Implant-associated periprosthetic inflammation is accompanied by a complex bone immune microenvironment disorder, presenting a phased pathological feature of acute oxidative stress and chronic imbalance in immune bone regulation. The clinical intervention is challenging. In this study, a biocompatible injectable chiral hydrogel composed of gelatin methacryloyl (GelMA) and L/D-cysteine-modified Fe₃O₄ nanoparticles was constructed. It was confirmed that this chiral hydrogel could regulate macrophage polarization through the integrin β3 (Itgb3) pathway and reshape the bone immune microenvironment. Among them, the L-type chiral hydrogel could promote bone formation in the chronic bone resorption stage, while the D-type chiral hydrogel could alleviate oxidative stress in the acute inflammatory stage. Both could effectively enhance bone regeneration in animal models, providing a new idea of stage-specific adaptive chiral material regulation for the intervention of implant-associated periprosthetic inflammation-related bone damage. This review focuses on the regenerative repair dilemma caused by the heterogeneity of bone-cartilage tissue, with the tissue engineering system combining mesenchymal stem cells and biomaterial scaffolds as the core, clarifying the regulatory mechanism of biological physical signals on stem cell fate, systematically summarizing the progress in the design of biomimetic microenvironment scaffolds guided by mechanical biology, and achieving precise regulation of mesenchymal stem cell lineage differentiation, providing theoretical support and design references for layered bone-cartilage regeneration, especially the regeneration of subchondral bone. 
01 Research Background
The core pathological feature of implant-associated periprosthetic inflammation is the complex disorder of the bone immune microenvironment. The pathological process will gradually evolve from acute inflammation-driven oxidative stress to chronic stage immune-mediated bone regulation imbalance. This phased pathological progression directly interferes with the bone tissue homeostasis and aggravates the bone damage process. The stage-specific pathological characteristics of this disease make it difficult to adapt a single intervention strategy to the bone immune regulation requirements of different pathological stages. Therefore, it is urgent to develop functional materials and intervention schemes that can precisely regulate the bone immune microenvironment for different pathological stages of implant-associated periprosthetic inflammation. The tendon-bone transitional tissue has a highly specialized extracellular matrix structure, with the core feature being the hierarchical arrangement of collagen and the gradient composition of minerals. This structure system can achieve stable force transmission and guide the cell phenotype of spatial organization. At present, it is impossible to precisely reproduce the complex multi-scale structure and composition gradient at the tendon-bone interface, which has become a key bottleneck in the integration regeneration of soft and hard tissues. It is urgently needed to develop a biomimetic matrix construction scheme that conforms to the natural structure characteristics. 02 Main Content
This study focuses on solving the bone immune disorder in different pathological stages of implant-associated periprosthetic inflammation. The L/D-cysteine-modified Fe₃O₄ nanoparticles were combined with GelMA to design and prepare injectable chiral hydrogels of two configurations (L-FG, D-FG); the molecular mechanisms of regulating oxidative stress levels and macrophage polarization phenotypes by the two chiral configurations were explored, and the action mode of regulating the bone immune microenvironment through the Itgb3-related pathway was clarified; the effects of the chiral hydrogels on bone regeneration at the implant-associated periprosthetic inflammation lesion site, macrophage infiltration, and related protein expression were verified in an animal model, and a stage-specific adaptive bone immune regulation material system was constructed.
03 Research Design
1. Material Preparation: Synthesize L/D-cysteine-modified Fe₃O₄ nanoparticles, combine them with GelMA to prepare two types of injectable chiral Fe₃O₄/GelMA hydrogels (L-FG, D-FG);
2. In vitro Mechanism Exploration: Analyze the key molecular signaling pathways regulating macrophage polarization and oxidative stress clearance by L-FG and D-FG, clarify the correlation between chiral structure and bone immune regulation;
3. In vivo Function Verification: Establish a rat implant-associated periprosthetic inflammation model, administer the two chiral hydrogels for intervention, detect the bone regeneration at the lesion site, the distribution of macrophage phenotypes, and the co-expression levels of related proteins, and verify the bone immune regulation and bone repair effects of the materials.
04 Results 1. At the molecular pathway level: L-FG can induce macrophages to polarize into the M2 type through the YTHDF1-m6A-Itgb3 signaling axis, exerting regulatory effects on bone immune disorders during the chronic bone resorption stage and providing microenvironment support for bone formation; D-FG can enhance the peroxidase-like activity of Fe₃O₄, activate the PI3K/Akt signaling pathway, and effectively alleviate oxidative stress damage during the acute inflammatory stage.
2. At the in vivo bone repair level: After intervention with the two chiral hydrogels, the bone regeneration levels in the rat implant osteoarthritis models were significantly improved; L-FG could significantly increase the infiltration degree of M2-type macrophages in the lesion area and upregulate the co-expression level of YTHDF1 and CD61, further confirming its regulatory effect on the bone immune microenvironment.
05 Extension of the thinking
1. The stage-specific regulatory characteristics of the chiral structure provide a new design idea for precise targeted intervention of the bone immune microenvironment, which can be extended to the development of other materials for bone inflammatory damage;
2. Based on the macrophage polarization regulation pathway mediated by m6A modification, it can serve as a potential target for bone immune regulation, providing a new research direction for the study of bone regeneration mechanisms;
3. The bone immune regulatory network mediated by integrin Itgb3 can further explore its core role in bone homeostasis maintenance and bone regeneration process.
Original source:
1. Journal: Bioactive Materials
2. Publication date: 2026-03-31
3. DOI: 10.1016/j.bioactmat.2026.03.055
4. Authors: Diwen Shi, Xin Mu, Hongjuan Cao, Fengyu Hao, Xiaoqian Xu, Lin Wu