Cellulose nanofibers reinforced biomimetic hydrogel featuring orthogonal anisotropic architecture for guiding BMSCs directional migration and osteogenic differentiation

Natural trabecular bone is typically a complex 3D honeycomb-like material, which can influence the behavior of bone marrow mesenchymal stem cells (BMSCs), particularly their migration and differentiation direction. However, engineering such biomimetic hydrogels with an orthogonal anisotropic structure similar with trabecular bone via a universal and scalable manner still poses a great challenge. This study develops a cellulose nanofiber (CNF) reinforced composite hydrogel with an orthogonal anisotropic structure, which exhibits a highly aligned fibrous configuration and structural densification, endowing it with excellent mechanical properties and damage-tolerant architectures. Moreover, compared with the composite hydrogel with uniaxially anisotropic structure, this as-developed composite hydrogel with orthogonal anisotropic structure utilizes the interactions between rigid and flexible components to form an anisotropic network structure in orthogonal directions, mimicking the microscopic interactions between collagen fibers and proteoglycans in natural ECMs. It could not only facilitate the physical alignment and directional migration of BMSCs, but also enhance their proliferation and differentiation into osteoblasts. Overall, replicating the structure and properties of natural trabecular bone enhances insights into cellular mechanisms, but also improves the efficiency of bone regenerative medicine treatments.