In the past few years, microfluidic-based technology has developed microscale models recapitulating key physical and biological cues typical of the native myocardium. However, the application of controlled physiological uniaxial cyclic strains on a defined three-dimension cellular environment is not yet possible. Two-dimension mechanical stimulation was particularly investigated, neglecting the complex three-dimensional cell-cell and cell-matrix interactions. For this purpose, we developed a heart-on-a-chip platform, which recapitulates the physiologic mechanical environment experienced by cells in the native myocardium. The device includes an array of hanging posts to confine cell-laden gels, and a pneumatic actuation system to induce homogeneous uniaxial cyclic strains to the 3D cell constructs during culture. The device was used to generate mature and highly functional micro-engineered cardiac tissues (μECTs), from both neonatal rat and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), strongly suggesting the robustness of our engineered cardiac micro-niche. Our results demonstrated that the cyclic strain was effectively highly uniaxial and uniformly transferred to cells in culture. As compared to control, stimulated μECTs showed superior cardiac differentiation, as well as electrical and mechanical coupling, owing to a remarkable increase in junction complexes. Mechanical stimulation also promoted early spontaneous synchronous beating and better contractile capability in response to electric pacing. Pacing analyses of hiPSC-CM constructs upon controlled administration of isoprenaline showed further promising applications of our platform in drug discovery, delivery and toxicology fields. The proposed heart-on-a-chip device represents a relevant step forward in the field, providing a standard functional three-dimensional cardiac model to possibly predict signs of hypertrophic changes in cardiac phenotype by mechanical and biochemical co-stimulation.

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In the current scientific literature, particular attention is dedicated to the study of the mitral valve and to comprehension of the mechanisms that lead to its normal function, as well as those that trigger possible pathological conditions. One of the adopted approaches consists of computational modelling, which allows quantitative analysis of the mechanical behaviour of the valve by means of continuum mechanics theory and numerical techniques. However, none of the currently available models realistically accounts for all of the aspects that characterize the function of the mitral valve. Here, a new computational model of the mitral valve has been developed from in vivo data, as a first step towards the development of patient-specific models for the evaluation of annuloplasty procedures. A structural finiteelement model of the mitral valve has been developed to account for all of the main valvular substructures. In particular, it includes the real geometry and the movement of the annulus and papillary muscles, reconstructed from four-dimensional ultrasound data from a healthy human subject, and a realistic description of the complex mechanical properties of mitral tissues. Preliminary simulations allowed mitral valve closure to be realistically mimicked and the role of annulus and papillary muscle dynamics to be quantified.

We aim at testing the possibility to build patientspecific structural finite element models (FEMs) of the mitral valve (MV) from cardiac magnetic resonance (CMR) imaging and to use them to predict the outcome of mitral annuloplasty procedures. MV FEMs were built for one healthy subject and for one patient with ischemic mitral regurgitation. On both subjects, CMR imaging of 18 longaxis planes was performed with a temporal resolution of 55 time-frames per cardiac cycle. Three-dimensional MV annulus geometry, leaflets surface and PM position were manually obtained using custom software. Hyperelastic anisotropic mechanical properties were assigned to MV tissues. A physiological pressure load was applied to the leaflets to simulate valve closure until peak systole. For the pathological model only, a further simulation was run, simulating undersized rigid annuloplasty before valve closure. Closure dynamics, leaflets stresses and tensions in the subvalvular apparatus in the healthy MV were consistent with previous computational and experimental data. The regurgitant valve model captured with good approximation the real size and position of regurgitant areas at peak systole, and highlighted abnormal tensions in the annular region and sub-valvular apparatus. The simulation of undersized rigid annuloplasty showed the restoration of MV continence and normal tensions in the subvalvular apparatus and at the annulus. Our method seems suitable for implementing detailed patient-specific MV FEMs to simulate different scenarios of clinical interest. Further work is mandatory to test the method more deeply, to reduce its computational time and to expand the range of modeled surgical procedures.

Objective: Congenital bicuspid aortic valves frequently cause aortic stenosis or regurgitation. Improved understanding of valve and root biomechanics is needed to achieve advancements in surgical repair techniques. By using imaging-derived data, finite element models were developed to quantify aortic valve and root biomechanical alterations associated with bicuspid geometry.Methods: A dynamic 3-dimensional finite element model of the aortic root with a bicuspid aortic valve (type 1 right/left) was developed. The model's geometry was based on measurements from 2-dimensional magnetic resonance images acquired in 8 normotensive and otherwise healthy subjects with echocardiographically normal function of their bicuspid aortic valves. Numeric results were compared with those obtained from our previous model representing the normal root with a tricuspid aortic valve. The effects of raphe thickening on valve kinematics and stresses were also evaluated.Results: During systole, the bicuspid valve opened asymmetrically compared with the normal valve, resulting in an elliptic shape of its orifice. During diastole, the conjoint cusp occluded a larger proportion of the valve orifice and leaflet bending was altered, although competence was preserved. The bicuspid model presented higher stresses compared with the tricuspid model, particularly in the central basal region of the conjoint cusp (þ800%). The presence of a raphe partially reduced stress in this region but increased stress in the other cusp.Conclusions: Aortic valve function is altered in clinically normally functioning bicuspid aortic valves. Bicuspid geometry per se entails abnormal leaflet stress. The stress location suggests that leaflet stress may play a role in tissue remodeling at the raphe region and in early leaflet degeneration.

Lung edema forms (possibly as an all-or-none response) depending not only on global strain but also on its components. Large static are less harmful than large dynamic strains, but not because the former merely counteracts fluid extravasation.

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