Objective The natural collagen extracted from biological tissues generally exhibits defects such as insufficient mechanical strength and poor enzymatic stability, which limit its applications in many fields including wound healing, tissue engineering, and drug delivery. Although the conventional covalent crosslinking strategies can improve collagen’s mechanical performance, they inevitably consume active sites of collagen such as carboxyl and amino groups, thereby impairing the biological functions of collagen. In contrast, supramolecular crosslinking dynamically regulates collagen molecular networks through hydrogen bonding and other noncovalent interactions. This approach not only markedly enhances the mechanical strength and enzymatic resistance of collagen but also preserves its bioactive sites to the greatest extent, making it a research hotspot in the field of biomedical materials. Hence, systematic elucidation of the mechanisms of supramolecular crosslinking, together with a summary of recent progress of this technology in collagen-based biomaterials, an analysis of current technical bottlenecks, and a perspective on the future development directions, will provide valuable insights for the development of novel crosslinking strategies and the preparation of high-performance collagen-based biomedical materials.

Progress In recent years, researchers have utilized noncovalent interactions such as hydrogen bonding, electrostatic attraction, hydrophobic interactions, metal coordination, and host-guest chemistry to construct dynamic and reversible supramolecular crosslinking networks among collagen molecules. This technology has successfully addressed the long-standing trade-off between physicochemical performance and biological activity of collagen-based materials, showing significant application potential in fields such as wound healing, tissue engineering, and drug delivery. For example, exogenous molecules (e.g. pomegranate tannin, polyvinylpyrrolidone), containing polar groups such as phenolic hydroxyl groups and amino groups, can form hydrogen bonds with polar amino acid residues of collagen, thereby establishing the crosslinking networks among collagen molecules that substantially enhance the mechanical stability of collagen. Electrostatic crosslinking, which utilizes the strong ionic interactions between positively charged and negatively charged amino acid residues in collagen molecules to construct a dynamic crosslinking network, imparts collagen pH-responsive behavior and thus enables the “on-demand” drug release that is widely used in drug controlled-release systems. Hydrophobic crosslinking constructs a dynamic network through the hydrophobic interactions among nonpolar groups to improve the stability of collagen and exhibits reversible strengthening or weakening with temperature changes, making it particularly attractive for thermosensitive hydrogels. In addition, metal coordination crosslinking employs metal ions such as Zr⁴⁺, Fe³⁺, and Zn²⁺ as “bridges” to form coordination bonds with carboxyl or amino groups of collagen, thereby reinforcing its mechanical properties. Depending on the differences in coordination characteristics, dynamic monodentate systems such as Zn²⁺ are suitable for short-term mechanical support applications like acute wound dressings, while rigid bidentate systems such as Zr⁴⁺ can provide long-term structural stability for cartilage tissue engineering scaffolds. Moreover, host-guest chemistry allows selective encapsulation of collagen’s aromatic residues by macrocyclic host molecules such as cyclodextrins and cucurbiturils, followed by chemical conjugation via functional groups on the host macromolecules. This strategy can endow collagen with the ability of dynamic crosslinking tunability while preserving its biological activity. Despite these advances, several challenges hinder clinical applications of this technology. For example, the single crosslinking mechanism often fails to meet requirements for both mechanical reinforcement and functional adaptation; some supramolecular crosslinkers have problems such as complex synthesis processes and poor biocompatibility; and ionic shielding or competitive binding in physiological environments may weaken crosslinking efficiency.

Prospect Future work should focus on developing synergistic multi-mechanism crosslinking strategies that integrate the advantages of different noncovalent interactions to achieve cooperative enhancement of material properties. At the same time, it is also essential to optimize the molecular structures of supramolecular crosslinkers to improve their biocompatibility and crosslinking efficiency while simplifying their synthesis processes to reduce the costs and enable large-scale production and application. Furthermore, incorporating biomimetic design principles to create collagen-based biomaterials with hierarchical structures and intelligent responsiveness will be key to advancing their biomedical applications.