Mechanobiology

Blood vessels deliver oxygen, nutrients and immune cells to all the tissues in our body. Once they reach target tissues, tissue-specific regulation of vascular permeability is critical for the controlled transport of macromolecules and immune cells across endothelial monolayers. Dysregulation of vascular integrity is involved in a number of vascular as well as non-vascular diseases. Blood flow patterns and flow rates vary depending on vessel type and geometry and regulate vascular barrier function by modulating endothelial mechanotransduction. In this review, we will focus on how shear stress influences various types of vascular permeability by acting on cell-cell adhesion, cell-ECM interaction, cytoskeletal changes and investigate related pathways. Flow-dependent vascular permeability diseases will be discussed in detail with updated therapeutic perspectives.

Mechanoadaptation, a process by which living cells adjust to the mechanical properties of the environment, is fundamental to their function and behavior. Generating mechanical forces is the main way a cell can acquire information about the physical nature of the immediate micro-environment. Crucially, mechanical force during this interaction is the sole stimulus upon which the cell performs mechanoadaptation. However, quantifying this mechanical interaction is notoriously challenging due to the interdependent relationship between mechanical force, mechanical substrate stiffness, and the resulting spatial displacements. A critical issue, often overlooked in common measurement techniques like traction force microscopy, is that a change in substrate stiffness inherently alters measurement sensitivity. This perspective argues that this oversight can lead to misinterpretation of cellular function and behavior, creating an ’illusion of adaptation.’ We present a conceptual framework to highlight the importance of accounting for the measurement sensitivity and advocate for a more accurate quantification of the biological processes governing mechanoadaptation to avoid pitfalls and advance the field of mechanobiology.

Pancreatic intraepithelial neoplasia (PanIN) is a precursor to pancreatic adenocarcinoma (PDAC) and key for early diagnosis and therapy. During PanIN, epithelial-to-mesenchymal transition (EMT) promotes invasion and early cell dissemination. Tissue mechanics change during progression, with elasticity previously modelled as a diagnostic tool. However, viscoelasticity—combining elastic and viscous properties—is increasingly recognized as critical in cancer and mechanosensitive cell behaviour. Using PDAC mouse models and 2D polyacrylamide hydrogels, this study shows that viscoelasticity shifts dynamically from healthy to PanIN tissue. By separating elasticity and viscosity, it identifies viscosity as a key driver of EMT-related phenotypic changes, suggesting an important role for facilitating invasive potential which could be a novel target for diagnostics and therapy.

Mechanical forces are fundamental regulators of cell behavior, tissue architecture and disease. The Hippo–YAP/TAZ pathway has emerged as a key mechanosensitive system that integrates extracellular matrix stiffness, cytoskeletal tension, cell–cell contact, and shear stress into transcriptional responses. Mechanical regulation of Hippo signaling operates across multiple cellular scales—from membrane-associated scaffolds and cytoskeletal dynamics to nuclear transport, chromatin organization and enhancer activation—shaping proliferation, differentiation, regeneration and tissue repair. Dysregulation of this mechanotransductive axis contributes to fibrosis, cancer progression, vascular remodeling and metabolic disorders. Recent advances reveal that Hippo signaling is structurally organized through spatially confined signaling assemblies, providing a physical framework for coupling mechanical inputs to biochemical activation. These assemblies modulate MST1/2–LATS activity, influence YAP/TAZ nuclear localization and support the formation of transcriptionally active TEAD complexes. Mechanical cues, osmotic adaptation and metabolic states converge on these regulatory architectures, enabling cells to translate physical forces into sustained gene-expression programs. Viewing Hippo signaling as a mechanochemical system unifies diverse observations across physiology, disease and emerging structural biology. This framework highlights new therapeutic opportunities, including modulation of YAP/TAZ activity through targeting upstream mechanosensors, nuclear transport mechanisms or TEAD-associated regulatory complexes.

The extracellular matrix (ECM) is a dynamic mechanochemical network that integrates biochemical ligands with physical cues—such as stiffness, viscoelasticity, topography, and confinement—to regulate cell fate and tissue homeostasis. Cells sense and transmit ECM-derived forces through integrin-based adhesions, the actin cytoskeleton, mechanosensitive ion channels, and the LINC complex, coupling cytoplasmic tension to nuclear mechanics, chromatin organization, and transcriptional programs. In this review, we summarize key mechanobiological principles across major ECM contexts and outline how “mechanical niches” are established and remodeled during development and repair. We highlight the adhesion–nucleus–chromatin axis and central transcriptional hubs, including YAP/TAZ-mediated mechanotransduction, that translate extracellular mechanics into gene expression and epigenetic memory. We further discuss how ECM stiffening, altered viscoelastic relaxation, and matrix compositional switching drive disease progression, with emphasis on fibrosis, cancer, and vascular pathologies. Finally, we survey emerging experimental platforms—tunable hydrogels, engineered and decellularized ECM, and quantitative 3D culture/organoid systems—that enable controlled perturbation of ECM mechanics and multiscale readouts. These approaches provide a foundation for improved biomarkers and therapeutic strategies aimed at normalizing pathological microenvironments and restoring tissue function.

Mechanobiological roles for zona pellucida domain (ZPD) proteins (Piopio, Dumpy) are well established in structuring insect trachea, epidermis, and tendons. A recent study by Itakura et al. (2026) fundamentally extends this framework, demonstrating that a compositionally distinct pre-cuticle assembly, the “cloud ECM” generates sustained compressive forces that mechanically constrain olfactory hair geometry to pattern functional nanoscale cuticular pores. In this Perspective, we integrate these findings into the broader landscape of ZPD mechanobiology through three original conceptual frameworks. First, we propose that cloud ECM self-organization constitutes an extracellular analogue of liquid-liquid phase separation (LLPS) operating under geometric confinement. Second, we examine the evolutionary and ecological tunability of cloud ECM mechanics as a parameter for olfactory performance, noting how multi-component functional redundancy refines evolutionary inference. Third, we identify a novel mechanobiological route to environmental olfactory impairment via stress-induced cloud ECM degradation. Collectively, these frameworks position ZPD-mediated extracellular mechanostatics as a conserved, evolutionarily malleable principle whose resolution demands the integration of quantitative biophysics, comparative genomics, and applied entomology.

Mechanobiology investigates how mechanical forces influence cellular behavior across scales, from molecular interactions to tissue-level responses. Advances in force measurement, high-resolution imaging, and multiomic profiling have generated datasets of increasing dimensionality, modality, and scale. Artificial intelligence (AI) and machine learning (ML) methods are well suited to analyzing such data, predicting cellular responses to mechanical stimuli, and identifying candidate mechanistic relationships. Here we review key applications of AI and ML in mechanobiology, including force inference from imaging data, tissue stiffness mapping, cell phenotype classification, chromatin-based prediction of protein localization, and computational modeling of mechanosensitive protein dynamics. We discuss emerging tools such as foundation models for cell segmentation and protein structure prediction, as well as the integration of AI-predicted mechanical properties with spatial transcriptomics. We also examine current limitations—including data scarcity, the gap between proof-of-concept and validated tools, and the challenge of causal interpretation—and identify opportunities for real-time closed-loop systems, therapeutic translation, and multiscale modeling.

Nanotopography has emerged as a powerful tool for regulating cellular behavior through mechanotransduction. This review explores how engineered nanoscale features, including grooves, ridges, and pillars, modulate integrin clustering, cytoskeletal organization, and nuclear signaling via YAP/TAZ and PIEZO1, ultimately influencing cell fate, epigenetic remodeling, and tissue regeneration. We discuss the hierarchical pathways linking extracellular topographies to chromatin regulation, emphasizing cell-type–specific responses in mesenchymal stem cells, fibroblasts, and myoblasts. Advances in nanofabrication, including electron-beam lithography, nanoimprinting, electrospinning, and self-assembly, have enabled reproducible topographical platforms to mimic extracellular matrix geometry. These have been applied across diverse biomedical fields, including bone, nerve, skin, and liver tissue engineering, as well as for implant surface optimization. Despite the growing clinical potential of these, challenges remain in topography standardization, biomarker development, sterilization resilience, and in vivo integration. Future directions include AI-driven design, dynamic topography, and integrated physical–biochemical cue delivery. Together, these strategies will drive next-generation mechanotherapeutic materials and deepen our understanding of cell–material interactions at the nanoscale.

Localized hyperthermia not only causes thermal injury to the tissues but also causes mechanical deformation of the tissues due to expansion of the tissues resulting from temperature changes, stress creation, and strain concentration. In this paper, an exclusive mechanobiological model for nanoparticle-enhanced hyperthermia is developed by modeling transient bioheat transfer, Arrhenius thermal damage, and thermoelastic responses of the tissues due to temperature change. It combines the transient Pennes bioheat transfer model, spatially heterogeneous nanoparticle-specific absorption rate-based heat sources, Arrhenius thermal damage kinetics, and linear isotropic thermoelasticity based on temperature-based eigenstrain. To circumvent the requirement for domain discretization to incorporate internal heat source, perfusion, and transient heat storage in the bioheat transfer model, a Dual Reciprocity Boundary Element Model is developed. Temperature histories are then used to assess the level of accumulated thermal damage and provide the inputs for thermoelastic boundary integral formulation, where displacements, strains, and stresses will be obtained. Through the correlation of nanoparticle-generated internal heat into mechanical deformations, the proposed methodology establishes the connection between thermal therapy, tissue reaction, and elastography. Numerical validation through manufactured solutions, comparison to the analytical steady state solution, and overall energy balance analysis reveals the first-order convergence and stability of transient simulation along with overall energy conservation up to 2.7% in the transient energy balance test. The simulations show that nanoparticle heating creates detectable thermoelastic displacements, which could be the early signs of treatment.

Graphical Abstract

Cell membrane tension is a fundamental biophysical parameter that governs a wide range of cellular processes, including migration, division, mechanosensitive signaling, and membrane repair. Rather than serving as a passive structural property, membrane tension functions as a dynamic mechanical regulator that integrates cytoskeletal forces, membrane reservoir dynamics, and extracellular mechanical cues to coordinate cell behavior. In this review, we discuss the molecular mechanisms underlying membrane tension regulation, its pathological significance, and the emerging experimental techniques available for its measurement and manipulation. By integrating mechanobiological and disease-oriented perspectives, this review presents a comprehensive framework for understanding how membrane tension is regulated and perturbed in health and disease, and highlights open questions and future directions for the field.

Diabetes mellitus remains a growing global health burden, yet advances in mechanobiology highlight a pivotal role for mechanical cues in regulating pancreatic β-cell function. This review summarizes evidence that the extracellular matrix (ECM) surrounding pancreatic islets is not merely structural support but a dynamic mechanosignaling platform integrating biochemical and physical stimuli to govern β-cell fate. In healthy tissue, a compliant ECM enriched in collagen IV and laminin supports optimal insulin secretion and glucose responsiveness. In contrast, obesity- and diabetes-associated fibrosis induces excessive ECM deposition, aberrant crosslinking, and pathological stiffening, disrupting mechanosensing, glucose signaling, and β-cell maturation. Mechanical forces are transmitted through integrin-mediated focal adhesions and FAK activation, triggering MAPK, PI3K–AKT, and Rho GTPase pathways that regulate cytoskeletal tension, transcriptional programming, and survival. Mechanosensitive Piezo1 channels convert membrane stretch into Ca²⁺ influx, modulating insulin exocytosis, while the Hippo–YAP/TAZ axis interprets matrix stiffness to control β-cell proliferation and phenotypic stability. Chronic hyperglycemia further induces nuclear deformation and chromatin remodeling, impairing transcription factors such as PDX1 and accelerating β-cell dysfunction. These pathways intersect with inflammatory and oxidative stress signaling, driving apoptosis and progressive β-cell loss in type 2 diabetes. By reframing diabetes as a disorder of aberrant cell–matrix communication, this review highlights mechanobiology-guided strategies including stiffness-tunable matrices, viscoelastic hydrogels, and mechano-responsive scaffolds to restore a functional microenvironment. Targeting ECM remodeling, modulating Piezo1 activity, and fine-tuning YAP signaling, particularly with stem cell-derived β-cell replacement, offers a promising approach for restoring β-cell mass and achieving durable glycemic control.

Cells continuously sense and respond to mechanical cues from their microenvironment, converting physical stimuli into biochemical signals that regulate gene expression and cellular behavior. This review focuses on the structural and molecular basis of nuclear mechanotransduction and highlights recent advances in fluorescence resonance energy transfer (FRET)-based biosensors developed to interrogate these processes in living cells. We conceptualize nuclear mechanotransduction as three interconnected pillars: (i) direct force transmission through the LINC complex, (ii) structural mechanosensing mediated by nuclear deformation involving the nuclear lamina and nuclear pore complex, and (iii) transcriptional mechanotransduction driven by epigenetic regulation and mechanosensitive signaling pathways. Because mechanical signals are rapid, spatially localized, and highly dynamic, FRET has emerged as a powerful approach for real-time visualization of nuclear mechanics. Its sensitivity to nanoscale distance and molecular orientation enables detection of force-induced protein rearrangements and dynamic structural transitions within the nucleus. Accordingly, we review recent FRET-based strategies for probing force transmission at the nuclear envelope, lamina strain, and LEM-domain/BAF protein dynamics, as well as biosensors reporting mechanically regulated histone modifications and YAP nuclear localization. Together, this review provides a unified framework for understanding nuclear mechanotransduction and underscores the expanding role of FRET-based tools in dissecting nuclear mechanics with high spatiotemporal resolution.

Mechanobiology investigates mechanotransduction—the conversion of mechanical forces into biochemical signals essential for development, homeostasis, and pathophysiology. While contact-based techniques provided foundational insights, they are limited by surface-centered analysis, substrate artifacts, and insufficient 3D spatiotemporal resolution. This review systematically explores non-invasive optical technologies designed to overcome these constraints. We first overview advancements in high-resolution 3D imaging and high-throughput platforms, followed by a discussion on label-free viscoelastic mapping via Brillouin microscopy and depth-resolved quantification via optical coherence elastography (OCE). We also address molecular-level readouts via fluorescence resonance energy transfer (FRET)-based tension sensors and pN-scale manipulation using optical tweezers, extending the research paradigm to active spatiotemporal control via optogenetics. Finally, we discuss the clinical potential of these tools, emphasizing their role in establishing quantitative biomarkers and mechanistic insights for diverse physiological and pathological conditions.

Mechanobiology has emerged as a critical framework for understanding how physical forces regulate cell behavior, tissue homeostasis, regeneration, and disease progression. This review examines the development of smart mechanobiological systems, defined as force-responsive biomaterials that can sense, transmit, and adapt to dynamic mechanical cues in living tissues. First, the mechanobiological foundations relevant to material design are discussed, including tissue stiffness, viscoelasticity, stress relaxation, mechanotransduction pathways, and the role of dynamic microenvironments in repair and pathology. Next, major classes of engineered smart biomaterials are reviewed, with emphasis on mechanically responsive polymers, hydrogels, multifunctional materials, mechanoresponsive drug delivery systems, and programmable self-adaptive platforms. The review further summarizes applications in regenerative medicine, including wound healing, musculoskeletal repair, cardiovascular regeneration, neural repair, and stem-cell engineering, followed by disease-focused applications in fibrosis, cancer, cardiovascular disorders, and chronic wounds. Across these contexts, smart materials are shown to offer advantages over passive systems by enabling spatiotemporal control, adaptive mechanical regulation, and improved therapeutic precision.