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.
Abstract
Critical-sized and load-bearing bone defects remain major clinical challenges. The intrinsic regenerative capacity of bone is frequently insufficient to achieve complete functional repair. Recent advances in smart nanocomposite scaffolds have shifted bone tissue engineering from passive structural support toward biologically instructive platforms capable of dynamically regulating cellular behavior and tissue repair. These advances represent a major conceptual and mechanobiological transformation in scaffold design; however, they should not be interpreted as indicating widespread clinical readiness. Despite encouraging preclinical outcomes, most smart scaffold systems remain in the preclinical or early translational stage because critical challenges related to mechanical reliability, scalable manufacturing, long-term biosafety, and regulatory approval remain unresolved. 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. Key regenerative pathways involving osteoconduction, mechanotransduction, ion-mediated signaling, electrical conductivity, and stimuli-responsive activation are analyzed in relation to scaffold composition, nanotopography, and microenvironmental regulation. Comparative translational analysis is provided for bone marrow-derived mesenchymal stem cells, adipose-derived stem cells, induced pluripotent stem cell-derived progenitors, and emerging exosome-based acellular regenerative strategies. In addition, major translational barriers, including manufacturing scalability, mechanical limitations in load-bearing environments, regulatory complexity, long-term biosafety, and reproducibility of cell-based therapies, are critically analyzed. Overall, this review provides a mechanobiological and translational framework for development of clinically applicable smart biomaterials for next-generation bone regenerative engineering. This review presents an evidence-stratified translational framework linking mechanistic pathways to supporting study types and corresponding translational barriers.
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
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
Repair of the tendon-to-bone interface remains a major clinical challenge owing to its complex hierarchical architecture and limited intrinsic regenerative capacity. Decellularized biomaterials have emerged as promising scaffolds for tendon and ligament repair due to their native extracellular matrix composition, structural similarity, and biological activity. This review summarizes recent advances in the application of decellularized biomaterials for tendon-to-bone interface healing, covering both preclinical investigations and clinical trials of scaffolds derived from diverse sources, including porcine small intestinal submucosa, dermal matrix, tendon, amniotic membrane, pericardium, and Wharton's jelly. Particular emphasis is placed on current design strategies aimed at improving regenerative performance, including biomimetic architectural design, three-dimensional bioprinting for gradient interface engineering, regulation of the immune microenvironment, integration of stem cells or their derivatives, and sequential delivery of bioactive components. Despite encouraging preclinical outcomes, clinical translation remains limited and inconsistent. Major barriers include residual immunogenicity, batch-to-batch variations in bioactivity, an incomplete understanding of the mechanisms governing interface regeneration, and the scarcity of high-quality clinical evidence. Future research should therefore focus on optimizing decellularization protocols, refining scaffold architecture and functional modification strategies, integrating stem cells or stem cell-derived therapeutics, and conducting rigorous translational and clinical studies to bridge the gap between experimental success and clinical application. STATEMENT OF SIGNIFICANCE: Tendon-to-bone interface (TBI) healing remains a major challenge in regenerative medicine because the native enthesis has a complex graded architecture that is difficult to restore after injury. Decellularized biomaterials are promising for TBI repair because they retain native extracellular matrix components, structural biomimicry, and intrinsic bioactivity. This review provides a critical synthesis of recent advances in decellularized biomaterials for TBI healing, covering tissue sources and preclinical and clinical evidence. It also highlights emerging functionalization strategies, including biomimetic design, three-dimensional bioprinting, immune modulation, stem cell integration, and spatiotemporally controlled bioactive delivery. By addressing both regenerative potential and translational barriers, this review offers a timely framework for designing decellularized scaffolds for clinically effective tendon-to-bone regeneration.
Scaffold carriers are three dimensional porous biomaterial structures that provide structural support, metabolic signalling and an appropriate cellular environment for tissue regeneration. This article covers the effects of scaffold carrier mechanisms on tissue healing and rehabilitation in three key tissue systems: bone and cartilage, skin and soft tissue and neural tissue. This review integrates principles of extracellular matrix (ECM) biomimicry, scaffold material classification frameworks and cell-scaffold mechanotransduction theory, and uses evidence from in vitro and in vivo studies to illustrate how the scaffold architecture, material composition, surface chemistry and degradation kinetics collectively dictate the cellular responses (adhesion, proliferation and directed differentiation) that underlie functional tissue regeneration. Major design challenges, such as immunogenicity, inadequate vascularisation and degradation–regeneration kinetic mismatch, are comprehensively discussed. Finally, the paper explores the emerging concept of stimulus-responsive smart scaffolds as the next-generation technique to dynamically recapitulate the natural ECM environment and overcome translational restrictions that now hinder clinical use.
Yu-Wei Jiang· International Journal of Pub...· 0 citations
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
Tissue engineering aims to repair, replace, or regenerate damaged tissues by integrating principles of biology, engineering, and material science. Traditional ex vivo strategies, involving prefabricated cell/scaffold constructs followed by implantation, have shown promise but face significant limitations, including poor vascularization, immune rejection, high costs, and clinical translation challenges. These limitations have driven the emergence of in situ tissue engineering, which harnesses the body’s intrinsic regenerative capacity by recruiting endogenous stem or progenitor cells to sites of injury for repair. A key requirement for successful in situ regeneration is the design of biomimetic three‐dimensional scaffolds capable of delivering bioactive molecules such as growth factors and cytokines in a controlled and spatiotemporal manner. In addition to biochemical cues, mechanobiology plays a central role by regulating cell adhesion, migration, proliferation, and differentiation through mechanotransduction pathways involving cytoskeletal remodeling, extracellular matrix (ECM) dynamics, and nuclear signaling. This review highlights mechanobiology‐mediated strategies, scaffold designs, and applications for hard and soft tissue repair, as well as challenges and future directions in regenerative medicine.
H. Agbe, B. N. Jaato, Dominic A Dadzie et al.· International Journal of Bio...· 0 citations