Jul 2026· International Journal of Molecular Sciences· Vol 27· 0 citations· 214 references
Medicine
TL;DR
Current challenges, emerging trends, and future directions in the development of next-generation biomaterials that integrate biochemical and physicomechanical approaches for clinical applications in bone repair and regeneration are discussed.
Abstract
Bone regeneration remains a significant clinical challenge, particularly for large or critical-sized defects caused by trauma, disease, or congenital abnormalities. Mesenchymal stem cells (MSCs) have emerged as a promising cell source for bone tissue engineering, with their osteogenic differentiation playing a crucial role in bone repair. Biomaterials serve as scaffolds that facilitate MSC-mediated bone regeneration by providing structural support and mimicking the extracellular matrix (ECM). This review explores recent advancements in biomaterials designed to promote MSC osteogenesis through two primary approaches: biochemical and physicomechanical stimuli. Therapeutic agent-loaded scaffolds, incorporating growth factors, small molecules, gene materials, peptides, proteins, and extracellular vesicles (EVs), have been extensively studied for their ability to enhance osteogenic differentiation. However, concerns regarding toxicity, off-target effects, and regulatory limitations have led to increasing interest in biomaterials that utilize physicomechanical cues such as stiffness, viscoelasticity, topography, porosity, and dynamic forces (shear stress, compression, vibration) as alternative or complementary strategies. Furthermore, the synergistic effects of multiple physicomechanical cues are being explored to regulate MSC behavior for promoting bone regeneration. This review discusses current challenges, emerging trends, and future directions in the development of next-generation biomaterials that integrate biochemical and physicomechanical approaches for clinical applications in bone repair and regeneration.
Bone defects, especially critical-sized bone defects, still remain a major challenge due to limited intrinsic regenerative capacity. Limitations in biomimetic structure and functional performance in existing bone repair materials motivate the development of multifunctional osteogenic scaffolds. Herein, hierarchical topological nanofibrous mats (HTNFMs) functionalized with triple-helical piezoelectric collagen fibrils (PECFs, d33 = 9.92 pm V-1) were fabricated, with gradient PECF loadings of 5, 10, and 20 wt‰. Quantitative cellular assays verify that the 10 wt‰ PECF-modified group (HTNFM-10) achieves the optimal osteogenic performance, with alkaline phosphatase activity and extracellular mineral deposition reaching 1.82-fold and 2.16-fold of pure polycaprolactone (PCL) substrates, respectively. This unique structural design enables HTNFMs to create a multimodal extracellular osteogenic microenvironment with synergistic structural, mechanical, and electrical cues. Benefiting from their intrinsic piezoelectricity, HTNFMs can effectively convert endogenous cell traction forces and physiological external mechanical stimuli into bioelectric signals in situ, independent of external power sources, while providing biomimetic mechanical support for cell adhesion and tissue regeneration. The synergistic regulation of multiple microenvironmental cues significantly promotes osteogenic differentiation of bone marrow mesenchymal stem cells in vitro and accelerates bone regeneration in vivo. Furthermore, transcriptomic analysis revealed that the multimodal extracellular osteogenic microenvironment constructed by HTNFMs activates intracellular calcium signaling cascades to mediate the upregulation of osteogenic-related genes. This work proposes a self-stimulating novel piezoelectric biomimetic design strategy and validates HTNFMs as a promising platform for complex bone defect repair.
Xiaotong Wang, Xiaofeng Hu, Ruiqi Sheng et al.· Journal of materials chemist...· 0 citations
Pure and hybrid DNA hydrogels are proposed as novel therapeutic platforms to restore the dynamic balance between bone resorption and formation, thereby enhancing osteogenesis and facilitating bone regeneration and remodeling under osteoporotic conditions.
Jiaqi Chen, Hui-Yu Jia, Xin-Yue Zhang et al.· Journal of Functional Biomat...· 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.
Implementing biomaterials, scaffolds, and stem cell therapy for neural tissue regeneration introduces a revolutionary strategy in regenerative healthcare. By embedding stem cells within intricately engineered scaffolds that replicate the natural extracellular matrix (ECM), remarkable advancements in patient well-being can be realized. These biomimetic scaffolds not only emulate native tissues; they also possess a dynamic, multidimensional structure. Their biocompatibility and capacity to influence cellular metabolism position them as exceptional platforms for bioengineering. The outstanding flexibility of this technique enables optimal selection of biomaterials, scaffold designs, cells, and inorganic materials. A formidable body of evidence is emerging to highlight the vast potential of biomimetic scaffolds in tissue engineering and personalized medicine. Recent scientific studies reveal a significant rise in in vivo testing of biomimetic scaffold-based products, highlighting the critical importance of this research domain and the pressing necessity for continued exploration to facilitate the safe advancement of human-compatible biomimetic tissues and organs. This comprehensive analysis illuminates the vital conditions, challenges, and exciting innovations in scaffold design, especially in the context of brain tissue engineering. Ultimately, this review formulates a comprehensive framework for generating scaffolds that incorporate biomimetic attributes and optimal structures. The innovation of brain-implantable scaffolds holds great promise for reducing the impact of neurological disorders (ND).
Somayeh Kakehbaraei, Cyrus Jalili, A. Bahreini et al.· Stem cell research & therape...· 0 citations
This review examines the mechanobiological mechanisms by which smart nanocomposite scaffolds regulate bone regeneration, with particular emphasis on interactions between scaffolds and stem cells, immune modulation, angiogenic coupling, and translational feasibility.
Osteoporosis is characterized by progressive bone loss and structural deterioration caused by an imbalance between bone resorption and formation. Although mesenchymal stem cells (MSCs) possess strong osteogenic potential, their therapeutic use is limited by poor retention, low survival, and insufficient maturation after direct injection. Here, we report an injectable, self-healing polysaccharide hydrogel designed to enhance MSC delivery and osteogenic differentiation for bone regeneration. The hydrogel forms through dynamic Schiff-base crosslinking between succinylated chitosan and aldehyde-modified hyaluronic acid, enabling rapid in situ gelation, uniform cell encapsulation, and structural recovery after mechanical disruption. The system exhibits tunable mechanical properties compatible with osteogenic mechanotransduction. Encapsulated MSCs maintained high viability, formed spheroid-like structures, and showed accelerated osteogenic maturation, evidenced by increased alkaline phosphatase activity, enhanced mineral deposition, and upregulation of osteoblast and osteocyte markers. Notably, the hydrogel microenvironment promoted osteogenic commitment even without differentiation supplements. These findings demonstrate that the hydrogel provides a mechanically instructive and biologically supportive environment for MSC-mediated bone regeneration and represents a promising minimally invasive strategy for osteoporotic bone repair.
Jacob Beitzel, Xiaojie Lin, Yang Zhou et al.· ACS Applied Bio Materials· 0 citations
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