Javiera Jilberto

Use of universal ventricular coordinates to integrate information from cine and late gadolinium enhancement cardiac MRI enabled generation of high-resolution fibrosis maps and revealed distinct spatial patterns across disease severity in desmoplakin cardiomyopathy.

Myocardial infarction significantly degrades heart function, and current treatments can bring forth serious cost and complications including blood clots and infections. To improve the current state of treatment, researchers are developing tissue patches from induced-pluripotent stem cells that can be incorporated into the heart, improving organ function after a myocardial infarction. These tissue patches include surface patches, attached to the epicardium of the heart, and thick transmural patches that replace the infarcted region. However, little is known about the impact of cardiac tissue patches on pump function in a patient's heart. In addition, it is not clear what patch structural properties - such as active stress generation, muscle fiber alignment, or material stiffness - may best augment existing heart tissue. Computational modeling can be used to examine different implementations and patch properties, illuminating the mechanical impact of cardiac tissue patches in the beating heart. In this work, we computationally implement different cardiac tissue patches to understand benefits of particular patch types and properties. We find that in transmural cardiac tissue patches, both activation and fiber alignment improve function. A transmural patch generating 10% of healthy active stress can increase stroke volume by 18%, and higher generated active stress in a circumferential muscle fiber orientation can recover stroke volume by over 50%. Furthermore, we find that surface cardiac tissue patches can enhance heart function slightly despite limiting diastolic filling, especially when fibrotic thinning has occurred. These conclusions identify broad design goals for the engineering of cardiac tissue patches to improve heart function after a myocardial infarction.

Determining the unloaded, or reference, configuration of the heart is essential for developing patient-specific models that can accurately estimate in-vivo strains and stresses. Various strategies have been proposed to obtain this configuration, with inverse mechanics being a practical approach. The inverse mechanics method estimates the unloaded geometry from a deformed state and its known loads without the need for optimization procedures. However, for the resulting unloaded geometry to be physiologically meaningful, accurate boundary conditions are crucial. While spring boundary conditions are commonly applied to the epicardium to model interactions with surroundings, they do not account for the localized forces exerted by structures like the ribs and diaphragm. Since these external forces cannot be directly measured from medical images, we propose a novel approach that integrates them into the inverse mechanics formulation by penalizing large deformations. Using a series of test problems, we show this approach produces a reference configuration that closely matches the ground truth and improves circumferential strain estimations by an order of magnitude compared to standard inverse mechanics methods.

The mechanical function of the myocardium is defined by cardiomyocyte contractility and the biomechanics of the extracellular matrix (ECM). Understanding this relationship remains an important unmet challenge due to limitations in existing approaches for engineering myocardial tissue. Here, they established arrays of cardiac microtissues with tunable mechanics and architecture by integrating ECM‐mimetic synthetic, fiber matrices, and induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs), enabling real‐time contractility readouts, in‐depth structural assessment, and tissue‐specific computational modeling. They found that the stiffness and alignment of matrix fibers distinctly affect the structural development and contractile function of pure iPSC‐CM tissues. Further examination into the impact of fibrous matrix stiffness enabled by computational models and quantitative immunofluorescence implicates cell‐ECM interactions in myofibril assembly, myofibril maturation, and notably costamere assembly, which correlates with improved contractile function of tissues. These results highlight how iPSC‐CM tissue models with controllable architecture and mechanics can elucidate mechanisms of tissue maturation and disease.

Advancing human induced pluripotent stem cell derived cardiomyocyte (hiPSC-CM) technology will lead to significant progress ranging from disease modeling, to drug discovery, to regenerative tissue engineering. Yet, alongside these potential opportunities comes a critical challenge: attaining mature hiPSC-CM tissues. At present, there are multiple techniques to promote maturity of hiPSC-CMs including physical platforms and cell culture protocols. However, when it comes to making quantitative comparisons of functional behavior, there are limited options for reliably and reproducibly computing functional metrics that are suitable for direct cross-system comparison. In addition, the current standard functional metrics obtained from time-lapse images of cardiac microbundle contraction reported in the field (i.e., post forces, average tissue stress) do not take full advantage of the available information present in these data (i.e., full-field tissue displacements and strains). Thus, we present "MicroBundleCompute," a computational framework for automatic quantification of morphology-based mechanical metrics from movies of cardiac microbundles. Briefly, this computational framework offers tools for automatic tissue segmentation, tracking, and analysis of brightfield and phase contrast movies of beating cardiac microbundles. It is straightforward to implement, requires little to no parameter tuning, and runs quickly on a personal computer. In this paper, we describe the methods underlying this computational framework, show the results of our extensive validation studies, and demonstrate the utility of exploring heterogeneous tissue deformations and strains as functional metrics. With this manuscript, we disseminate "MicroBundleCompute" as an open-source computational tool with the aim of making automated quantitative analysis of beating cardiac microbundles more accessible to the community.