Multifunctional metal–organic cages accelerate tissue regeneration via regulating microenvironment and mediating endogenous growth factor production.

Objective: The repair of large-size skin and bone defects remains an important clinical challenge. On one hand, the microenvironment of trauma is complicated and affects the tissue regeneration. On the other hand, using exogenous growth factors is limited by poor stability, high cost, and dysfunction in a harmful microenvironment. Recently, a great deal of attention has been paid to the development of metal–organic frameworks (MOF) as alternative biomaterials. However, creating MOF with negligible cytotoxicity, excellent chemical stability, ROS scavenging ability, and functions regulating endogenous growth factor production remains challenging.

Results: We synthetized magnesium-seamed and zinc-seamed C-propylpyrogallol[4]arene (PgC₃Mg and PgC₃Zn, separately). These two kinds of metal–organic cages both exhibited excellent stability, biocompatibility, and efficient antioxidant properties. Afterward, we investigated the function of PgC₃Mg in bone regeneration and PgC₃Zn in wound healing. PgC₃Mg promoted osteogenic differentiation of bone-marrow-derived mesenchymal stem cells. In vivo results indicated that PgC₃Mg significantly accelerated cranial bone regeneration. PgC₃Mg functionalized GelMA hydrogel exhibited a better effect than commercial Bio-Gide membranes. Immunostaining showed that PgC₃Mg increased the formation of type H vessels and the expression of platelet-derived growth factor BB. For soft tissue repair, PgC₃Zn exerted a bacteriostatic effect against S. aureus and E. coli, and more significantly promoted proliferation and migration of L929 fibroblast cells compared with ZnCl₂. Animal experiments suggested that PgC₃Zn accelerated acute and that S. aureus infected skin defect healing. Histological staining revealed a high level of collagen deposition, epithelialization, and vascularization after PgC₃Zn treatment. Immunostaining revealed that PgC₃Zn remarkably increased the expression of TGF-β, EGF and VEGF growth factors.

Conclusion: All these results demonstrated that PgC₃Mg and PgC₃Zn are promising treatment strategies in tissue engineering, and have become potential alternative materials for multiple growth factors.