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Bone defect repair has always been a major challenge in the field of orthopedics, especially for patients with chronic inflammatory microenvironments such as diabetes and atrophic non-union of bones, which often lead to delayed bone regeneration or the formation of fibrous encapsulation. An ideal bone repair material should simultaneously possess osteogenic activity, immunomodulatory and anti-infective capabilities. Bioactive metal ions play a crucial role in coordinating the bone immune microenvironment and promoting bone integration. A recent study published in "Bioactive Materials" designed a Zn²⁺/Ce³⁺ co-doped hydroxyapatite (WH)/GelMA composite hydrogel scaffold (GM&Zn²⁺/Ce³⁺-WH) through a biomimetic strategy, achieving the synergistic optimization of immunomodulation, antibacterial activity and osteogenic performance, providing a new idea for bone regeneration. one Core Design: Biomimetic Ion Doping + Hydrogel Sustained Release System
1. Material System Construction
(1) Base material: Phosphate rock (WH) serves as the second most abundant mineral in bone tissue, rich in Mg²⁺, with excellent bone conductivity and osteogenic differentiation-promoting ability, superior to traditional hydroxyapatite (HA).
(2) Dual-ion synergistic doping: Zn²⁺ can upregulate the expression of anti-inflammatory cytokine IL-10, disrupt the integrity of bacterial cell membranes; Ce³⁺ through the Ce³⁺/Ce⁴⁺ redox cycle removes reactive oxygen species (ROS) and nitric oxide (NO), promoting macrophage M2 polarization.
(3) GelMA hydrogel carrier: It has a porous structure, biocompatibility, and degradability, providing a three-dimensional network for ion sustained release and supporting cell proliferation and differentiation.
2. Preparation Process
Zn²⁺/Ce³⁺ co-doped WH nanoparticles were synthesized by chemical precipitation, dispersed in GelMA pre-polymer solution, and cross-linked by ultraviolet light and freeze-dried to form a porous composite hydrogel scaffold. By adjusting the ion doping ratio, the physicochemical properties and biological activity of the material were optimized. Among them, sample 3# (0.00015 mol Zn²⁺ + 0.002 mol Ce³⁺) performed the best. two Key Performance: Multi-dimensional Enabling Bone Repair
1. Physical and Chemical Characteristics Optimization
(1) Structure and Mechanics: The scaffold presents a uniform porous structure (porosity ≈ 80%), facilitating cell infiltration and material transportation; the compressive modulus reaches 249.94 ± 9.70 kPa, which is within the optimal elastic modulus range for bone regeneration hydrogels (200 - 300 kPa).
(2) Release Performance: Achieves continuous release of Zn²⁺, Ce³⁺, and Mg²⁺ in simulated body fluids, with ion concentrations maintained within the biological safety range within 14 days, avoiding burst release-induced cytotoxicity.
(3) Degradation Behavior: The degradation rates in vitro and in vivo match the bone repair process; the in vivo degradation rate is approximately 21% after 21 days, providing space for new bone growth.
2. Biological Activity Verification
(1) Immune Regulation and Antioxidation
Promotes M2 polarization of macrophages: Significantly upregulates the expression of M2 markers such as CD206 and CD163, downregulates M1 markers such as CD86, inhibits NF-κB signaling pathway activation, and reduces the release of pro-inflammatory factor TNF-α.
Efficient ROS clearance: The Ce³⁺/Ce⁴⁺ redox cycle exhibits SOD and CAT-like activities, reducing intracellular ROS and MDA levels, protecting mitochondrial function, and alleviating oxidative stress damage.
(2) Antibacterial and Biocompatibility
Broad-spectrum antibacterial: Exhibits significant inhibition against Escherichia coli and Staphylococcus aureus, by disrupting the integrity of bacterial cell membranes and interfering with metabolic processes, inhibiting biofilm formation.
Excellent biocompatibility: MC3T3-E1 osteoblasts proliferate actively on the scaffold surface, with a cell survival rate of 473.34 ± 10.80%; the hemolysis rate is lower than 1.14%, meeting the requirements of blood compatibility for biomaterials.
(3) Osteogenesis Promotion and Anti-Osteoclastogenesis
In vitro osteogenesis: Significantly enhances alkaline phosphatase (ALP) activity and calcium nodule deposition, upregulates the expression of osteogenic-related genes and proteins such as RUNX2, BMP2, and OCN.
Inhibits osteoclastogenesis: Reduces the number of TRAP-positive osteoclasts, inhibits F-actin ring formation, reduces bone resorption activity, and maintains the balance between bone formation and bone resorption.
3. In Vivo Bone Repair Effect
In the rat femoral critical-sized defect model, after 8 weeks of implantation of sample 3#:
The amount of new bone formation significantly increased, with bone volume/tissue volume (BV/TV) reaching 48.23%, twice that of the control group, and the thickness and number of bone trabeculae (Tb.Th) and Tb.N significantly increased. Histological analysis showed that the scaffold was closely integrated with the host bone, forming mature bone bridges, with the expression of osteogenic markers such as BMP2 and OPN upregulated, and the inflammatory response significantly reduced.
III. Mechanism Summary: Triple Synergistic Remodeling of Bone Regeneration Microenvironment
1. Immune Regulation Axis: Ce³⁺ eliminates ROS + Zn²⁺ regulates cytokines, synergistically inducing M2 polarization of macrophages, constructing an anti-inflammatory immune microenvironment.
2. Antibacterial Protection Axis: Zn²⁺ damages bacterial cell membranes + Ce³⁺ interferes with bacterial redox balance, inhibiting postoperative infection and biofilm formation.
3. Osteogenesis Promotion Axis: The bone conductivity of WH + ion release activates the osteogenic signaling pathway, while inhibiting osteoclast differentiation, accelerating bone integration and defect repair.
IV. Clinical Transformation Potential
This composite scaffold achieves the synergistic effect of "immune regulation - antibacterial - osteogenesis" through biomimetic design, addressing the single-function pain point of traditional bone repair materials. Its advantages lie in: material composition mimicking natural bone minerals, high biocompatibility, and safe and non-toxic degradation products; it can be customized in 3D printing to match irregular bone defects; the ion release system does not require additional drug loading, reducing immunogenicity and side effects risks. The future can further optimize the ion doping ratio and the microstructure of the scaffold, and combine microfluidic technology to achieve sequential release of multiple factors, providing personalized treatment plans for difficult diseases such as inflammatory-related bone defects and infectious nonunion of bones.
Paper link (doi): https://doi.org/10.1016/j.bioactmat.2025.11.009
