Degradation products of magnesium implant synergistically enhance bone regeneration: Unraveling the roles of hydrogen gas and alkaline environment

Abstract

Biodegradable magnesium (Mg) implant generally provides temporary fracture fixation and facilitates bone regeneration. However, the exact effects of generated Mg ions (Mg2+), hydrogen gas (H2), and hydroxide ions (OH-) by Mg degradation on enhancing fracture healing are not fully understood. Here we investigate the in vivo degradation of Mg intramedullary nail (Mg-IMN), revealing the generation of these degradation products around the fracture site during early stages. Bulk-RNA seq indicates that H2 and alkaline pH increase periosteal cell proliferation, while Mg2+ may mainly enhance extracellular matrix formation and cell adhesion in the femur ex vivo. In vivo studies further reveal that H2, Mg2+ and alkaline pH individually generate comparable effects to the enhanced bone regeneration in the Mg-IMN group. Mechanistically, the degradation products elevate sensory calcitonin gene-related peptide (CGRP) and simultaneously suppress adrenergic factors in newly formed bone. H2 and Mg2+, instead of alkaline pH, increase CGRP synthesis and inhibit adrenergic receptors. Our findings, for the first time, elucidate that Mg2+, H2, and alkaline pH environment generated by Mg-IMN act distinctly and synergistically mediated by the skeletal interoceptive regulation to accelerate bone regeneration. These findings may advance the understanding on biological functions of Mg-IMN in fracture repair and even other bone disorders.

Study details

Article type

Original Research

Disease / injury model

Osteoporotic bone fracture (OVX-induced osteoporosis)

Duration

15 days

Dose comparison

Different concentrations and forms of Mg2+, H2, and alkaline pH were compared for their effects on bone regeneration, including time-course and spatial distribution of H2 and pH.

Dose-dependent effect

Yes

Outcome

Positive

Findings

The study demonstrates that the degradation products of magnesium implants—Mg2+, H2, and alkaline pH—are generated locally at the fracture site and each individually and synergistically enhance bone regeneration. Mechanistically, these products activate sensory CGRP pathways and suppress sympathetic adrenergic signaling, accelerating bone healing.