogel scaffolds. Cysteine cross-linking enhances the scaffolds' stability, printability, biocompatibility, degradability, and biological performance of scaffolds with an 85% increase in Young's modulus. Cysteine adequately enhances the mechanical properties and degradation rates of adipose tissue scaffolds. This review addresses the underexplored use of cysteine cross-linking in soft tissue scaffolds, beyond its common bone tissue applications.