Jul 2026· Advancement of science· 0 citations· 43 references
Medicine
TL;DR
A dynamic stiffness hydrogel system designed to mimic the stiffness variation of the ECM during bone repair, based on a 3D interpenetrating polymer network, that exhibited the ability to repair critical‐sized bone defects, underscoring its therapeutic potential.
Abstract
ABSTRACT Bone defect healing is a dynamic process involving changes in the mechanical properties of the extracellular matrix (ECM), which significantly influence cellular behavior and tissue regeneration. In this study, we developed a dynamic stiffness hydrogel system designed to mimic the stiffness variation of the ECM during bone repair. The hydrogel, based on a 3D interpenetrating polymer network, enables in situ modulation of matrix stiffness by adjusting calcium ion concentrations through photothermal effects induced under near‐infrared (NIR) irradiation. The dynamic stiffness of the hydrogel was shown to support stem cell maintenance and promote osteogenic differentiation, aligning with the ECM characteristics observed in natural bone repair processes. Both in vitro and in vivo studies demonstrated that the mechanical cues provided by the hydrogel system significantly impact stem cell stemness and osteogenic potential. Furthermore, the hydrogel exhibited the ability to repair critical‐sized bone defects, underscoring its therapeutic potential. This work introduces a novel platform for bone tissue engineering, combining biomimicry and functional adaptability to optimize bone regeneration and laying the foundation for future clinical applications.
Piezoelectric hydrogels have emerged as a class of biomaterials that have garnered significant attention in bone tissue engineering in recent years. Their unique property lies in their ability to generate electrical charges under mechanical deformation. This piezoelectric effect is key to enhancing bone regeneration by mimicking the natural mechanical forces that stimulate osteogenesis in vivo. With their high water content, elasticity, biocompatibility, and capacity to modulate cellular responses through electrical stimulation (ES), they present an ideal choice for bone defect repair. Recent studies have demonstrated that ES can significantly promote osteoblast differentiation and bone formation, making piezoelectric hydrogels a critical factor in facilitating bone tissue regeneration. By integrating piezoelectric materials into hydrogels, they not only support cell growth but also actively promote bone healing through mechanoelectrical signaling. Specifically, this review (i) quantifies the range of piezoelectric coefficients and electrical outputs reported for hydrogels, (ii) critically compares fabrication methods with their scalability limitations, and (iii) outlines design guidelines for achieving stable, clinically translatable piezoelectric systems. By bridging materials science and bioelectric medicine, this review provides a roadmap for developing next-generation bone repair scaffolds. Unlike previous narrative reviews, our work provides a critical comparative assessment—quantitatively comparing piezoelectric coefficients, fabrication scalability, and translational bottlenecks.
Effective tissue regeneration requires precise spatiotemporal therapeutic delivery while maintaining scaffold mechanical integrity, which remains a major challenge in regenerative medicine. Here, we present an ultrasound (US)-activated tissue regeneration platform based on engineered osteogenic microbubbles (MMB-BMPs) embedded in a dynamic hyaluronic acid hydrogel (dHA), forming a mechanically robust scaffold (dHAMBH). Upon repeated US stimulation at the resonant frequency, MMB-BMPs underwent stable oscillation within the hydrogel, enabling stepwise, on-demand release of iron oxide nanoparticles (IONPs) and bone morphogenetic protein-2 (BMP-2), while maintaining scaffold integrity after multiple stimulations cycles. This controlled co-delivery enhances osteogenic differentiation of human bone marrow-derived mesenchymal stromal cells (hMSCs). In a mouse critical-sized calvarial defect model, the dHAMBH hydrogel combined with US stimulation accelerated bone regeneration, achieving a 1.7-fold increase in new bone volume compared with the non-US stimulated control. Overall, this work establishes a US-activated platform that enables precise, repeatable therapeutic delivery to enhance tissue regeneration.
Lili Ren, Jingyi Su, Yuxuan Chen et al.· Nano Reseach· 0 citations
This review critically examines recent advances in the development and application of HAp–hydrogel composites for cartilage regeneration, highlighting material design principles, fabrication strategies, healing mechanisms, and the key challenges that continue to influence their clinical translation.
Bone defects remain a significant clinical challenge due to the limited regenerative capacity. Biomaterials can offer effective therapeutic approaches to address this challenge, where their physical properties play a critical role in determining the success of regeneration. Here, we fabricated cryogelated 3D porous scaffolds with independently controlled pore sizes and stiffness. These scaffolds were then seeded separately with bone marrow stromal cells (BMSCs) and MLO-A5 cells to create osteogenic cell-scaffold composites. To determine the optimal physical properties for promoting bone regeneration, we evaluated the scaffolds using both in vitro osteogenic cultures and a rat critical-sized calvarial defect model. Transcriptomic analysis was performed concurrently to explore the molecular link between physical scaffold cues and osteogenic differentiation. The results indicated that the small-pore high-stiffness scaffold exhibited the optimal osteogenic performance in vitro. In rats, the small pore scaffold groups also showed superior bone regeneration. Furthermore, transcriptomic analysis revealed that scaffold pore size significantly changed the expression of Apolipoprotein E (ApoE) and Osteoglycin (OGN). Our findings suggest a feasible strategy to enhance the efficiency of bone regeneration by leveraging the properties of tailored scaffolds, enabling personalized repair approaches.
Qianqian Chen, Shichun Xu, Yiqi Su et al.· Stem cell research & therape...· 0 citations
Successful functional tissue regeneration demands biomaterials that can recapitulate the dynamic structural, mechanical, and biochemical properties of native extracellular matrices (ECMs). Conventional biomaterials fall short in this regard. Biomimetic hydrogels serve as a transformative paradigm rather than simple scaffolds, evolving from structural mimics to actively programmable platforms for cell guidance. This review first dissects the design principles for hydrogels to mimic key ECM features, including biochemical composition, spatiotemporal microenvironment, and tunable mechanical properties. It then illustrates how these biologically inspired principles contribute to advanced functions such as strong adhesion, self-healing, adaptive lubrication, and intelligent responsiveness. We further discuss how these integrated properties overcome tissue-specific regeneration challenges in osteochondral defects, nerve injuries, and chronic wounds, establishing a function-driven design framework that links material performance to clinical efficacy. Finally, we propose a development roadmap for next-generation intelligent hydrogels. We highlight the importance of constructing systems with closed-loop feedback to enable dynamic adaptation to the changing microenvironment. The translation of such intelligent systems via scalable fabrication and strict validation represents a critical research direction. This review summarizes recent progress and provides a conceptual framework for developing biomimetic hydrogels into interactive therapeutic agents that synergize with tissue regeneration.
Kaige Gao, Yutian Guan, Jin Lei et al.· International journal of pha...· 0 citations
Introduction Regenerative endodontic therapy aims to restore the pulp-dentin complex through biological approaches; however, current cell-free techniques often fail to achieve true dental pulp regeneration and may result in fibrous tissue formation or canal calcification. This study investigated dynamic hydrogels as advanced scaffolds for dental pulp stem cell (DPSC)-mediated regeneration, leveraging their viscoelastic properties to regulate cellular behavior and immune responses. Methods Dynamic hydrogels were synthesized using host-guest chemistry (Gel-Mal/HA-Ada-CD-SH) to mimic aspects of the native extracellular matrix and were compared with non-dynamic Gel-Mal hydrogels. DPSCs and macrophages were encapsulated within the hydrogels to evaluate cellular viability, morphology, inflammatory marker expression, and gene expression profiles. Results Dynamic hydrogels exhibited a distinct porous microarchitecture and significantly increased NF-κB and VEGF expression while reducing IL-1RA expression compared with non-dynamic hydrogels. Gene expression analysis demonstrated significantly increased TGFβ1, SMAD3, and MAPK expression, together with reduced CD80 expression, in macrophages cultured within dynamic hydrogels. Although iNOS expression was lower in the dynamic hydrogel group, the difference was not statistically significant. Discussion These findings suggest that dynamic hydrogels do not simply suppress inflammatory signaling but may modulate inflammatory and tissue remodeling pathways while promoting angiogenesis-associated responses. Limitations of the study include the short-term in vitro design and evaluation of a limited panel of inflammatory and fibrosis-associated markers. Within these limitations, dynamic hydrogels demonstrated favorable cellular and immunomodulatory responses and may provide a biologically active microenvironment that supports cellular activities relevant to regenerative endodontic applications. Further in vivo studies are required to validate their translational potential.
Y. AlMaimouni, Weihao Yuan, Shorouq Houtari et al.· Frontiers in Dental Medicine· 0 citations
