Engineering a functional tendon-bone interface: mechanisms and prospects of magnesium alloys in promoting neurotized regeneration via modulating stem cell-nerve interplay.

OBJECTIVE

Conventional strategies for tendon-bone interface (TBI) repair primarily focus on structural healing, often overlooking the essential processes of neural regeneration and proprioceptive recovery required for functional restoration. This review aims to explore the potential of biodegradable magnesium (Mg) alloys and the released magnesium ions (Mg2 +) in establishing a "Mg2 +-Stem Cell-Nerve" axis as a novel strategic foundation for achieving neurotized regeneration at the TBI.

METHODS

This review provides a narrative synthesis of the existing literature on the roles of Mg2 + in regulating stem cell functions and promoting neural regeneration. A multidimensional perspective integrating "immunity-metabolism-nerve" interactions was adopted to dissect the underlying synergistic molecular mechanisms. Furthermore, the design of intelligent Mg-based implants predicated on this theory was discussed.

RESULTS

Analysis of the existing evidence suggests that Mg2 + may act as a pivotal bioactive signal, independently and synergistically regulating stem cell behavior and neural regeneration processes, thereby supporting the proposal of a conceptual "Mg2 +-Stem Cell-Nerve" axis. This proposed axis could theoretically synchronize structural repair and neural re-innervation of the TBI. Based on this mechanism, the design of intelligent Mg-based implants demonstrates significant potential for achieving spatiotemporally precise modulation.

CONCLUSION

Biodegradable Mg alloys, through the proposed "Mg2 +-Stem Cell-Nerve" axis, offer a promising paradigm for advancing TBI healing from structural integration toward neurotized functional regeneration. However, clinical translation remains at an early stage, requiring further validation in large-animal models, resolution of degradation control challenges, and rigorous long-term safety and efficacy evaluation. Although the proposed "Mg2 +-Stem Cell-Nerve" axis provides a novel integrative framework, it is important to note that its full sequential and closed-loop operation currently remains a working hypothesis derived from synthesizing fragmented pairwise evidence from disparate model systems, rather than a fully established pathway directly validated in the TBI microenvironment.