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Numerous hypotheses invoke tissue stiffness as a key parameter that regulates morphogenesis and disease progression. However, current methods are insufficient to test hypotheses that concern physical properties deep in living tissues. Here we introduce, validate, and apply a magnetic device that generates a uniform magnetic field gradient within a space that is sufficient to accommodate an organ-stage mouse embryo under live conditions. The method allows rapid, nontoxic measurement of the three-dimensional (3D) spatial distribution of viscoelastic properties within mesenchyme and epithelia. Using the device, we identify an anteriorly biased mesodermal stiffness gradient along which cells move to shape the early limb bud. The stiffness gradient corresponds to a Wnt5a-dependent domain of fibronectin expression, raising the possibility that durotaxis underlies cell movements. Three-dimensional stiffness mapping enables the generation of hypotheses and potentially the rigorous testing of mechanisms of development and disease.

The soleus is an important plantarflexor muscle with complex fascicle and connective tissue arrangement. In this study we created an image-based finite element model representing the 3D structure of the soleus muscle and its aponeurosis connective tissue, including distinct fascicle architecture of the posterior and anterior compartments. The model was used to simulate passive and active soleus lengthening during ankle motion to predict tissue displacements and fascicle architecture changes. Both the model’s initial architecture and changes incurred during passive lengthening were consistent with prior in vivo data from diffusion tensor imaging. Model predictions of active lengthening were consistent with axial plane muscle displacements that we measured in eight subjects’ lower legs using cine DENSE (Displacement Encoding with Stimulated Echoes) MRI during eccentric dorsiflexion. Regional strains were variable and nonuniform in the model, but average fascicle strains were similar between the compartments for both passive (anterior: 0.18 ± 0.06, posterior: 0.19 ± 0.05) and active (anterior: 0.12 ± 0.05, posterior: 0.13 ± 0.06) lengthening and were two- to three-times greater than muscle belly strain (0.06). We used additional model simulations to investigate the effects of aponeurosis material properties on muscle deformation, by independently varying the longitudinal or transverse stiffness of the posterior or anterior aponeurosis. Results of model variations elucidate how properties of soleus aponeuroses contribute to fascicle architecture changes. Greater longitudinal stiffness of posterior compared to anterior aponeurosis promoted more uniform spatial distribution of muscle tissue deformation. Reduced transverse stiffness in both aponeuroses resulted in larger differences between passive and active soleus lengthening.

Pancreatic ductal adenocarcinoma (PDAC) has an extraordinarily dense fibrotic stroma that impedes tumor perfusion and delivery of anticancer drugs. Since the extracellular matrix (ECM) comprises the bulk of the stroma, it is primarily responsible for the increased interstitial tissue pressure and stiff mechanical properties of the stroma. Besides its mechanical influence, the ECM provides important biochemical and physical cues that promote survival, proliferation, and metastasis. By serving as a nutritional source, the ECM also enables PDAC cells to survive under the nutrient-poor conditions. While therapeutic strategies using stroma-depleting drugs have yielded disappointing results, an increasing body of research indicates the ECM may offer a variety of potential therapeutic targets. As preclinical studies of ECM-targeted drugs have shown promising effects, a number of clinical trials are currently investigating agents with the potential to advance the future treatment of PDAC. Thus, the present review seeks to give an overview of the complex relationship between the ECM and PDAC.

Handheld percussive therapy (PT) massage guns have seen a rapid rise in use and with-it increased attention within injury prevention and sport performance settings. Early studies have proposed beneficial effects upon range of motion (ROM), however the mechanism behind these increases remains unreported. This study aimed to determine the influence of a minimal frequency PT dose upon ROM and myotonometry outcomes. Twenty participants (N = 20; 13 males and 7 females, height 1.78cm ± 9.62; weight 77.35kg ± 8.46) participants were allocated to either a PT group receiving 2 x 60-seconds (plus 30-seconds rest) via a Theragun™ Pro4 to the hamstrings covering a standardised 20 lengths from proximal to distal via the standard ball attachment at 1 bar of pressure or a control group (CON) of 2-minutes 30-seconds passive supine rest. Pre and post intervention outcomes were measured for ROM via passive straight leg raise (PSLR) and tissue dynamics via MyotonPro (Tone, Stiffness, Elasticity, Relaxation Time). Results showed significant within-group increases (p < 0.0001, ηp2 0.656, +11.4%) in ROM following PT and between group difference against CON (P < 0.026). Significant within-group differences in stiffness (p < 0.016, ηp2 0.144, -6%), tone (p < 0.003, ηp2 0.213, +2%) and relaxation time (p < 0.002, ηp2 0.232, +6.3%) were also reported following PT. No significant difference was reported in elasticity (P > 0.05) or any other between group outcomes. PT therapy can provide an acute increase in hamstring group ROM following a resultant decrease in tissue stiffness.

Lower limb tissue stiffness is contingent on various factors, including location, tissue composition, loading rates, and the geometry of the indenting object. Previous studies demonstrated that tissue stiffness varies greatly between individuals and between locations on an individual. Additionally, some studies have shown that activation of underlying muscle tissue increases bulk soft tissue stiffness. Yet, few studies have simultaneously considered both location and activation; this could be particularly important for measuring and predicting the function of devices such as prostheses and exoskeletons that interact with limbs at various locations during dynamic movement. In the present study, a custom handheld indentation device was used to explore changes in bulk leg tissue stiffness at rest and during isometric contractions. The indentation force-displacement curves were modelled using a Hertz model. At each level of activation (active/inactive), the shank had dramatically (∼150%) greater tissue stiffness than the thigh (p < 0.001). However, results suggested location independence for stiffness ratio (active/inactive, p = 0.42); for either location, stiffness was approximately 2x greater for active vs inactive muscle. These results should be considered during the development of biomechanical models to simulate human tissue indentation stiffness across a range of activation states and locations.

Cardiomyocytes are permanently exposed to mechanical stimulation due to cardiac contractility. Passive myocardial stiffness is a crucial factor, which defines the physiological ventricular compliance and volume of diastolic filling with blood. Heart diseases often present with increased myocardial stiffness, for instance when fibrotic changes modify the composition of the cardiac extracellular matrix (ECM). Consequently, the ventricle loses its compliance, and the diastolic blood volume is reduced. Recent advances in the field of cardiac mechanobiology revealed that disease-related environmental stiffness changes cause severe alterations in cardiomyocyte cellular behavior and function. Here, we review the molecular mechanotransduction pathways that enable cardiomyocytes to sense stiffness changes and translate those into an altered gene expression. We will also summarize current knowledge about when myocardial stiffness increases in the diseased heart. Sophisticated in vitro studies revealed functional changes, when cardiomyocytes faced a stiffer matrix. Finally, we will highlight recent studies that described modulations of cardiac stiffness and thus myocardial performance in vivo . Mechanobiology research is just at the cusp of systematic investigations related to mechanical changes in the diseased heart but what is known already makes way for new therapeutic approaches in regenerative biology.

Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by progressive replacement of cardiomyocytes by fibrofatty tissue, ventricular dilatation, cardiac dysfunction, arrhythmias, and sudden cardiac death. Interest in molecular biomechanics for these disorders is constantly growing. Atomic force microscopy (AFM) is a well-established technic to study the mechanobiology of biological samples under physiological and pathological conditions at the cellular scale. However, a review which described all the different data that can be obtained using the AFM (cell elasticity, adhesion behavior, viscoelasticity, beating force, and frequency) is still missing. In this review, we will discuss several techniques that highlight the potential of AFM to be used as a tool for assessing the biomechanics involved in ACM. Indeed, analysis of genetically mutated cells with AFM reveal abnormalities of the cytoskeleton, cell membrane structures, and defects of contractility. The higher the Young’s modulus, the stiffer the cell, and it is well known that abnormal tissue stiffness is symptomatic of a range of diseases. The cell beating force and frequency provide information during the depolarization and repolarization phases, complementary to cell electrophysiology (calcium imaging, MEA, patch clamp). In addition, original data is also presented to emphasize the unique potential of AFM as a tool to assess fibrosis in cardiac tissue.

Purpose Quantify in vivo biomechanical tissue properties in various breast densities and in average risk and high-risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association between breast biomechanical properties and cancer risk based on patient demographics and clinical data. Methods Patients with average risk or high-risk of breast cancer underwent 3.0 T breast MR imaging and elastography. Breast parenchymal enhancement (BPE), density (from most recent mammogram), stiffness, elasticity, and viscosity were recorded. Within each breast density group (non-dense versus dense), stiffness, elasticity, and viscosity were compared across risk groups (average versus high). Separately for stiffness, elasticity, and viscosity, a multivariable logistic regression model was used to evaluate whether the MRE parameter predicted risk status after controlling for clinical factors. Results 50 average risk and 86 high-risk patients were included. Risk groups were similar in age, density, and menopausal status. Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high-risk patients ( N  = 55) compared to average risk patients ( N  = 34; all p  < 0.001). Stiffness remained a significant predictor of risk status (OR = 4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, BPE, age, and menopausal status. Similar results were seen for elasticity and viscosity. Conclusion A structurally based, quantitative biomarker of tissue stiffness obtained from MRE is associated with differences in breast cancer risk in dense breasts. Tissue stiffness could provide a novel prognostic marker to help identify high-risk women with dense breasts who would benefit from increased surveillance and/or risk reduction measures.

Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano‐molecular programs that orchestrate region‐ and layer‐specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic aorta (ATA) compared to distal segments of the aorta and that collagen content increases in both the medial and adventitial compartments of the ATA during aging. The single‐cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T‐lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T lymphocyte clusters accumulate in the adventitia, while the activation of mechanosensitive Piezo‐1 enhances vasoconstriction and contributes to the overall functional decline of ATA tissues. These results portray the immuno‐mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi‐gerogenic signals priming to disease development. The decline in passive cyclic distensibility of the aorta during aging is more pronounced in the ascending thoracic aorta (ATA) compared to distal segments. Aging induces cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of adventitial T‐lymphocytes and rarefaction of medial vascular smooth muscle cells in ATA tissues. Activation of mechanosensitive Piezo‐1 enhances vasoconstriction and contributes to the overall functional decline of the aged ATA.

Murine syngeneic tumor models have been used extensively for cancer research for several decades and have been instrumental in driving the discovery and development of cancer immunotherapies. These tumor models are very simplistic cancer models, but recent reports have, however, indicated that the different inoculated cancer cell lines can lead to the formation of unique tumor microenvironments (TMEs). To gain more knowledge from studies based on syngeneic tumor models, it is essential to obtain an in-depth understanding of the cellular and molecular composition of the TME in the different models. Additionally, other parameters that are important for cancer progression, such as collagen content and mechanical tissue stiffness across syngeneic tumor models have not previously been reported. Here, we compare the TME of tumors derived from six common syngeneic tumor models. Using flow cytometry and transcriptomic analyses, we show that strikingly unique TMEs are formed by the different cancer cell lines. The differences are reflected as changes in abundance and phenotype of myeloid, lymphoid, and stromal cells in the tumors. Gene expression analyses support the different cellular composition of the TMEs and indicate that distinct immunosuppressive mechanisms are employed depending on the tumor model. Cancer-associated fibroblasts (CAFs) also acquire very different phenotypes across the tumor models. These differences include differential expression of genes encoding extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and immunosuppressive factors. The gene expression profiles suggest that CAFs can contribute to the formation of an immunosuppressive TME, and flow cytometry analyses show increased PD-L1 expression by CAFs in the immunogenic tumor models, MC38 and CT26. Comparison with CAF subsets identified in other studies shows that CAFs are skewed towards specific subsets depending on the model. In athymic mice lacking tumor-infiltrating cytotoxic T cells, CAFs express lower levels of PD-L1 and lower levels of fibroblast activation markers. Our data underscores that CAFs can be involved in the formation of an immunosuppressive TME.