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Jorba, I., Beltrán, G., Falcones, B., Suki, B., Farré, R., García-Aznar, J. M., Navajas, D., (2019). Nonlinear elasticity of the lung extracellular microenvironment is regulated by macroscale tissue strain Acta Biomaterialia 92, 265-276

The extracellular matrix (ECM) of the lung provides physical support and key mechanical signals to pulmonary cells. Although lung ECM is continuously subjected to different stretch levels, detailed mechanics of the ECM at the scale of the cell is poorly understood. Here, we developed a new polydimethylsiloxane (PDMS) chip to probe nonlinear mechanics of tissue samples with atomic force microscopy (AFM). Using this chip, we performed AFM measurements in decellularized rat lung slices at controlled stretch levels. The AFM revealed highly nonlinear ECM elasticity with the microscale stiffness increasing with tissue strain. To correlate micro- and macroscale ECM mechanics, we also assessed macromechanics of decellularized rat lung strips under uniaxial tensile testing. The lung strips exhibited exponential macromechanical behavior but with stiffness values one order of magnitude lower than at the microscale. To interpret the relationship between micro- and macromechanical properties, we carried out a finite element (FE) analysis which revealed that the stiffness of the alveolar cell microenvironment is regulated by the global strain of the lung scaffold. The FE modeling also indicates that the scale dependence of stiffness is mainly due to the porous architecture of the lung parenchyma. We conclude that changes in tissue strain during breathing result in marked changes in the ECM stiffness sensed by alveolar cells providing tissue-specific mechanical signals to the cells. Statement of Significance: The micromechanical properties of the extracellular matrix (ECM) are a major determinant of cell behavior. The ECM is exposed to mechanical stretching in the lung and other organs during physiological function. Therefore, a thorough knowledge of the nonlinear micromechanical properties of the ECM at the length scale that cells probe is required to advance our understanding of cell-matrix interplay. We designed a novel PDMS chip to perform atomic force microscopy measurements of ECM micromechanics on decellularized rat lung slices at different macroscopic strain levels. For the first time, our results reveal that the microscale stiffness of lung ECM markedly increases with macroscopic tissue strain. Therefore, changes in tissue strain during breathing result in variations in ECM stiffness providing tissue-specific mechanical signals to lung cells.

Keywords: AFM, ECM micromechanics, Multiscale lung mechanics, Tensile testing


Farré, N., Otero, J., Falcones, B., Torres, M., Jorba, I., Gozal, D., Almendros, I., Farré, R., Navajas, D., (2018). Intermittent hypoxia mimicking sleep apnea increases passive stiffness of myocardial extracellular matrix. A multiscale study Frontiers in Physiology 9, Article 1143

Background: Tissue hypoxia-reoxygenation characterizes obstructive sleep apnea (OSA), a very prevalent respiratory disease associated with increased cardiovascular morbidity and mortality. Experimental studies indicate that intermittent hypoxia (IH) mimicking OSA induces oxidative stress and inflammation in heart tissue at the cell and molecular levels. However, it remains unclear whether IH modifies the passive stiffness of the cardiac tissue extracellular matrix (ECM). Aim: To investigate multiscale changes of stiffness induced by chronic IH in the ECM of left ventricular (LV) myocardium in a murine model of OSA. Methods: Two-month and 18-month old mice (N = 10 each) were subjected to IH (20% O2 40 s–6% O2 20 s) for 6 weeks (6 h/day). Corresponding control groups for each age were kept under normoxia. Fresh LV myocardial strips (~7 mm × 1 mm × 1 mm) were prepared, and their ECM was obtained by decellularization. Myocardium ECM macroscale mechanics were measured by performing uniaxial stress–strain tensile tests. Strip macroscale stiffness was assessed as the stress value (σ) measured at 0.2 strain and Young’s modulus (EM) computed at 0.2 strain by fitting Fung’s constitutive model to the stress–strain relationship. ECM stiffness was characterized at the microscale as the Young’s modulus (Em) measured in decellularized tissue slices (~12 μm tick) by atomic force microscopy. Results: Intermittent hypoxia induced a ~1.5-fold increase in σ (p < 0.001) and a ~2.5-fold increase in EM (p < 0.001) of young mice as compared with normoxic controls. In contrast, no significant differences emerged in Em among IH-exposed and normoxic mice. Moreover, the mechanical effects of IH on myocardial ECM were similar in young and aged mice. Conclusion: The marked IH-induced increases in macroscale stiffness of LV myocardium ECM suggests that the ECM plays a role in the cardiac dysfunction induced by OSA. Furthermore, absence of any significant effects of IH on the microscale ECM stiffness suggests that the significant increases in macroscale stiffening are primarily mediated by 3D structural ECM remodeling.

Keywords: Atomic force microscopy, Heart mechanics, Myocardial stiffness, Obstructive sleep apnea, Tensile test, Ventricular strain