Biodegradable materials: Applications and advances of magnesium alloys in bone defects

Abstract

Bone defects represent a significant clinical challenge with diverse etiologies, including but not limited to tumors, trauma, necrosis, and congenital deformities, imposing substantial patient suffering and socioeconomic burdens. In recent years, novel approaches for bone defect repair have been continuously explored. Biodegradable synthetic materials, particularly those capable of gradual decomposition during tissue regeneration processes, are recognized as ideal candidates for bone repair implants. Natural or synthetic polymer-based materials have been extensively employed in osteochondral repair due to their favorable biocompatibility. Furthermore, biodegradable magnesium (Mg)-based metals constitute another crucial category of bone substitutes. Mg alloys demonstrate unique advantages, including tunable degradation rates, excellent biocompatibility, appropriate mechanical strength, and remarkable osteogenic potential, positioning Mg-containing implants as a pivotal direction in bone regenerative medicine. However, clinical applications of Mg alloys still face challenges such as rapid degradation kinetics and insufficient osteogenic performance. Further investigation into advanced application strategies for Mg alloys holds significant clinical implications for bone defect therapeutics.

Key Words: Bone defects; Biodegradable synthetic materials; Magnesium alloys; Multiple mechanisms; Biocompatibility

Core Tip: Degradable magnesium (Mg) alloys have been extensively utilized in the treatment of bone defects owing to their superior mechanical properties, excellent biocompatibility, and potent osteogenic capabilities. Mg alloys enhance bone tissue regeneration via multiple mechanisms, including the bone-nerve circuit, promotion of vascular regeneration, modulation of the immune microenvironment, and upregulation of osteogenic signaling pathways. Additionally, Mg alloys have been engineered into diverse application forms, such as Mg-infused metallic scaffolds and Mg-based bone regeneration membranes. The therapeutic potential of Mg alloys for addressing bone defects warrants further investigation in future studies.

TO THE EDITOR

Bone is one of the most crucial connective tissues in the human body, offering mechanical support for muscle attachment and safeguarding internal organs[1]. Bone tissue possesses a certain capacity for repair and regeneration[2,3]. However, when the body experiences severe trauma, infection, tumors, or osteoporosis, its limited self-repair ability often leads to large-scale bone defects, significantly impacting patients’ quality of life[4,5]. Autologous bone and allogeneic bone transplantation have traditionally been the primary methods for addressing bone defects[6]. However, these approaches are associated with significant limitations, including donor site morbidity, limited availability of graft sources, and the risk of immune rejection[7,8]. Consequently, the development of novel bone implant materials has become an important focus within the field of bone regenerative medicine.

Recently, Pagani et al[9] conducted a systematic review of the application advancements of synthetic biomaterials in conjunction with fibrin within the field of bone regeneration. They provided an in-depth analysis of the significant therapeutic potential of fibrin-based biomaterials for addressing bone defects and proposed promising directions for future research[9]. The advantages of biodegradable implant materials as graft materials in bone defect repair are evident. These materials can be absorbed by the human body, thereby eliminating the necessity for secondary surgery to remove internal fixation devices[10]. It is important to highlight that magnesium (Mg) alloys exhibit mechanical properties analogous to those of natural bones and demonstrate exceptional osteogenic activity. Furthermore, they can be fully degraded within the body and are extensively utilized in the clinical management of bone diseases[11]. This advancement offers a novel direction for the utilization of Mg alloys in fracture treatment. Notably, our team has recently, for the first time, reported the successful and effective application of degradable Mg metal closure clips in achieving precise hemostasis for pelvic fractures[12]. This study aims to systematically elucidate the biological characteristics and functions of Mg alloys in facilitating bone defect repair, while comprehensively analyzing the advancements and challenges associated with their application in bone regeneration. This provides valuable insights for enhancing the reliability of Mg alloys in promoting bone repair.

Biological characteristics of Mg alloys utilized for bone defects repair

The widespread application of biodegradable medical Mg alloy materials in bone defect repair can be attributed to their superior biological properties, including a Young’s modulus closely matching that of cortical bone, excellent biocompatibility, and an appropriate natural degradation rate[13,14]. Mg alloys possess outstanding mechanical properties and are capable of providing adequate support strength for the regeneration of periosteal cells. The Young’s modulus of normal bone typically ranges from 3 GPa to 20 GPa, whereas that of Mg is approximately 45 GPa. In comparison to titanium alloys with a Young’s modulus of 110 GPa, Mg alloys exhibit a modulus closer to that of natural bone. This similarity significantly mitigates the stress shielding effect associated with internal fixation implants, thereby promoting optimal bone growth[15,16]. In addition, Mg alloys exhibit excellent biocompatibility. The primary degradation product of Mg is positively charged Mg ions, which play a critical role in bone development and reconstruction. And excessive Mg ions can be fully excreted via urine. One study has demonstrated that Mg alloys can significantly enhance the healing of tibial defects in vivo, while no adverse reactions have been reported[17]. Another study confirmed that the Mg scaffold LAE442 showed exceptional vascularization and cellular responses in vivo, thereby effectively facilitating bone healing[18]. Besides, the outstanding osteogenic properties of Mg alloys have been extensively validated in numerous studies. Zheng et al[19] found that fracture healing is modulated by the release of neuropeptides from peripheral sensory nerves, and the expression of calcitonin gene-related peptide can inhibit fibroblast differentiation while promoting callus formation. Furthermore, a Mg-containing hybrid intramedullary nail fixation system has been shown to enhance fracture healing by upregulating calcitonin gene-related peptide expression levels in vivo[19]. Vascularization serves as an essential prerequisite for bone formation. Liu et al[20] demonstrated that a Mg ion concentration of 5 mmol/L could enhance the secretion of MC3T3-E1 and platelet-derived growth factor, thereby effectively promoting angiogenesis and accelerating bone healing. Furthermore, Mg alloys are capable of directly stimulating bone formation via multiple pathways. For instance, nano-platforms incorporating Mg ions can effectively modulate the inflammatory microenvironment by inhibiting the nuclear factor kappa-B signaling pathway, thus facilitating bone remodeling[21]. Another study showed that ultra-high purity Mg and its alloy ZX00 can facilitate new bone formation by upregulating the expression levels of bone morphogenetic protein 2 and osteoprotegerin proteins[22]. In conclusion, Mg alloys exhibit multiple properties that are highly conducive to bone tissue regeneration (Figure 1). However, their excellent biological properties warrant further exploration and development to fully realize their potential in biomedical applications.

Figure 1 Magnesium alloys facilitate the repair of bone defects via multiple mechanisms. Mg: Magnesium.

The application forms of Mg alloy in repairing bone defects

The application of Mg alloys for bone defect filling or drug-loaded composite system fabrication represents a prominent research thrust in contemporary bone tissue engineering. Although Mg alloys have demonstrated promising potential as bone regeneration implant materials, their clinical application remains constrained by several factors, including hydrogen accumulation and the corrosion rate in physiological environments. To enhance the performance of Mg alloys effectively, a range of advanced modification technologies has been developed. Guo et al[23] fabricated a composite chitosan-Mg membrane by immersing Mg alloy in chitosan solution. This membrane demonstrated enhanced osteogenic activity in both in vivo and in vitro studies. Similarly, a subsequent study developed a dicalcium phosphate dihydrate (CaHPO₄·2H₂O)/MgF₂ Janus membrane, which was capable of effectively promoting periosteal regeneration[24]. Furthermore, Ye et al[25] developed a three-dimensional-printed porous Mg metal scaffold and applied a Sr-containing composite coating onto its surface. This design exhibited remarkable biocompatibility and osteogenic capacity in both in vitro and in vivo experiments[25]. Besides, another study prepared Mg-doped micro-nano bioactive glass, which has the potential to promote osteogenesis through the regulation of inflammatory responses[26]. Surface modification enhances the environmental adaptability and confers specialized functionalities to Mg alloys without altering their bulk properties. For instance, calcium orthophosphate coatings significantly improve corrosion resistance and biocompatibility of Mg-based substrates[27].

CONCLUSION

Biodegradable Mg alloys exhibit substantial advantages in bone defect repair owing to their degradability, superior mechanical properties, and osteogenic activity. In the future, it will be essential to further explore the role of Mg alloys in promoting osteogenesis via mechanisms such as inflammation inhibition, antibacterial properties, and regulation of the balance between osteoblasts and osteoclasts. Additionally, it is crucial to thoroughly investigate various application forms of Mg alloys to enhance their long-term effects on the human body. Furthermore, in the future, the biological properties of Mg alloys need to be further optimized, such as improving mechanical properties and controlling the degradation rate.