The role of magnesium hydrogels in bone regeneration: a systematic review and meta-analysis

Abstract

Magnesium, an essential element in human physiology, is predominantly located in bone tissue. Since the early 20th century, magnesium-based biomaterials have demonstrated osteoinductive and angiogenic potential, positioning them as promising candidates for bone regeneration strategies. Hydrogels, composed of crosslinked hydrophilic polymers, provide a three-dimensional microenvironment mimicking the extracellular matrix (ECM), thereby supporting cell adhesion, nutrient diffusion, and controlled release of bioactive ions such as Mg²⁺. Recent advances in material science have enabled the design of multifunctional magnesium-loaded hydrogels that synergistically combine mechanical stability, immunomodulation, and spatiotemporal Mg²⁺ release to address critical-sized bone defects. This review systematically examines hydrogel classifications and elucidates magnesium-mediated biological signaling pathways that drive bone repair. A meta-analysis of 10 studies retrieved from PubMed, Web of Science, Scopus, and Embase was performed to assess the efficacy of magnesium-containing hydrogels in bone repair. The findings demonstrate that magnesium significantly enhances bone repair processes, underscoring its potential as a therapeutic agent for bone defect treatment.

Graphical Abstract

Introduction

Magnesium is an essential element in human physiology, constituting approximately 20–28 g. Approximately 60% of total body magnesium resides in bone tissue, where it participates in critical biochemical reactions. As a divalent cation, magnesium functions as an indispensable cofactor in hundreds of intracellular enzymatic reactions [1–3]. Furthermore, magnesium exhibits dual anti-inflammatory and antioxidant capabilities [4], which are mechanistically linked to its osteogenic potential. Magnesium-based implants were first utilized in European orthopedic surgeries during the early 20th century. However, the advent of synthetic biomaterials led to diminished interest in magnesium-based solutions. In recent years, escalating demands for bioactive bone substitutes have revitalized research efforts toward magnesium-containing biomaterials [5]. Juan et al. demonstrated that Mg²⁺ enhances osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) via Notch1 signaling pathway activation [6]. Notably, Mg²⁺ regulates Notch signaling exclusively in undifferentiated mesenchymal stem cells, with no observable effect on mature osteoblasts. These findings suggest that Mg²⁺ primarily sustains stem cell pluripotency rather than directly driving osteogenic maturation [7]. Qiao et al. reported that Mg²⁺ modulates macrophage-mediated transcriptional regulation of osteogenic and osteoclastic genes during initial bone repair phases [8].

Hydrogels are hydrophilic polymers characterized by a three-dimensional network structure, exhibiting compressive strength, mechanical stability, biocompatibility, and controlled degradability [9–11]. These polymers can be engineered to exhibit antibacterial [12] and hemostatic functions [13], while also serving as effective drug delivery systems [14]. Consequently, hydrogels demonstrate versatile applications in tissue engineering. Hydrogels encapsulating bioactive molecules and cells have been extensively developed for bone regeneration and cartilage repair [15]. In addition to bioactive molecules and cells, metal ions such as Mg²⁺, Ca²⁺, Zn²⁺, and Cu²⁺ are employed in tissue engineering owing to their osteogenic capacity, antimicrobial effects, and immunomodulatory roles in bone repair [16]. Studies have demonstrated that Mg²⁺ exerts pronounced osteoinductive and angiogenic effects [17]. Magnesium-based biomembranes have been clinically implemented in oral implantology with favorable outcomes. Marko et al. documented two clinical cases of magnesium membrane implantation showing successful outcomes without adverse effects [18] These findings underscore the clinical significance of advancing magnesium-based biomaterials.

In clinical settings, bone defects caused by diverse etiologies are commonly encountered. Although bone tissue possesses intrinsic regenerative capacity, impaired healing remains a significant clinical challenge. Multiple strategies, such as bone grafting and tissue engineering, have been developed to address this issue. Bone tissue engineering integrates biomaterial scaffolds, cells, and growth factors to regenerate and sustain bone tissue [19–21] Such substitutes must replicate the extracellular matrix while exhibiting biocompatibility, controlled degradability, and osteoinductive properties. Hydrogels with tunable physicochemical properties provide distinct advantages in this context [22] Barik et al. demonstrated mucin’s critical role in osteogenesis and subsequently engineered a mucin-collagen thermosensitive hydrogel that enhances vascularization, neurogenesis, and bone regeneration [23] This study undertakes a systematic literature review combined with meta-analysis to examine the efficacy of magnesium-ion-loaded hydrogels in bone regeneration and evaluate the reliability of the reported outcomes.

Materials and methods

Data sources

A comprehensive literature search was performed in March 2024, spanning publications from January 2013 to March 2024. The search encompassed PubMed and other relevant databases, using key terms such as “magnesium,” “hydrogel,” and “bone regeneration” (complete search strategy detailed in Table 1).

Table 1.

Search strategy

Databases	Search strategy
Pubmed	((“bone regeneration”) OR (“bone repair”) OR (“bone tissue engineering”) OR (BTE)) AND (hydrogel) AND ((magnesium) OR (“magnesium ion”))
Web of science	(“bone regeneration”) OR (“bone repair”) OR (“bone tissue engineering”) OR (BTE) (Topic) and (magnesium) OR (“magnesium ion”) (Topic) and (hydrogel) (Topic)
Scopus	(TITLE-ABS-KEY ((“bone regeneration”) OR (“bone repair”) OR (“bone tissue engineering”) OR (bte)) AND TITLE-ABS-KEY ((magnesium) OR (“magnesium ion”)) AND TITLE-ABS-KEY ((hydrogel)))
Embase	(‘bone regeneration’/exp OR ‘bone regeneration’ OR ‘bone repair’/exp OR ‘bone repair’ OR ‘bone tissue engineering’/exp OR ‘bone tissue engineering’ OR bte) AND (‘hydrogel’/exp OR hydrogel) AND (‘magnesium’/exp OR magnesium OR ‘magnesium ion’/exp OR ‘magnesium ion’)

Selection criteria

Inclusion criteria

Studies were included if they: (1) Investigated magnesium, its compounds, or hydrogel-based systems for bone regeneration; (2) Employed controlled animal models with bone defects; (3) Focused on single-component therapeutic agents (e.g., magnesium or magnesium compounds); (4) Were peer-reviewed English articles published in the last decade through specified platforms or in field-specific authoritative journals [24].

Exclusion criteria

Studies were excluded if they: (1) Were review articles, retrospective analyses, or lacked randomized controlled trial design; (2) Had no direct relevance to the research focus; (3) Used exclusively in vitro experimental models; (4) Combined multiple bone-regenerative components; (5) Contained methodological flaws in experimental design or statistical analysis.

Classification of magnesium-containing bioactive hydrogel systems for bone regeneration

Hydrogels are broadly classified as natural or synthetic. While natural hydrogels demonstrate favorable biocompatibility and biodegradability, their mechanical strength is generally suboptimal. Conversely, synthetic hydrogels possess superior mechanical properties but show limited biological activity Although each type presents distinct advantages and limitations, both exhibit restricted functionality for bone regeneration applications. To effectively promote bone repair, hydrogels must concurrently demonstrate robust biological activity with osteoinductive potential, while maintaining sufficient rigidity and elasticity - requirements that present significant challenges in hydrogel design. This has driven the development of diverse hydrogel formulations specifically tailored for bone repair applications.

Natural hydrogels

Gelatin

Gelatin, a biopolymer extensively utilized in tissue engineering and biomedical applications, exhibits limited clinical applicability due to its suboptimal mechanical strength and adhesive capabilities. Consequently, strategies involving chemical modification or composite formation with supplementary materials have emerged as prevalent approaches [25]. Huang et al. developed a modified gelatin composite (MgT-MCS/GB) that replicates natural bone microstructure while enabling controlled Mg²⁺ release, thereby enhancing osteogenic differentiation, angiogenesis, and neural growth [26]. Methacrylated gelatin (GelMA), synthesized through gelatin modification with methacrylate groups, has gained significant attention. This derivative contains arginine-glycine-aspartic acid (Arg-Gly-Asp; RGD) tripeptide sequences that facilitate cellular adhesion, spreading, and differentiation. Furthermore, GelMA incorporates matrix metalloproteinase (MMP)-responsive sequences that permit enzyme-mediated degradation, a mechanism crucial for supporting wound healing and tissue regeneration [27]. The distinctive photopolymerization capability of GelMA has enabled its fabrication into diverse architectures for tailored tissue engineering applications [28]. Dubey et al. engineered a GelMA-based membrane gel incorporating amorphous magnesium phosphate (AMP), which demonstrated enhanced osteogenic differentiation and mineralization in bone marrow mesenchymal stem cells, with AMP identified as a critical functional component. This modified hydrogel simultaneously exhibited superior barrier properties [29]. Jing et al. fabricated a photosensitive conductive hydrogel through the incorporation of magnesium-modified black phosphorus into GelMA. This formulation achieved sustained release of magnesium and phosphorus ions, potentially acting synergistically to stimulate Schwann cell migration, nerve fiber regeneration, and osteogenic microenvironment optimization. Animal model evaluations confirmed the hydrogel’s antimicrobial efficacy [30]. Subsequent development of a bilayer hydrogel architecture based on this photosensitive conductive system demonstrated accelerated early-phase vascularization and neural regeneration, ultimately promoting comprehensive bone regeneration and remodeling processes [31].

Silk protein

Silk protein, primarily composed of fibroin and sericin, possesses a distinctive structural architecture that confers exceptional mechanical properties including strength, elasticity, and processability. This biopolymer exhibits remarkable biocompatibility with minimal risk of foreign body reactions. Its tunable degradation profile aligns with the temporal requirements of long-term tissue regeneration [32]. The material’s properties can be precisely tailored through physical, chemical, or genetic engineering approaches, enabling its fabrication into diverse forms for biomedical, tissue engineering, and textile applications. Recent research has particularly focused on developing functionalized silk protein hydrogels [33]. Cheng et al. demonstrated that infusing Mg²⁺ into Bombyx mori silk nanofiber (BSNF) hydrogels creates metal-coordinated networks where the binding affinity between nanofibers and Mg²⁺ directly modulates angiogenic and osteogenic potential [34]. Subsequent investigations have explored silk protein as carriers for bioactive ions (including Mg²⁺) to modulate bone regeneration. Notably, incorporation of tricalcium phosphate-releasing ions (Mg, Si, Sr) was shown to modify silk protein’s gelation kinetics and physicochemical characteristics while enhancing angiogenesis coupled with osteoblast proliferation and differentiation [35]. Wu et al. further developed ion-incorporated silk scaffolds that synergistically promoted osseous/vascular tissue formation while simultaneously suppressing osteoclastogenesis [36]. In an innovative approach, Cai et al. engineered magnesium-encapsulated microspheres using modified silk protein, which activated the PI3K/Akt pathway to enhance osteoinductive potential and effectively delivered mesenchymal stem cells to establish functional bone regeneration-enhancing units (BREUs) [37].

Hyaluronic acid (HA)

Hyaluronic acid (HA), a high-molecular-weight linear glycosaminoglycan ubiquitously present in the extracellular matrix, has been engineered into diverse biomedical formulations due to its inherent biocompatibility, biodegradability, non-immunogenicity, and anti-inflammatory properties. These formulations demonstrate significant potential in tissue regeneration, wound healing, and drug delivery applications [38]. Li et al. demonstrated that chemically modified HA enables the coordinated release of bisphosphonates and Mg²⁺, effectively inhibiting osteoclast activity while preserving osteogenic factor secretion [39]. The photosensitive nature of methacrylated hyaluronic acid (HAMA) permits crosslinking and solidification via photoinitiators, with resultant pore architectures modulated by crosslinking density. Wang et al. developed a bilayered composite hydrogel (GCDH-M) that orchestrates BMSC differentiation pathways, demonstrating sequential enhancement of cell migration, proliferation, osteogenic differentiation, and bone formation through improved cellular recruitment and vascularization [40]. Zhang et al. engineered an injectable RGD-conjugated HAMA composite gel capable of simultaneous bioactive ion and small-molecule drug release. This platform induces MSC osteoblastic differentiation via Mg²⁺-mediated ALP production, which subsequently triggers dexamethasone release through positive feedback mechanisms to amplify osteogenesis. The system presents a promising strategy for minimally invasive delivery of bone repair therapeutics [41].

Sodium alginate (SA)

Sodium alginate (SA), a linear anionic polysaccharide, is characterized by hydrophilicity, biodegradability, biocompatibility, and water-absorbent properties. Notably, it exhibits immunostimulatory effects by inducing monocyte production of interleukins and tumor necrosis factors. Current applications primarily employ SA in hydrogel formulations for tissue engineering, wound dressings, and drug delivery systems [42]. Zhang et al. developed SAG hydrogels through the combination of sodium alginate, akermanite, and glutamic acid. Their findings demonstrated that ionic release (Mg²⁺, Ca²⁺, and Si⁴⁺) from these gels enhances stem cell migration and osteogenic differentiation [43]. In a separate approach, Jin et al. engineered a dual-layer hydrogel system using oxidized sodium alginate (OSA) and polyacrylamide (PAM), incorporating calcium-magnesium phosphate cement (CMPC) to support bone regeneration. The CMPC component releases Ca²⁺ to promote tissue mineralization, while Mg²⁺ facilitates hydroxyapatite formation, regulates osteogenic differentiation, and stimulates neobone formation. Furthermore, Mg²⁺ synergizes with RGD motifs to modulate cellular adhesion and differentiation processes. The study revealed that Mg²⁺ not only improves material biocompatibility and mineralization capacity but also enhances vascularization through activation of the TRPM7/PI3K signaling pathway, which upregulates Runx2 and alkaline phosphatase (ALP) expression to amplify osteoblast activity [44].

Chitosan (CS)

Chitosan (CS), a naturally derived cationic linear polysaccharide containing hydroxyl and amino groups, demonstrates broad applicability through functional group modifications. This biopolymer exhibits biocompatibility, biodegradability, and non-immunogenicity. The inherent positive charge facilitates electrostatic interactions with negatively charged microbial membranes, inducing structural disruption and conferring antibacterial efficacy. An additional antimicrobial mechanism involves DNA binding, thereby inhibiting RNA synthesis and cellular proliferation. However, chitosan’s solubility is restricted to acidic solutions, with minimal dissolution observed under neutral or alkaline conditions. This limitation necessitates material modification and crosslinking strategies for enhanced functionality [45, 46]. Qing et al. developed a chitosan-based hydrogel demonstrating dual functionality in antibacterial action and osteogenesis. Magnesium oxide degradation mediated calcium/phosphate enrichment and mesenchymal stem cell (MSC) recruitment, ultimately promoting cellular mineralization. This biological response potentially originates from Mg²⁺ and PO₄³⁻ co-activation of the PI3K-AKP signaling pathway [47].

Li et al. developed an injectable phosphorylated chitosan-based gel that provides stable Mg²⁺ release to enhance biomineralization, angiogenesis, and osteogenic activity. Their findings revealed phosphate groups’ regulatory role in Mg²⁺ release kinetics [48]. Xiong et al. engineered a dual-layer gel system combining CS and PAM, significantly improving the mechanical properties of chitosan. This system demonstrated that controlled co-delivery of Mg²⁺ and BMP-2 promotes osteoblast adhesion and facilitates cortical bone reconstruction. The staged release profile of these bioactive components ensures sequential activation of osteogenic processes, with Mg²⁺ potentially activating the Wnt/β-catenin pathway to enhance osteoblast functionality [49]. Alternative approaches employ modified chitosan matrices to encapsulate MgO within hydrogels for bone regeneration. These systems leverage MgO-derived Mg²⁺ release to simultaneously stimulate osseous/vascular tissue formation and improve hydrogel mechanical integrity, thereby supporting cellular adhesion and proliferation [50]. Li et al. developed a bilayer hydrogel system incorporating modified CS and PAM to deliver MgO-functionalized polydopamine (PDAM) particles, achieving dual functionality in bone regeneration and tumor ablation. Near-infrared irradiation triggers PDAM-mediated photothermal tumor ablation, while sustained Mg²⁺ release facilitates cellular adhesion, proliferation, and osteogenic differentiation. Notably, the study identified concentration-dependent effects of Mg²⁺, with elevated levels potentially suppressing cellular proliferation. This combinatorial approach shows promise for post-resection osteosarcoma management and recurrence prevention [51]. An innovative formulation utilizing hydroxybutyl chitosan to encapsulate PDAM-coated Mg-CaCO₃ microspheres demonstrated precision in controlled Asp/BMP-2 co-delivery. The hydrogel system achieved NIR-responsive sustained BMP-2 release, which proved critical for facilitating mineral deposition and accelerating matrix mineralization processes, establishing a novel platform for spatiotemporal drug delivery [52]. Lu et al. specifically addressed bone defect repair in femoral head necrosis models. Their investigation demonstrated that BMSC-loaded gel application effectively stimulated de novo bone formation, achieving three critical outcomes: bridging necrotic bone with newly formed callus, enhancing vascular network development, and facilitating medullary cavity reformation. These findings establish a therapeutic framework for addressing osteogenic challenges in femoral head necrosis management [53].

Synthetic hydrogels 2.2.1 polyethylene glycol (PEG)

Polyethylene glycol (PEG) demonstrates unique advantages in hydrogel fabrication. Thermosensitive PEG gels can be functionalized with RGD peptide sequences and BMP2 to support cellular growth despite their intrinsic lack of bioactivity [54]. Modified PEG derivatives and their composites serve as effective delivery vehicles for bioactive molecules in bioengineering applications. Incorporation of attapulgite clay into the PPR system yielded hydrogels with enhanced biocompatibility, mechanical strength, and intra-articular drug delivery potential [55]. Zhai et al. engineered a PEG-based nanocomposite hydrogel demonstrating sustained release of Mg²⁺ and Si⁴⁺ ions alongside superior mechanical performance, effectively promoting osteoblast proliferation and differentiation [56]. Subsequently, the team implemented 3D printing technology to develop a composite hydrogel capable of co-releasing Mg²⁺, Si⁴⁺, and osteoblasts, which significantly amplified the osteogenic potential mediated by these ions. Their findings suggested this construct serves as a safe scaffold for short-term osteoblast distribution and viability while exhibiting long-term capacity for neobone formation [57]. Liu et al. developed an osteoinductive PEG-modified hydrogel, demonstrating that Mg²⁺ modulates both physicochemical hydrogel properties and activates the PI3K/Akt/GSK3β/β-catenin signaling pathway to enhance osteogenic activity [58].

Poly(lactic-co-glycolic acid) (PLGA)

PLGA demonstrates outstanding biocompatibility and biodegradability while offering customizable forms to accommodate diverse drug release kinetics and encapsulation efficiency demands [59, 60]. Experimental evidence indicates that incorporating PLGA into mineralized collagen matrices elevates porosity, thereby enhancing nutrient transport and cellular migration [61]. Zhou et al. engineered a bone-inducing PMM gel incorporating PLGA, which accelerated mineral deposition, promoted cell migration, and enhanced osteogenic differentiation of iMEFs via Mg²⁺ release [62]. In subsequent research targeting osteosarcoma-related bone defects, the same team demonstrated that the composite gel synergistically amplified iMEF osteogenic differentiation through Mg²⁺ release following magnetic hyperthermia and starvation therapy, consequently improving in situ bone regeneration and mineralization [63]. In a parallel investigation of PLGA applications, Xie et al. discovered that PLGA-doped attapulgite (ATT) gel functioned as a protective barrier against fibroblast infiltration while simultaneously stimulating bone marrow-derived mesenchymal stem cell adhesion, proliferation, and mineralized nodule formation. Although they documented the presence of bioactive magnesium and silicon ions in ATT, their potential correlation with osteogenic processes remained unelucidated [64].

Polyvinyl alcohol (PVA)

Polyvinyl alcohol (PVA), a linear water-soluble polymer, is widely employed in hydrogel fabrication. The hydroxyl groups in its monomeric structure enable precise control of physicochemical characteristics post-polymerization. Demonstrating favorable water-swelling capacity and biocompatibility, PVA can form composite materials through integration with diverse polymers, biomolecules, and functional materials. Its compatibility with 3D printing technologies further expands its biomedical applications [65, 66]. Ma et al. developed a PVA-based bio-scaffold demonstrating enhanced vascularization and osteogenic potential. Their findings revealed that nano-attapulgite reinforcement significantly improved the scaffold’s porosity and mechanical integrity while synergizing with hydroxyapatite (HA) to amplify osteoinductive capacity, ultimately promoting both neovascularization and bone formation [67]. Parallel research demonstrated that amorphous magnesium phosphate-PVA composites exhibit tunable mechanical properties dependent on phase composition ratios, with magnesium incorporation imparting bioactive characteristics [68]. Investigators have additionally explored PVA’s utility in guided tissue regeneration paradigms [69]. Composite systems combining PVA with sodium alginate not only achieved superior mechanical strength and controlled swelling behavior but also demonstrated osteoinductive potential through magnesium diboride nanosheet incorporation [70]. While PVA has shown promise in cartilage regeneration applications, its inherent bioactivity limitations necessitate material optimization. Recent evidence suggests that magnesium-enhanced PVA formulations can effectively address cartilage defects through targeted modifications [71].

γ-Polyglutamic acid (PGA)

γ-Polyglutamic acid (PGA) is a biopolymer composed of repeating glutamic acid units linked through amide bonds between α-amino and γ-carboxyl groups. Its notable biocompatibility, hydrophilicity, and abundant γ-carboxyl groups—which provide sites for chemical functionalization—make PGA particularly suitable for tissue engineering applications [72]. Luo et al. engineered a bilayered PGA hydrogel designed to structurally emulate native cartilage and osseous tissue. Their findings demonstrated the construct’s chondrogenic potential, with neotissue demonstrating integration capacity with subchondral bone. While the study did not investigate the underlying mechanisms, the researchers proposed that divalent cation incorporation (Mg²⁺/Cu²⁺) may enhance mechanical strength through ionic crosslinking, thereby replicating native cartilage biomechanics and creating a favorable microenvironment for tissue repair. Furthermore, these bioactive ions may enhance chondrogenic processes through multiple pathways, including mesenchymal stem cell (MSC) adhesion, differentiation modulation, and immunoregulatory effects [73]. Chen et al. developed a PGA-based hydrogel system that achieved controlled release of Mg²⁺/Ca²⁺ ions for bone regeneration applications. Their research revealed synergistic effects between hydroxyapatite (HA) and magnesium oxide (MgO) in enhancing osteogenic differentiation of bone marrow stromal cells (BMSCs), particularly under hyperglycemic conditions. In vivo analysis demonstrated concurrent endochondral and intramembranous ossification processes, with endochondral bone formation being the predominant pathway. The hydrogel system significantly reduced inflammatory macrophage infiltration while augmenting vascular network development, both mechanisms contributing to improved bone formation. These findings advance therapeutic strategies for diabetic bone defect repair [74]. In a separate methodology, investigators fabricated extracellular matrix-inspired PGA hydrogels that promoted cellular infiltration into architectured magnesium alloy implants, ultimately leading to new bone generation [75].

Beyond PGA-based systems, alternative hydrogel carriers including xanthan gum (XG) [76], gellan gum (GG) [77], and poly(N-acryloyl glycinamide) (PNAGA) [78] have been effectively utilized for magnesium ion delivery in bone repair. Current evidence indicates that composite hydrogel matrices combining multiple components improve therapeutic efficacy through enhanced mechanical stability and optimized drug-loading capacity for controlled release applications.

Research progress in magnesium-loaded hydrogels for bone regeneration

With growing experimental evidence supporting magnesium’s osteogenic and angiogenic properties, research focus has shifted to elucidating its underlying mechanisms. Bone repair processes involving key signaling pathways - Wnt/β-catenin, PI3K/Akt/mTOR, MAPK, and PDGF [79] - show potential magnesium-mediated regulation. Current findings demonstrate that Mg²⁺ release enhances neural function and osteogenic activity, while magnesium whitlockite may activate the PTEN/mTOR pathway, thereby stimulating neurite growth [80]. Experimental data further reveal Mg²⁺‘s dual action in suppressing pro-inflammatory responses through NF-κB and TLR pathway inhibition, which reduces inflammatory factor expression and M1 macrophage polarization. Concurrently, Mg²⁺ appears to upregulate VEGF and HIF-1α expression, thereby promoting angiogenesis and facilitating osteogenic microenvironment optimization [81]. Zhao et al. specifically documented Mg²⁺-induced angiogenesis via e-NOS and VEGF pathway activation [82]. In complementary research, Zhang et al. demonstrated that magnesium ascorbyl phosphate (MAP) enhances bone marrow stromal cell antioxidant capacity through AMPK-SIRT1 signaling, mitigating oxidative damage while concurrently exhibiting potential to stimulate bone regeneration via the CGRP-FAK-VEGF axis [83].

Mg²⁺ plays a crucial role in energy metabolism regulation. Studies have demonstrated that Mg²⁺ upregulates both glycolysis and oxidative phosphorylation while activating the Akt-glycolysis-Mrs2-mitochondria axis, thereby coordinating energy metabolism with osteogenic differentiation. This mechanism significantly enhances the osteoinductive potential of low-dose BMP-2 [84]. Emerging evidence reveals synergistic interactions between Mg²⁺ and other biomolecules. Experimental data indicate that Mg²⁺ stimulates calcitonin gene-related peptide (CGRP) secretion, which subsequently modulates vascular endothelial growth factor (VEGF) to enhance angiogenesis. Complementary studies demonstrate that Ca²⁺ activates multiple osteoblast signaling pathways, including ERK1/2, P38, PKD, PI3K, and PCL, to potentiate bone regeneration. Concurrently, alendronate (ALN) activates the Rap1/MAPK pathway through stimulation of intracellular adenylate cyclase 6, further promoting bone regeneration. These findings collectively suggest that Mg²⁺ not only augments osteogenesis and angiogenesis but also exhibits concentration-dependent synergistic effects with Ca²⁺ and ALN [85]. Parallel research demonstrates that Mg²⁺/Zn⁺ combinations activate the MAPK pathway in bone marrow mesenchymal stem cells, enhancing cellular proliferation, migration, and differentiation processes [86, 87]. Zhang et al. further elucidated that Mg²⁺ enhances osteoblast activity through the TRPM7/PI3K pathway while facilitating osteoblast recruitment from low-Mg²⁺ microenvironments. Notably, Mg²⁺-mediated PI3K phosphorylation confers cellular protection against alkaline stress-induced cytotoxicity [88].

Magnesium facilitates bone repair through PDGF-BB-mediated recruitment of bone marrow mesenchymal stem cells (MSCs) to implantation sites [89]. Although magnesium deficiency suppresses osteoblast activity, the biological significance of hypermagnesemia remains unclear due to rapid renal clearance mechanisms. Experimental evidence demonstrates that elevated extracellular Mg²⁺ concentrations impair osteoblast differentiation and matrix mineralization processes [90]. While high-magnesium environments promote chondrogenic differentiation of MSCs, they simultaneously suppress matrix mineralization through reduced calcium oscillation frequency. Notably, magnesium concentration gradients exhibit dual regulatory effects on autophagy-mediated osteogenic differentiation of MSCs. The degradation of magnesium releases hydroxide ions, generating a localized alkaline microenvironment. While such alkaline conditions demonstrate antibacterial efficacy, they may concurrently suppress cellular activity and osteogenic potential [91]. Emerging evidence also associates increased Mg²⁺ concentrations with diminished endothelial cell functionality [17]. These mechanistic insights advance our understanding of magnesium’s biological effects while offering novel perspectives for optimizing magnesium-based biomaterials.

Current magnesium research primarily focuses on its chemical forms. Magnesium and its alloys have gained prominence owing to their bone-matching elastic modulus and inherent biodegradability. Upon physiological corrosion, these materials generate magnesium ions, alloying elements, hydrogen gas, and hydroxides, with hydrogen demonstrating osteoclast inhibitory properties [5]. Clinically applied in fracture fixation, magnesium nails provide dual benefits: structural stabilization and enhanced bone healing, while alloy formulations address pure magnesium’s rapid degradation limitations [92]. Zhou et al. developed an osteogenic hydrogel system by encapsulating pure magnesium within PEG-PLGA matrices, enabling controlled hydrogen gas release. Their mechanistic investigation revealed three key effects: (1) hydrogen gas generated during magnesium degradation acts as a reactive oxygen species scavenger, (2) liberated magnesium ions modulate macrophage polarization while suppressing the IκBα/NF-κB pathway to achieve anti-inflammatory outcomes, and (3) synergistic bone-inductive properties emerge through these combined mechanisms [93]. Analogously, magnesium oxide facilitates osseous and vascular regeneration through ionic release [49, 94]. This bioactivity mechanism extends to other magnesium-based nanomaterials, where ion-mediated microenvironments drive biological responses [95]. Collectively, the reviewed evidence suggests that diverse magnesium compounds exhibit equivalent osteogenic, angiogenic, and neuroregenerative capacities, with magnesium ion release constituting the fundamental mechanism underlying these therapeutic effects (Table 2).

Table 2.

Literature information extraction table for promoting bone regeneration by hydrogels containing magnesium

File	Hydrogel	Magnesium containing substance	Magnesium forms of action	animal model	Main biological activity
2022[81]	P(ACG-GelMA-L)-Mg²⁺	GelMA-nHA/poly (N-acryloyl 2-lycine) (PACG) -GelMA-Mg2+	Mg2+	Critical-sized cranial bone defect in rats	Regulating immunity (M2 macrophage polarization), promoting angiogenesis, and synergistically promoting bone regeneration with nHA
2017[78]	PNAGA/Laponite XLG	Laponite XLG	Mg2+	Tibia defect in Sprague-Dawley rats	Synergistic silicon ions promote osteogenic gene expression, mechanical support and degradation match bone regeneration rate
2021[74]	HA/ PGA-Cys/MgO	MgO nanoparticles	Mg2+	Diabetes-induced rat femoral bone defect model	By modulating macrophage polarization and promoting angiogenesis, this approach enhances the proliferation, migration, and osteogenic differentiation of BMSCs, significantly facilitating bone regeneration under diabetic conditions.
2018[56]	PEGDA/Laponite XLG	Laponite XLG	Mg2+	Critical-sized cranial bone defect in rats	Modulating the osteogenic differentiation and mineralization of BMSCs significantly enhances the new bone volume fraction in the bone defect region.
2022[99]	GelMA/ PgC₃Mg	PgC₃Mg	Mg2+	Critical-sized cranial bone defect in rats	Activate osteogenic related genes to promote bone regeneration
2017[100]	MeHA-BP-Mg	MgCl2	Mg2+	Critical-sized cranial bone defect in rats	Enhanced cell adhesion and spreading, promoted osteogenesis of hMSCs, and in-situ bone regeneration
2020[101]	ECM/AMP bioink	AMP nanoparticles	Mg2+	–	Improved cell morphology, enhanced cell viability, and promoted osteogenic differentiation of DPSCs
2022[73]	PGA/CMCS/BC-Mg/Cu	MgSO4	Mg2+	Femoral defect model in diabetic rabbits	Enhanced mechanical properties, promoted chondrocyte proliferation, and improved cartilage repair
2024[102]	SMeHA@CM	MgSO4	Mg2+	Critical-sized cranial bone defect in rats	Enhanced osteogenic differentiation, promoted angiogenesis, and recruited BMSCs
2022[52]	HBC@PAM + 5MP-BMP	5MP-BMP	Mg2+	SD rat calvarial defect model	Promotes bone regeneration and sequentially regulates anti-inflammatory and osteogenic activities
2024[85]	SHA@CM	MgCl2·6H2O	Mg2+	SD rat calvarial defect model	Promote angiogenesis, improve microenvironment, and enhance osteogenic ability
2021[103]	GelMA/TCS/POSS-Mg	MgCl2·6H2O	Mg2+	SD rat calvarial defect model	Promote angiogenesis, improve microenvironment, and enhance osteogenic ability
2020[104]	Mg-IHC	Magnesium(95%)-Zinc alloy	Mg2+	SD rat calvarial defect model	Promote osteoblast proliferation, osteogenic differentiation, and mineralization
2024[105]	GM@MOF/DOPA-BMP-2	Mg-MOF	Mg2+	Rotator cuff injury model in rat	Inducing phenotypic transformation of macrophages from M1 to M2, promoting vascular regeneration, and enhancing bone repair levels
2022[31]	GelMA-BP@Mg/GelMA-PEGDA/β-TCP	BP@Mg	Mg2+	SD rat calvarial defect model	Promote angiogenesis, neurogenesis, and synergistically enhance bone regeneration ability
2023[106]	CS/ NGQD/ZK60	ZK60	Mg2+	Femoral defect model in rabbits	Enhance osteoblast proliferation, calcium deposition, and bone integration, providing mechanical support
2024[34]	BSNF-Mg	MgCl2	Mg2+	Critical-sized cranial bone defect in rats	Regulating angiogenesis and osteogenic differentiation, promoting calcium deposition and bone formation
2023[107]	GelMA/PEG-(SS)2/PgC3Mg	PgC3Mg	Mg2+	SD rat calvarial defect model	Activate early macrophages and stem cells to secrete endogenous growth factors
2023[26]	GB/MgT-MCS	MgT	Mg2+	Rat femoral defect model	Promote osteogenesis, angiogenesis, and neurogenesis
2019[35]	SMH	MSM-10	Mg2+	–	Promote proliferation and differentiation of osteoblasts, promote angiogenesis, and reduce inflammatory reactions
2023[37]	SilMA@MgP	MgP	Mg2+	Rat model of distal femoral defect	Promoting bone regeneration by inducing mineral deposition and differentiation of bone marrow mesenchymal stem cells into osteoblasts
2020[58]	PEG-SH/Mg2+	MgCl2	Mg2+	–	Promoting proliferation and differentiation of bone marrow mesenchymal stem cells through the PI3K/Akt/GSK3 β/β - catenin signaling pathway
2020[29]	GelMA/AMP	AMP	Mg2+	Cranial bone defect in rats	Promote the expression of osteogenic related genes to enhance the differentiation and mineralization ability of osteoblasts
2021[62]	PLGA-Mg	MgO、MgCO3	Mg2+	Cranial bone defect in rats	Promote proliferation of bone marrow mesenchymal stem cells, differentiation and mineralization of osteoblasts
2018[108]	PLGA/MgO-alginate	MgO	Mg2+	Femoral defect model in rats	Enhance cell vitality and proliferation ability, promote differentiation and mineralization of osteoblasts
2021[109]	CSMAP-MgO	MgO	Mg2+	Cranial bone defect in rats	Enhance cell vitality and proliferation ability, promote differentiation and mineralization of osteoblasts
2021[82]	GelMA-BP-Mg	MgCl2	Mg2+	the distal femur of rats with osteoporotic bone defects	Promote vascular repair and enhance osteoblast adhesion and mineralization
2020[110]	GelMA-co-PEG	MgO	Mg2+	Cranial bone defect in rats	Promote the adhesion, proliferation, and differentiation of osteoblasts, as well as promote angiogenesis
2022[50]	CSMP- MgO	MgO	Mg2+	Cranial bone defect in rats	Promote the adhesion, proliferation, and differentiation of osteoblasts, as well as promote angiogenesis
2024[7]	GelMA/MPC	MPC	Mg2+	Cranial bone defect in rats	Promote the proliferation and differentiation of osteoblasts, enhance bone tissue regeneration
2023[30]	GelMA-BP@Mg	BP@Mg	Mg2+	Cranial bone defect in rats	Promote nerve repair and bone regeneration by enhancing the function of Schwann cells and CGRP+nerve fiber regeneration
2018[111]	Fibrin- CS-Mg8	MgSiO3	Mg2+	Rabbit knee joint defect model	Promote adhesion and proliferation of osteoblasts, and promote mineralization of bone tissue
2021[86]	CS/PEG/Mg/T4M-Zn2+	Mg-GP	Mg2+	Femoral defect model in rats	By synergistically regulating the MAPK signaling pathway with zinc, osteogenic differentiation is enhanced
2022[84]	AlMA/GelMA	AlMA	Mg2+	SD rat calvarial defect model	Acts as an ‘energy booster’ to enhance cellular bioenergetic levels through the Akt-glycolysis-Mrs2-mitochondrial axis, thereby improving the osteogenic induction capability of BMP-2
2022[67]	PVA/COL/ATP/HA	ATP	Mg2+	SD rat calvarial defect model	Promote the proliferation and differentiation of osteoblasts and angiogenesis
2022[47]	PVA/CS-MgO-BPNS	MgO	Mg2+	Cranial bone defect in rats	Promote the migration and osteogenic differentiation of mesenchymal stem cells and angiogenesis
2023[83]	GelMA/MAP	MAP	Mg2+	Cranial bone defect in rats	Promote the proliferation and differentiation of osteoblasts, accelerate the mineralization process, activate the ERK/Akt signaling pathway, and stimulate angiogenesis
2023[63]	Fe3O4/GOx/MgCO3@PLGA	MgCO3	Mg2+	Femoral defect model in rabbits	Promote the proliferation and differentiation of osteoblasts, enhance angiogenesis, and accelerate bone defect repair
2024[77]	GG	MgSO4	Mg2+	Cranial bone defect in rats	Promote the proliferation and migration of vascular endothelial cells, enhance angiogenesis, and stimulate the differentiation and mineralization of osteoblasts
2020[80]	GelMA/ Whitlockite	Whitlockite	Mg2+	Cranial bone defect in rats	Promotes neural differentiation, neurite growth, and osteogenic differentiation, simultaneously activates the PTEN/mTOR pathway and increases CGRP secretion, thereby exerting neural and osteogenic bioactivities

Meta-analysis

A four-stage literature search was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1). The Cochrane Risk of Bias Tool was utilized to evaluate methodological quality across the 10 included studies, with detailed risk assessment outcomes presented in Table 3. All included studies implemented rigorous experimental methodologies, featuring comprehensive descriptions of procedural protocols and analytical approaches, and maintained compliance with scientific rigor and ethical standards. Our meta-analysis evaluated the comparative efficacy of magnesium-containing versus magnesium-free hydrogels in bone regeneration through four key parameters: bone mineral density (BMD), new bone volume percentage (%), bone volume/tissue volume ratio (BV/TV), and trabecular thickness (Tb.Th). Quantitative data extracted from the selected articles were analyzed using single-factor variance analysis with SPSS software. Effect sizes with corresponding confidence intervals were calculated by dividing the mean difference between experimental and control groups by the pooled standard deviation, with results visualized in a forest plot (Figs. 2 and 3). The meta-analysis consistently demonstrated statistically significant enhancement of bone regeneration by magnesium-containing biomaterials. The robustness of the overall effect size and inter-study consistency highlights Mg²⁺‘s therapeutic potential warranting further clinical translation and biomedical investigation.

Fig. 1.

Flowchart of literature retrieval for systematic review and Meta-analysis (PRISMA). A total of 433 articles were retrieved from databases such as Pubmed, Web of Science, Scopus, and Embase. Firstly, 107 duplicate articles were removed. Then, the titles and abstracts of the remaining 326 articles were read, and 60 articles that did not involve randomized controlled trials or were unrelated to this study were excluded. Finally, the full texts of the remaining 266 articles were read, and 256 articles that involved multiple bone repair materials or did not conduct randomized controlled trials, including animal experiments, were excluded. Ultimately, 10 articles were included for Meta-analysis

Table 3.

Risk assessment using the Cochrane Risk Bias Tool

File Name	Random Sequence Generation	Allocation Concealment	Blinding of Participants and Personnel	Blinding of Outcome Assessment	Incomplete Outcome Data	Selective Reporting
Zhou[62]	Low	Low	Low	Low	Low	Low
Lin[108]	Unclear	Unclear	Low	Unclear	Low	Low
Chen[109]	Low	Low	Low	Low	Low	Low
Chen[50]	Low	Low	Unclear	Unclear	Low	Low
Pan[110]	Low	Unclear	Low	Low	Low	Unclear
Zhang[7]	Unclear	Unclear	Unclear	Unclear	Low	Low
Zhang[100]	Low	Low	Low	Low	Low	Low
Zhao[82]	Unclear	Unclear	Low	Unclear	Low	Low
Cheng[34]	Low	Low	Unclear	Low	Low	Unclear
Dubey[29]	Low	Low	Low	Low	Low	Low

Fig. 2.

Data chart of the included articles for analysis. The chart displays the titles, experimental time points, experimental groups, effect sizes, and 95% confidence intervals of the ten articles included in the analysis

Fig. 3.

Forest plot of the included articles for analysis. The forest plot is drawn based on the effect sizes and 95% confidence intervals of each experimental group of the included articles for analysis. The dashed line represents the line of no effect, each point represents the effect size of the study subject, and the horizontal line represents the 95% confidence interval. As shown in the figure, the effect values of all articles are on the right side of the line of no effect, indicating that all studies show a positive effect of magnesium ions on bone regeneration; most confidence intervals do not cross the line of no effect, which enhances the statistical significance of the research results

Conclusion

Extensive research has explored the efficacy of magnesium (Mg)-incorporated hydrogels, including Mg oxides and compounds, in enhancing bone repair. Magnesium demonstrates unique advantages for bone implantation due to its biodegradability, cortical bone-like mechanical strength, and osteoinductive capabilities [96]. Notably, hydrogen release occurs during Mg degradation, which Tang et al. strategically leveraged by developing macroporous hydrogels using Mg particles as foaming agents. This approach not only generates interconnected pores that enhance nutrient transport and enable tissue infiltration but also confers bioactive properties through Mg²⁺ release during particle degradation [97]. Collectively, these findings and meta-analysis data confirm the beneficial role of Mg-based biomaterials in bone regeneration.

The human skeletal system presents complex biomechanical demands, requiring structural rigidity for load-bearing capacity and elastic energy absorption to fulfill both mechanical and biological functions [98]. Such dual requirements create substantial challenges in bone reconstruction. Although hydrogels overcome the anatomical mismatch limitations of conventional alloys, their inherent viscoelastic properties still limit effective stress resistance. Consequently, the development of advanced hydrogel composites that synergistically integrate bioactive Mg²⁺ with bone-mimetic mechanical performance emerges as a critical research frontier.

Author contributions

Zhifeng Chen contributed to data analysis and interpretation. Dan Yang assisted with bioinformatics analysis and manuscript revision. Chunbo Hao and Shan Wang, as corresponding authors, supervised the project and provided critical feedback throughout the research process. All authors reviewed and approved the final version of the manuscript.

Funding

Supported by Hainan Province Science and Technology Special Fund (ZDYF2022SHFZ017). Supported by Hainan Province Science and Technology Special Fund(ZDYF2019216). Supported by Higher Education Teaching Reform Research Project of Hainan Province(Hnjg2023ZD-29).

Compliance with ethical standards

Conflict of interest

The authors declare no competing interests.