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 (Mg 2+ ), hydrogen gas (H 2 ), 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 H 2 and alkaline pH increase periosteal cell proliferation, while Mg 2+ may mainly enhance extracellular matrix formation and cell adhesion in the femur ex vivo . In vivo studies further reveal that H 2 , Mg 2+ 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. H 2 and Mg 2+ , instead of alkaline pH, increase CGRP synthesis and inhibit adrenergic receptors. Our findings, for the first time, elucidate that Mg 2+ , H 2 , 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. • H 2 and alkaline pH are mainly generated around the implant-fracture site during the early osteoporotic fracture healing. • H 2 and alkaline pH increase periosteal cell proliferation, while Mg 2+ mainly enhance ECM formation and cell adhesion in ex vivo femur. • H 2 , alkaline pH, and Mg 2+ each contributed to improved bone regeneration in the Mg-IMN group. • H 2 , alkaline pH, and Mg 2+ activate sensory nerves while suppress adrenergic signaling in bone regeneration.