Cross-linking Collagen Using Divalent Metal Ions

Cross-linking collagen with high-valent metal ions such as Cr(III), Zr(IV), Fe(III), and Al(III) significantly enhances its physicochemical properties, making collagen-based materials suitable for advanced applications. However, the use of high-valent metal ions is limited by concerns regarding toxicity, redox instability, and low cross-linking efficiency. Here, we present a proof-of-concept demonstrating that nontoxic, stable divalent metal ions (M(II), such as Mg(II), Ca(II)), previously considered ineffective for collagen cross-linking, can facilitate linkage formation within collagen. This is achieved through selective binding of molecularly engineered cucurbit[7]uril to aromatic residues (Phe/Tyr) in collagen, creating tailored coordination sites for M(II). The resulting cross-linking efficiency rivals or exceeds that of high-valent metal ions, with in vitro experiments confirming the nontoxic nature of M(II)-cross-linked collagen. This study expands the repertoire of metal ions capable of cross-linking collagen, addressing the limitations associated with high-valent metal ions and potentially enabling the development of high-performance, biocompatible collagen-based materials.