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Implant-related infections can interfere with the aggregation process of mesenchymal stem cells in adjacent regions, and also restrict the survival, vitality, and osteogenic differentiation potential of the stem cells. This study constructs a pH-responsive biomaterial interface, utilizing the local acidification characteristic induced by infection, to synergistically achieve antibacterial effects and the functional reprogramming of stem cells and immune cells; the system can release bactericidal peptides directly acting on pathogenic bacteria, and magnesium ions and cell-targeting peptides can respectively mediate positive immune regulation and the recruitment behavior of bone marrow mesenchymal stem cells, thereby promoting the osteogenic lineage differentiation of stem cells at the implant interface. Transcriptomic analysis confirmed that the activation of the Wnt pathway in stem cells and the polarized remodeled macrophages can jointly upregulate the expression of antibacterial-related effects and core osteogenic genes, relying on the combined effect of the biomaterial and endogenous cells to complete the antibacterial process, and simultaneously achieving the growth and integration of bone tissue at the implant interface in the infection-responsive biomaterial environment, and activating endogenous cells into multifunctional functional carriers by the infection-responsive biomaterial, establishing an integrated research idea for controlling infection and bone tissue development.
This review addresses 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 the fate of stem cells, systematically summarizing the progress in the design of biomimetic microenvironment scaffolds under mechanical biology guidance, achieving precise regulation of lineage-specific differentiation of mesenchymal stem cells, and providing theoretical support and design references for layered bone-cartilage regeneration, especially the regeneration of subchondral bone.
01 Research Background
Secondary infections at the implant site can disrupt the local stem cell homeostatic environment, not only hindering the enrichment and retention of stem cells in the surrounding implant area, but also weakening the natural osteogenic physiological potential of stem cells, causing the co-restraint of pathogen persistence and bone tissue remodeling process, making it difficult to simultaneously promote antibacterial protection and the adaptation growth of bone tissue at the implant interface, and urgently requiring the development of new biomaterial regulatory strategies adapted to the infection-in situ microenvironment to balance the cellular functional homeostasis and the requirements of bone remodeling development.
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 structural system can achieve stable force transmission and guide the cell phenotype of the spatial organization. Currently, it is impossible to precisely reproduce the complex multi-scale structure and composition gradient of the tendon-bone interface, which has become a key bottleneck in the integration regeneration of soft and hard tissue interfaces. It is urgently needed to develop a biomimetic matrix construction scheme that conforms to the natural structure characteristics.
02 Main Content
Design and develop a pH-responsive biomaterial interface system that is adapted to the acidic microenvironment of infection, to coordinate the release of antibacterial effects, the recruitment of stem cells, and the functional reprogramming of immune cells; on the one hand, through the release of functional bactericidal peptides to achieve direct antibacterial intervention, on the other hand, relying on magnesium ions to regulate the positive evolution of the immune microenvironment, and relying on the targeting peptide to guide the directional migration and colonization of bone marrow mesenchymal stem cells, inducing the formation of an osteogenic differentiation physiological trend at the implant contact surface; at the same time, from the transcriptomic perspective, analyze the activation of stem cell signaling pathways, the polarization transformation of macrophages, the intrinsic linkage regulatory logic between antibacterial function expression and activation of osteogenic genes.
03 Research Design
Based on the core issue of inhibiting the osteogenic physiological activity of stem cells by the pathological infection environment, a pH-intelligent responsive biological functional interface that conforms to the acidic characteristics of the infection site was constructed; two major pathways of direct antibacterial activity release of the material and ion and targeting peptide-mediated immune and stem cell function enhancement were divided for layered exploration; based on the animal infection model, the growth and development status of bone tissue at the implant interface was observed, and the characteristics of the cell signal transduction pathways and upstream and downstream gene expression regulatory networks were analyzed by transcriptomic sequencing technology.
04 Results This intelligent biomaterial interface can smoothly connect the physiological process of pathogen clearance with the bone remodeling growth process at the implant site, effectively alleviating the inhibitory effect of infection stress on the osteogenic physiological activities of stem cells, and assisting in the orderly construction of bone tissue structure in the implantation area; at the cellular and molecular level, it can achieve bidirectional linkage of the activation of classic stem cell pathways and the remodeling of macrophage phenotypes, simultaneously activating the expression modules related to antibacterial effects and the specific gene groups for osteogenesis, relying on the dual-mediated mode of material matrix and endogenous cells, shaping a benign local microenvironment suitable for bone tissue regeneration and interface integration.
05 Extension of Thoughts
It can broaden the selection range of the base materials for such pH-responsive intelligent biomaterials, explore precise regulatory targets for the interaction and crosstalk between immune cells and stem cells in the complex microenvironment of bone defects; deeply analyze the underlying mechanism of coupling and interaction between the key signaling pathways for osteogenesis and the regulatory units for antibacterial genes, optimize the release rhythm of material active components and the compatibility and matching degree of stem cell recruitment and osteogenic differentiation process, enriching the innovative design paradigm of biomaterials that synergistically mediate bone remodeling repair by endogenous cells.
Original Source:
1. Journal: Advanced Materials
2. Publication Date: 2026-03-28
3. DOI: 10.1002/adma.729414
Authors: Zhenyu Li, Siming Zhang, Jiale Dong, Ning Li, Mo Chen, Kunzheng Wang, Bin Li, Guoqing Pan, Jiaxiang Bai, Chen Zhu
