Aug 2026· Journal of Functional Biomaterials· 0 citations· 211 references
TL;DR
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.
Abstract
DNA hydrogels are an emerging class of biomaterials with programmability, biodegradability, biocompatibility, and dynamic responsiveness, enabling precise regulation of osteoblast and mesenchymal stem cell (MSC) proliferation and differentiation, activation of key signaling pathways, and promotion of angiogenesis and bone matrix mineralization. In contrast, conventional bone repair materials exhibit limitations including poor mechanical strength, uncontrollable degradation, and inadequate matching with native bone properties, restricting their application in osteoporotic defect repair. Current osteoporotic defect therapies, mainly anti-resorptive and anabolic agents, remain insufficient for many patients. Here, we propose pure and hybrid DNA hydrogels 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. Although challenges such as high production cost and long-term safety persist, integration with advanced technologies (e.g., 3D printing and gene editing) may provide theoretical support for further investigation of personalized and intelligent therapeutic strategies at the pre-clinical research stage, offering new insights into osteoporotic bone defects and bone tissue regeneration.
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.
Bofeng Pan, Adam Maalal, D. Hao· International Journal of Mol...· 0 citations
Bone is a mineralized connective tissue composed of osteoblasts, osteocytes, and osteoclasts, and its integrity is essential for structural and physiological function. Defects arising from trauma, tumors, or developmental abnormalities often require surgical reconstruction to restore normal performance. Autografts and allografts have long served as standard treatments for bone repair, however, their usefulness is restricted by limited availability, donor‑site complications, and the potential transmission of underlying diseases. These challenges have accelerated interest in bone tissue engineering (BTE) as an alternative strategy capable of enhancing regeneration while reducing postoperative risks. Advances in three‑dimensional (3D) printing have introduced powerful technique for fabrication of scaffolds with precisely controlled architectures and tunable mechanical and biological characteristics. This technology enables the creation of porous constructs that mimic the structural complexity of native bone, supporting cell infiltration, nutrient transport, and vascularization. Effective scaffolds for BTE must demonstrate biocompatibility, biodegradability, appropriate strength and stiffness, and the ability to promote osteogenesis and angiogenesis. Among natural polymers, alginate (Alg) has become a prominent candidate due to its inherent biocompatibility, degradability, abundance, low cost, and non‑immunogenic nature. Its versatility makes it suitable for developing customized 3D‑printed scaffolds. Additionally, bioactive glasses (BGs) are widely incorporated into composite scaffolds because their composition closely resembles the mineral phase of bone. BGs significantly enhance osteoconductivity, support mineral deposition, and can improve the mechanical resilience of polymer-based constructs. This review highlights recent progress in 3D‑printed Alg-based scaffolds for BTE, emphasizing how advanced fabrication techniques and BGs incorporation contribute to improved biological performance and structural reinforcement.
Afsaneh Jahani, M. H. Ebrahimzadeh, Ali Moradi et al.· The Archives of Bone & Joint...· 1 citation
Cranial bone defects remain a significant clinical challenge due to their limited intrinsic regenerative capacity and the complexity of coordinating osteogenesis, angiogenesis, and immune responses within a confined and poorly vascularised environment. Conventional approaches, including autologous grafts and synthetic implants, provide structural support but fail to actively modulate the biological processes required for effective bone regeneration. In this context, hydrogel-based systems have emerged as versatile platforms for localized and controlled drug delivery in cranial bone tissue engineering (BTE). This review provides a comprehensive overview of hydrogel-based delivery strategies designed to regulate the spatiotemporal presentation of bioactive agents within cranial defects. The main classes of hydrogels, natural, synthetic, semi-synthetic, and hybrid systems, are discussed in relation to their physicochemical properties and suitability for drug delivery applications. Current delivery approaches are analysed, including cell-free systems (growth factors, peptides, bioactive ions, nucleic acids, and small molecules drugs), cell-based platforms, and multifunctional systems integrating secondary carriers such as nanoparticles (NPs), microparticles (MPs), and extracellular vesicles (EVs). Particular emphasis is placed on how hydrogel design parameters, including crosslinking density, degradation kinetics, and responsiveness to microenvironmental cues, govern therapeutic release and influence regenerative outcomes. Emerging strategies and key translational challenges are also highlighted.
Martina Salvati, A. Vita, Alessandro Arcovito et al.· Journal of Functional Biomat...· 0 citations
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.
Yuxin Yang, Fan Yang, Lu Wang et al.· Advancement of science· 0 citations
Bone regeneration presents a significant clinical challenge due to the complex interplay between biological processes and the local mechanical environment. While polymeric scaffolds are widely utilized for their tunable physicochemical properties, traditional designs often fail to replicate the dynamic mechanical cues required for optimal tissue remodeling. This review critically examines the mechanobiological design of bioinspired polymeric scaffolds. We first categorize native bone mechanics and the role of mechanical stimuli-such as stiffness, fluid shear, and stability-in regulating the fracture healing cascade. We then bridge these biological principles with advanced fabrication strategies, analyzing how natural, synthetic, and composite polymers can be engineered to mimic the hierarchical stiffness and bioactivity of native bone. Furthermore, we discuss the role of computational modeling (e.g., Finite Element Analysis) in predicting scaffold performance and highlight emerging technologies, including 4D printing and piezoelectric scaffolds, which offer time-dependent and mechano-electrical adaptability. Finally, we address current barriers to clinical translation and propose future directions for mechanically adaptive systems that actively guide regeneration.
Shengyu Lyu, Jing Wang, Xiaoyan Ren et al.· Tissue engineering. Part B,...· 0 citations
Articular cartilage defects remain a significant clinical challenge due to the limited intrinsic regenerative capacity of cartilage and the inability of many current therapeutic approaches to restore the structure and function of native hyaline tissue. As a result, considerable research efforts have been directed toward the development of tissue-engineering and biomaterial-based strategies capable of promoting more effective regeneration. Among these, hydroxyapatite–hydrogel (HAp–hydrogel) composites have emerged as particularly promising candidates because they combine the biological functionality of HAp with the structural versatility of hydrogel networks. Hydrogels provide a highly hydrated, extracellular matrix-like environment that supports cell survival, facilitates matrix deposition, and enables the localized delivery of therapeutic agents. At the same time, their physicochemical properties can be tailored through a variety of crosslinking approaches and advanced responsive design strategies. The incorporation of HAp, either in nano- or microscale form, contributes to mechanical reinforcement, supports subchondral bone regeneration, and influences cellular behavior through both biochemical and mechanotransductive mechanisms. Beyond promoting chondrogenic differentiation, HAp–hydrogel composites have also been investigated for their capacity to modulate inflammation, stimulate angiogenesis within the subchondral region, provide antibacterial protection, and maintain a microenvironment conducive to tissue repair. 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.
A new method for surgically removing training examples from a model reveals that as datasets grow, the link between what a model learns and what it produces dissolves.
