Hydrogen releasing biomaterials for bone regeneration: mechanisms, design strategies, and applications

Abstract

Complex bone defects remain major clinical challenges due to their multifaceted pathological microenvironment. In recent years, hydrogen (H2) therapy has emerged as a rapidly developing strategy for bone repair, leveraging its redox-regulatory and other microenvironment-modulating effects. However, the rapid diffusion and short retention time of H2 limit its direct clinical application. The development of H2-releasing biomaterials partially addresses these limitations and offers a synergistic approach that integrates gas therapy with bone tissue engineering. Although recent studies on H2-releasing systems for bone regeneration have markedly increased, a dedicated review in this field remains absent. To address this gap, this review summarizes the pathological features of bone defect microenvironments and the multi-target biological mechanisms of H2 relevant to bone repair. It then discusses design objectives, optimization strategies, and classifications of H2-releasing biomaterials. Recent advances in their applications for bone regeneration are highlighted with an emphasis on material design and functional performance. Cross-disciplinary insights are also introduced to inspire next-generation H2-releasing systems for bone regeneration. Finally, the limitations and clinical translation challenges of such systems are critically discussed, and future research directions are proposed. H2-releasing biomaterials integrate gas therapy, materials engineering, and microenvironmental regulation, representing an emerging frontier for multi-mechanism synergistic bone regeneration.