Magnesium-loaded anisotropic hydrogel promotes tendon healing via combined immunomodulation and collagen remodeling

Poor tendon healing remains a challenging clinical problem. An ideal repair scaffold should create a favorable microenvironment for dynamic regeneration, including inflammation control, cell proliferation promotion, revascularization, and collagen remodeling. Herein, a dynamic self-adaptive hydrogel scaffold was developed using non-covalent crosslinking and pre-stretching-induced alignment. This biomimetic scaffold integrates tendon-inspired anisotropic surface topography, excellent mechanical properties, anti-inflammatory capacity, and a bioactive ion release gradient, enabling rapid construction of a favorable regenerative microenvironment. In vitro experiments confirmed that the scaffold significantly reduced TNF-α secretion, inhibited macrophage polarization toward the M1 phenotype, promoted the migration, proliferation, and differentiation of tendon stem cells (TSPCs), and enhanced endothelial cell migration, tube formation, and angiogenic factor expression. Meanwhile, in vivo results further demonstrated that the magnesium ion (Mg²⁺)-loaded anisotropic scaffold significantly increased the M2 macrophages proportion and IL-10 expression, while markedly reducing tissue adhesion. Moreover, endogenous tendon regeneration was significantly enhanced, as evidenced by activation of the HIF1-α/VEGF pathway, a clearly visible vascular network within the tissue, significantly improved proliferation and differentiation capabilities of TSPCs, abundant and well-aligned collagen expression, and substantially enhanced mechanical properties. By integrating the physiological tendon regeneration processes, this biomimetic multifunctional scaffold offers a promising strategy for accelerating tendon regeneration.