Search Results (395)

Background: Physical activity is widely recommended for preserving musculoskeletal health and managing osteoarthritis-related pain, although its benefits are commonly framed in terms of muscle strengthening, weight control, and physical performance. This narrative review aimed to examine movement more broadly as a physiological regulator of synovial joint homeostasis, sensory calibration, and functional adaptation. Methods: A structured literature search was performed in PubMed/MEDLINE, Scopus, and Web of Science from database inception to 1 February 2026. Experimental studies, observational studies, clinical trials, systematic reviews, meta-analyses, and selected narrative reviews addressing movement-responsive joint biology or pain regulation were considered. Evidence was synthesized across four interrelated domains: mechanical, fluidic, immune-metabolic, and sensory regulation. Results: The narrative synthesis indicates that the concept of the synovial joint as a dynamic mechano-fluidic organ in which cartilage, synovium, synovial fluid, capsule, subchondral bone, periarticular tissues, and sensory pathways interact continuously. Repeated physiological movement may promote synovial fluid exchange, lubrication, cartilage nutrition, hyaluronic acid and lubricin function, matrix turnover, anti-inflammatory signaling, proprioceptive control, and exercise-induced hypoalgesia. In contrast, inactivity and unloading may impair fluid dynamics, promote muscle inhibition, stiffness, inflammatory persistence, sensory deconditioning, and loss of function. Excessive or poorly distributed loading may also disrupt homeostasis through matrix injury, inflammation, fatigue, and nociceptive sensitization. These findings informed the proposed adaptive loading window, a hypothesis-generating conceptual framework rather than a clinically validated threshold, describing the dynamic range of movement within which joint function and pain regulation may be supported without sustained tissue or symptom aggravation. Conclusions: Movement should be viewed not only as a therapeutic intervention, but also as a continuous regulator of joint biology and perception. Its clinical value may depend on identifying an individualized loading range that supports adaptation, function, and confidence in movement while avoiding both underloading and overload. Full article

The extracellular matrix (ECM) in cancer differs from healthy tissue in structure, composition, and mechanical properties. Matricellular proteins (MCPs) play important roles in shaping ECM architecture during tissue remodeling. This narrative review, combined with a bioinformatics analysis, examines six major MCP families—Fasciclins, Tenascins, Thrombospondins, Small Leucine-Rich Proteoglycans, the SPARC family, and the CCN family—through a mechanobiological lens in bladder cancer. It summarizes current knowledge on the mechanical regulation of MCP expression, their effects on matrix stiffness, and their contributions to bladder cancer progression. Analyses of public datasets reveal that stromal cells are the predominant source of MCPs in the tumor microenvironment. Furthermore, mechanical upregulation and involvement in the formation of stiff ECM highlight MCPs as important players in a mechanotransduction feedback loop. While most MCPs exert pro-tumorigenic effects on bladder cancer cells, several display context-dependent or anti-tumorigenic activities. Existing studies have primarily focused on the isolated effects of MCPs on bladder cancer cell lines in two-dimensional systems or simple subcutaneous xenograft models. Both approaches fail to capture the context-dependent nature of MCPs and their involvement in ECM formation. These findings underscore the need for future studies to investigate the complex effects of MCPs on bladder cancer progression. Full article

Mesenchymal stem cells (MSCs) have become a focus of regenerative medicine research due to their potential utility in treating a variety of musculoskeletal disorders. Multiple qualities make them an ideal candidate to address musculoskeletal structural degeneration and inflammation, including their multi-lineage differentiation capacity, relative ease of extraction, and paracrine signaling capabilities. This narrative review examines the literature surrounding MSC-related therapies in musculoskeletal disorders, with a particular emphasis on mechanical and cellular factors affecting therapeutic efficacy. Multiple clinical and preclinical studies find that MSCs bolster tissue repair through a combination of extracellular matrix remodeling, inflammatory modulation, and regenerative signaling pathways. In addition, mechanotransduction signaling pathways have been discovered that convert mechanical tensile shear stress, compression, and strain forces into regulatory signals for matrix remodeling and tissue proliferation. Additional studies suggest that MSC efficacy and optimization are greatly influenced by a cell’s mechanical environment within the body. Further understanding of these mechanical factors can greatly bolster emerging regenerative therapies increasingly being utilized for musculoskeletal conditions. Full article

Cardiovascular diseases (CVDs) remain a leading cause of mortality worldwide, and ageing is strongly associated with progressive arterial stiffening. Age-related alterations in extracellular matrix (ECM) mechanics influence vascular smooth muscle cell (VSMC) behaviour, while sympathetic innervation represents an additional regulator of vascular homeostasis. However, how neural signalling interacts with ageing-associated mechanical conditions to regulate VSMC behaviour remains unclear. In this study, an in vitro sympathetic neuron–VSMC co-culture model was established to investigate neuro-mechanical regulation. Primary rat sympathetic neurons and A7r5 VSMCs were cultured on glass or polydimethylsiloxane (PDMS) substrates with defined stiffness (20 and 130 kPa), representing healthy and ageing-associated stiffened arterial environments, respectively. VSMC behaviour was assessed through analysis of cell area, proliferation, migration, cellular Young’s modulus (YM), and DNA damage marker γH2AX. Sympathetic neuronal co-culture was associated with reduced VSMC spreading and decreased γH2AX levels. Under the conditions tested, neural signalling exerted limited effects on cell proliferation and migration. In contrast, increased substrate stiffness promoted cell proliferation and elevated YM. Both neuronal input and substrate stiffness were associated with increased cellular YM. Together, these findings indicate that neural and mechanical cues may jointly influence VSMC behaviour within ageing-associated mechanical environments. This co-culture system provides a controllable platform for studying neuro-mechanical interactions in vascular biology. Full article

Scaffold architecture shapes tissue regeneration through the mechanical, topographical, and biochemical cues it presents to cells, yet geometrically elaborate scaffolds do not reliably produce more organized tissues, while comparatively simple architectures can exert strong organizational effects. We argue that scaffold performance is better understood by distinguishing geometric complexity from effective informational dimensionality: a relational property of the scaffold–cell system, defined as the number of independently manipulated architectural directions that produce distinguishable, above-noise changes in a jointly measured mechanotransductive response. Unlike structural entropy, fractal dimension, or feature-counting metrics, this construct depends on cellular accessibility, cue persistence, and non-redundancy. Mechanotransduction supplies its biological basis, integrating scaffold-derived cues through focal adhesions, cytoskeletal organization, nuclear deformation, and YAP/TAZ signaling, and we distinguish early resolvability from later organizational stabilization. We outline an operational strategy for estimating both from factorial scaffold libraries, common readout panels, and rank-based analysis of the response mapping, illustrated with selected experimental precedents rather than a systematic evidence sample. Positioned relative to biomimetic, mechanobiology-guided, and morphospace approaches, it yields testable predictions on dimensional compression, redundancy, and the resolvability–stability dissociation. Scaffold design is thus reframed from maximizing complexity or native resemblance toward engineering stable, cell-readable dimensions of organization. Full article

Atomic force microscopy (AFM) has emerged as a powerful platform for quantifying nanoscale mechanical properties of cells, tissues, and extracellular matrix (ECM) components, providing candidate biomarkers for disease diagnosis, classification, prognosis, and treatment monitoring. However, the clinical translation of AFM-based nanomechanical biomarkers remains limited by low throughput, operator dependence, complex force-curve interpretation, heterogeneous biological samples, and the lack of standardized analytical pipelines. Artificial intelligence (AI) and machine learning (ML) approaches are increasingly being used to address these limitations by enabling automated AFM image and force-curve analysis, multiparametric feature extraction, cell and tissue classification, quality control, and high-throughput mechanophenotyping. This review summarizes how AI and ML have already been applied to AFM-derived nanomechanical and morphological data, with emphasis on cancer, fibrotic disease, and treatment response monitoring. We discuss classical ML models, deep learning approaches, clustering, fuzzy logic methods, and emerging automated Bio-AFM workflows. We further highlight current limitations, including small datasets, limited external validation, lack of reproducible reporting standards, and insufficient integration with clinical metadata. Finally, we propose a roadmap for AI-enabled AFM mechanobiomarkers, focusing on standardized datasets, explainable models, multimodal mechano-optical imaging, and clinically relevant validation strategies. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) is frequently vascular and immune-infiltrated, yet durable responses to immune checkpoint blockade remain limited. This suggests that immune resistance may reflect tumor microenvironmental organization and mechanotransduction state rather than immune infiltration alone. We aimed to determine whether matrix reorganization and branch-specific integrin mechanosensing define immune-regulatory states in ccRCC, with particular attention to adenosine-associated immune resistance. Methods: We performed an integrative computational analysis of TCGA-KIRC bulk RNA-sequencing, clinical, survival, immune feature, and reverse-phase protein array data. Matrix- and mechanobiology-related programs were quantified using ssGSEA, compact z-score-based signatures, and principal component-based sensitivity analyses. Immune-regulatory programs, CAF and ECM scores, FAK/SRC activation features, and MINER-inferred transcriptional regulons were integrated using stage association, correlation, partial correlation, variance partitioning, survival, and transcriptional state analyses. Results: Matrix-centered transcriptional programs were the dominant stage-associated mechanobiology signal in ccRCC, including ECM deposition, collagen organization, matrix remodeling, fluid shear stress, and YAP/TAZ activity. A compact ECM-associated core (ECM_Stiffness_Core; a ten-gene signature whose highest-loading members include FN1, COL1A1, COL6A1, and LOX) captured a matrix reorganization program, indicating remodeling of ECM composition and architecture rather than uniform increases in tumor stiffness, pressure, or bulk mechanical load. Matrix remodeling was associated with CAF abundance, TGFβ signaling, CD276/B7-H3, CSF1-related myeloid biology, ENTPD1/CD39, and PRDM1, whereas associations with cytotoxic immune cells were weaker. Integrin mechanosensing separated into opposing branches: ITGA5/ILK/SRC-associated features aligned with higher-risk biology and adenosine-linked immune regulation, whereas PTK2/FAK–RHOA–ROCK components showed lower-risk directions. RPPA analyses supported SRC–FAK imbalance as an adverse signaling pattern. MINER analyses further separated matrix-associated immune-suppressive regulons from canonical integrin/focal adhesion states. Conclusions: Matrix reorganization and integrin branch imbalance appear to shift ccRCC toward distinct immune-regulatory states. We propose a conceptual model that matrix architecture may act as a directional suppressive amplifier, whereas the relative balance between ITGA5/ILK/SRC-associated signaling and canonical PTK2/FAK–RHOA–ROCK mechanosensing functions as an integrin branch rheostat. This framework identifies matrix remodeling, CD276/B7-H3, CSF1-related myeloid biology, adenosine signaling, and SRC–FAK imbalance as candidate biological axes for future investigation, including their potential relevance to combination strategies beyond PD-1/PD-L1 blockade. Future experimental, spatial, and treatment response studies may further clarify the mechanistic basis of these associations and evaluate their potential therapeutic relevance. Full article

Background/Objectives: The pericellular matrix (PCM), a highly hydrated hyaluronan (HA)-rich extracellular structure surrounding keratinocytes, serves as a critical regulator of cellular protection, mechanobiological signaling, and epidermal microenvironmental homeostasis. Increasing evidence suggests that age- and stress-associated degradation of the HA-rich PCM contributes to impaired regenerative capacity and increased cellular vulnerability. Recombinant human hyaluronan and proteoglycan link protein 1 (rhHAPLN1) has emerged as a promising PCM-stabilizing biomolecule; however, its therapeutic application remains limited by poor skin permeability resulting from the barrier properties of the stratum corneum and the molecular size constraints governing hydrophilic macromolecule delivery. Methods: In the present study, we developed Soluball^®, a dodecylamine-templated mesoporous silica-based carrier system designed to enhance the transdermal delivery of rhHAPLN1. Results: In vitro analyses demonstrated that rhHAPLN1 effectively preserved both the structural integrity and functional hydrodynamic volume of the PCM against hyaluronidase (HAdase)-induced degradation in HaCaT keratinocytes. Furthermore, rhHAPLN1 exhibited no significant cytotoxicity at concentrations up to 1 μg/mL and significantly enhanced keratinocyte proliferation under serum-free conditions. Physicochemical characterization revealed that Soluball^® possessed a relatively uniform particle size distribution (284.6 nm), a high specific surface area (1048 m²/g), and a mesoporous architecture with an average pore diameter of 3.8 nm, supporting efficient loading of hydrophilic biomolecules. Ex vivo permeation studies using human cadaver skin demonstrated that Soluball^®-encapsulated rhHAPLN1 (H-S powder) significantly enhanced cumulative transdermal permeation compared with free rhHAPLN1 (5.54% vs. 0.88%, respectively). To further evaluate platform versatility, water-soluble Vitamin C was employed as a secondary model cargo. Vita-Soluball^® exhibited markedly enhanced permeation across both Strat-M^® artificial membranes and pig epidermis, achieving cumulative permeation values of 119.12 ± 9.38 μg/mL and 150.39 ± 29.20 μg/mL, respectively. Conclusions: Collectively, these findings suggest that rhHAPLN1 functions as an effective stabilizer of the HA-rich PCM and that Soluball^® enhances the transdermal delivery of hydrophilic biomolecules. Overall, Soluball^® may represent a promising transdermal delivery platform for hydrophilic biomolecules, although further in vivo validation is warranted. Full article

Aging involves the accumulation of molecular alterations within cells and the extracellular matrix, resulting in cellular senescence and declining physiological functions. This study investigates the correlation between the biophysical environment and cellular aging, specifically examining how mechanical and biochemical cues affect cellular senescence and tissue degeneration. Cells were cultured on acrylamide hydrogels of different stiffnesses (4 and 19 kPa), and their mechanical properties were characterized by measuring Young’s modulus via compression tests. Cell proliferation, morphology, gene and protein expression, and autophagy activity were assessed using multiple assays and imaging techniques. Cells cultured on stiff hydrogels exhibited elongated morphologies, whereas cells on soft hydrogels formed spherical clusters. Notably, longevity-associated genes were upregulated in cells cultured on softer substrates. Reversibility experiments demonstrated that the aging phenotype could be reversed by modulating mechanical culture conditions, with softer environments enhancing autophagic activity. In summary, hydrogel stiffness significantly impacts aging-related cellular behavior. These findings suggest biomechanical cues as a promising strategy to promote cellular rejuvenation and combat aging. Full article

Volumetric muscle loss (VML) constitutes a significant clinical challenge, defined by the irreversible loss of skeletal muscle tissue and resulting in persistent functional deficits due to fibrosis, chronic inflammation, and insufficient endogenous regeneration. Existing clinical interventions, such as autologous grafting and free functional muscle transfer, are constrained by donor-site morbidity including infection, pain, suboptimal vascularization, and limited functional integration. Although tissue engineering has advanced considerably, no FDA-approved regenerative therapies currently exist for VML, underscoring a substantial translational gap. This review provides a systems-level synthesis of skeletal muscle repair through integrating fundamental biological processes, such as inflammation, satellite-cell activation, myogenesis, angiogenesis, and neuromuscular junction formation, with recent advances in biomaterials, scaffold engineering, and biofabrication technologies. The analysis addresses how critical scaffold design parameters, including alignment, porosity, stiffness, degradation kinetics, and bioactivity, influence cellular responses and tissue integration. Additionally, emerging strategies such as 3D bioprinting, nanofiber-based architectures, stem cell and exosome therapies, and bio-functional stimulation are evaluated inside a unified mechanobiological framework. This analysis is further extended to the regulatory setting, with emphasis on how scaffold composition, mechanism of action, and degree of biological integration affect classification pathways governed by the U.S. Food and Drug Administration. Most advanced VML therapies are anticipated to be regulated as combination products, which will require rigorous preclinical validation, standardized manufacturing processes, and carefully designed clinical studies. By integrating biological principles, engineering design, and regulatory considerations, this review highlights key opportunities, remaining challenges, and future priorities for the clinical translation of next-generation regenerative strategies for VML. Full article

Pulsatile blood flow is a fundamental characteristic of cardiovascular physiology that regulates endothelial function, vascular homeostasis, microcirculatory integrity, and organ adaptation through complex mechanobiological pathways. The widespread use of continuous-flow left ventricular assist devices (CF-LVADs) has created a unique clinical model of chronic pulsatility deprivation, whereas heart transplantation restores physiological pulsatile hemodynamics. This review examines the molecular, cellular, and systemic consequences of these contrasting circulatory states. Evidence from experimental and clinical studies indicates that reduced pulsatility during CF-LVAD support is associated with impaired endothelial mechanotransduction, glycocalyx disruption, oxidative stress, inflammatory activation, angiogenic dysregulation, acquired von Willebrand syndrome, and microvascular remodeling. These alterations contribute to bleeding, thrombosis, neurological events, and progressive end-organ dysfunction. In contrast, restoration of pulsatile flow following heart transplantation promotes recovery of endothelial signaling, nitric oxide bioavailability, vascular responsiveness, and tissue perfusion, although persistent immune-mediated injury may limit complete vascular normalization. Emerging concepts involving Piezo1 signaling, YAP/TAZ mechanotransduction, extracellular vesicles, immunometabolism, and multi-omics profiling further support the role of pulsatility as a biological regulator rather than a simple hemodynamic consequence of cardiac contraction. Understanding pulsatility-dependent cardiovascular remodeling may facilitate the development of next-generation circulatory support technologies and novel therapeutic strategies to preserve vascular health. Full article

Right ventricular (RV) failure secondary to pulmonary hypertension manifests in significant biomechanical alterations of myocardial tissue, including capillary rarefaction and enhanced stiffness and anisotropy. However, how the changes in mechanical cues affect the angiogenic potential of endothelial cells (ECs)—and thereby impact the RV failure progression—remains unclear. The aim of this study is to investigate the effects of RV-relevant substrate stiffness and anisotropy on different EC types using polyurethane urea scaffolds engineered to mimic RV tissues. We find that substrate anisotropy increased EC number but reduced metabolic activity in both cell types. In contrast, the two cell types exhibit divergent responses in their angiogenic potential and angiogenic protein secretome. For HUVECs, neovessel formation is suppressed by substrate stiffening and anisotropy, whereas for HCMECs, it is increased by stiffening and suppressed by anisotropy. Our results highlight the mechanobiological regulation of ECs in a tissue- and cell-type-dependent manner, which is critical for new biomaterial or in vitro model development for cardiac diseases. Full article

Bicuspid aortic valve (BAV) disease is a lifelong disorder in which congenital anatomy, tissue susceptibility, abnormal flow, and acquired fibrocalcific remodeling produce heterogeneous valve and aortic outcomes. This narrative review examined peer-reviewed literature indexed in PubMed/MEDLINE through June 2026 to evaluate how circulating proteomics could complement established imaging-based risk assessment. Published studies of incident aortic stenosis consistently implicate integrated stress, inflammation, apoptosis, and extracellular-matrix remodeling, with recurrent signals including GDF15, MMP12, and natriuretic peptides. These data support a long preclinical molecular phase, but existing proteomic models were developed predominantly in general aortic stenosis populations and cannot be transferred directly to BAV. We propose a five-layer framework integrating valve morphology and function, aortic phenotype and growth, flow and wall mechanics, molecular activity, and patient-specific lifetime context. In the near term, proteomics is best used for cohort enrichment, mechanistic phenotyping, and trial design rather than intervention decisions. Prospective BAV-specific cohorts, standardized imaging, repeated sampling, competing-risk analysis, external calibration, and demonstration of management-changing utility are required before clinical implementation. Molecular phenotyping should refine, not replace, guideline-based imaging and shared decision-making. Full article

The Achilles tendon, the largest and strongest tendon in the human body, exhibits dynamic adaptive changes in its structure and function through mechanobiological regulation. This review synthesizes the dual regulatory effects of mechanical loading on Achilles tendon homeostasis and pathology: Moderate mechanical stimulation activates integrin-mediated signaling pathways (including PI3K/Akt and MAPK/ERK cascades), promoting tenocyte proliferation/differentiation, collagen biosynthesis, and orderly remodeling of extracellular matrix (ECM), thereby enhancing tendon stiffness, elastic modulus, and ultimate tensile strength. Conversely, chronic overload or disuse conditions induce collagen disorganization, aberrant matrix metalloproteinase (MMP) expression, and inflammatory cascades, creating a predisposition to tendinopathy and degenerative disorders. Emerging evidence highlights the critical role of mechanotransduction in injury repair, with early-stage progressive loading regimens demonstrating enhanced healing outcomes through optimized ECM metabolism and biomechanical signal propagation. Clinically, individualized load management strategies, including blood flow restriction training and biomaterial-assisted mechanomodulation, show promise in injury prevention and rehabilitation. Future research integrating multi-omics approaches with intelligent load-monitoring technologies may clarify mechanobiological coupling mechanisms and facilitate precision interventions for Achilles tendon disorders. Full article

This study evaluates the mechanobiological responses of MC3T3-E1 cells to fluid shear stress utilizing a coupled CFD-CPM mesoscale framework. Computational fluid dynamics was utilized to calculate the distribution of fluid shear stress within the culture chamber, which was subsequently mapped onto a discrete system of lattices. The cellular Potts model was employed to simulate behaviors of the cells governed by rules for proliferation, migration, contact inhibition, and osteogenic differentiation. To accurately reflect developmental stages, the computational workflow dictated that the cells complete the phase of growth prior to the initiation of differentiation. Evaluations demonstrated that the culture region formed a relatively uniform plateau of shear stress. Within an optimal range, fluid shear stress accelerates the transition of these cells into mature osteoblasts. Furthermore, staining for alkaline phosphatase revealed responses of osteogenic differentiation strictly correlated with the local distribution of fluid shear stress. Ultimately, this study establishes a visualized framework of mesoscale modeling to analyze the collective behavior of osteoblasts under mechanical stimulation in microfluidic environments, demonstrating the feasibility of predicting subsequent extracellular matrix mineralization and providing valuable insights into the dynamic evolution of bone remodeling. Full article