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Movies of human induced pluripotent stem cell (hiPSC)-derived engineered cardiac tissue (microbundles) contain abundant information about structural and functional maturity. However, extracting these data in a reproducible and high-throughput manner remains a major challenge. Furthermore, it is not straightforward to make direct quantitative comparisons across the multiple in vitro experimental platforms employed to fabricate these tissues. Here, we present "MicroBundlePillarTrack," an open-source optical flow-based package developed in Python to track the deflection of pillars in cardiac microbundles grown on experimental platforms with two different pillar designs ("Type 1" and "Type 2" design). Our software is able to automatically segment the pillars, track their displacements, and output time-dependent metrics for contractility analysis, including beating amplitude and rate, contractile force, and tissue stress. Because this software is fully automated, it will allow for both faster and more reproducible analyses of larger datasets and it will enable more reliable cross-platform comparisons as compared to existing approaches that require manual steps and are tailored to a specific experimental platform. To complement this open-source software, we share a dataset of 1,540 brightfield example movies on which we have tested our software. Through sharing this data and software, our goal is to directly enable quantitative comparisons across labs, and facilitate future collective progress via the biomedical engineering open-source data and software ecosystem., Comment: 8 main pages, 1 main figure, Supplementary Information included. microPublication Biology (2024)

There has been significant recent interest in the mechanics community to design structures that can either violate reciprocity, or exhibit elastic asymmetry or odd elasticity. While these properties are highly desirable to enable mechanical metamaterials to exhibit novel wave propagation phenomena, it remains an open question as to how to design passive structures that exhibit both significant non-reciprocity and elastic asymmetry. In this paper, we first define several design spaces for chiral metamaterials leveraging specific design parameters, including the ligament contact angles, the ligament shape, and circle radius. Having defined the design spaces, we then leverage machine learning approaches, and specifically Bayesian optimization, to determine optimally performing designs within each design space satisfying maximal non-reciprocity or stiffness asymmetry. Finally, we perform multi-objective optimization by determining the Pareto optimum and find chiral metamaterials that simultaneously exhibit high non-reciprocity and stiffness asymmetry. Our analysis of the underlying mechanisms reveals that chiral metamaterials that can display multiple different contact states under loading in different directions are able to simultaneously exhibit both high non-reciprocity and stiffness asymmetry. Overall, this work demonstrates the effectiveness of employing ML to bring insights to a novel domain with limited prior information, and more generally will pave the way for metamaterials with unique properties and functionality in directing and guiding mechanical wave energy.

From biological organs to soft robotics, highly deformable materials are essential components of natural and engineered systems. These highly deformable materials can have heterogeneous material properties, and can experience heterogeneous deformations with or without underlying material heterogeneity. Many recent works have established that computational modeling approaches are well suited for understanding and predicting the consequences of material heterogeneity and for interpreting observed heterogeneous strain fields. In particular, there has been significant work towards developing inverse analysis approaches that can convert observed kinematic quantities (e.g., displacement, strain) to material properties and mechanical state. Despite the success of these approaches, they are not necessarily generalizable and often rely on tight control and knowledge of boundary conditions. Here, we will build on the recent advances (and ubiquity) of machine learning approaches to explore alternative approaches to detect patterns in heterogeneous material properties and mechanical behavior. Specifically, we will explore unsupervised learning approaches to clustering and ensemble clutering to identify heterogeneous regions. Overall, we find that these approaches are effective, yet limited in their abilities. Through this initial exploration (where all data and code is published alongside this manuscript), we set the stage for future studies that more specifically adapt these methods to mechanical data., Comment: 26 pages, 10 figures

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., Comment: 16 main pages, 7 main figures, Supplementary Information included as appendices

Engineered heart tissues (EHTs) present a potential solution to some of the current challenges in the treatment of heart disease; however, the development of mature, adult-like cardiac tissues remains elusive. Mechanical stimuli have been observed to improve whole-tissue function and cardiomyocyte (CM) maturation, although our ability to fully utilize these mechanisms is hampered, in part, by our incomplete understanding of the mechanobiology of EHTs. In this work, we leverage the experimental data produced by a mechanically tunable experimental setup to generate tissue-specific computational models of EHTs. Using imaging and functional data, our modeling pipeline generates models with tissue-specific ECM and myofibril structure, allowing us to estimate CM active stress. We use this experimental and modeling pipeline to study different mechanical environments, where we contrast the force output of the tissue with the computed active stress of CMs. We show that the significant differences in measured experimental forces can largely be explained by the levels of myofibril formation achieved by the CMs in the distinct mechanical environments, with active stress showing more muted variations across conditions. The presented model also enables us to dissect the relative contributions of myofibrils and extracellular matrix to tissue force output, a task difficult to address experimentally. These results highlight the importance of tissue-specific modeling to augment EHT experiments, providing deeper insights into the mechanobiology driving EHT function., Comment: 19 pages, 7 figures

From healing wounds to maintaining homeostasis in cyclically loaded tissue, living systems have a phenomenal ability to sense, store, and respond to mechanical stimuli. Broadly speaking, there is significant interest in designing engineered systems to recapitulate this incredible functionality. In engineered systems, we have seen significant recent computationally driven advances in sensing and control. And, there has been a growing interest - inspired in part by the incredible distributed and emergent functionality observed in the natural world - in exploring the ability of engineered systems to perform computation through mechanisms that are fundamentally driven by physical laws. In this work, we focus on a small segment of this broad and evolving field: locality sensitive hashing via mechanical behavior. Specifically, we will address the question: can mechanical information (i.e., loads) be transformed by mechanical systems (i.e., converted into sensor readouts) such that the mechanical system meets the requirements for a locality sensitive hash function? Overall, we not only find that mechanical systems are able to perform this function, but also that different mechanical systems vary widely in their efficacy at this task. Looking forward, we view this work as a starting point for significant future investigation into the design and optimization of mechanical systems for conveying mechanical information for downstream computing., Comment: 22 pages, 12 figures, 1 table

Recently, there has been a growing interest in applying machine learning methods to problems in engineering mechanics. In particular, there has been significant interest in applying deep learning techniques to predicting the mechanical behavior of heterogeneous materials and structures. Researchers have shown that deep learning methods are able to effectively predict mechanical behavior with low error for systems ranging from engineered composites, to geometrically complex metamaterials, to heterogeneous biological tissue. However, there has been comparatively little attention paid to deep learning model calibration, i.e., the match between predicted probabilities of outcomes and the true probabilities of outcomes. In this work, we perform a comprehensive investigation into ML model calibration across seven open access engineering mechanics datasets that cover three distinct types of mechanical problems. Specifically, we evaluate both model and model calibration error for multiple machine learning methods, and investigate the influence of ensemble averaging and post hoc model calibration via temperature scaling. Overall, we find that ensemble averaging of deep neural networks is both an effective and consistent tool for improving model calibration, while temperature scaling has comparatively limited benefits. Looking forward, we anticipate that this investigation will lay the foundation for future work in developing mechanics specific approaches to deep learning model calibration., Comment: 21 pages, 9 figures

There has been a massive increase in research interest towards applying data driven methods to problems in mechanics. While traditional machine learning (ML) methods have enabled many breakthroughs, they rely on the assumption that the training (observed) data and testing (unseen) data are independent and identically distributed (i.i.d). Thus, traditional ML approaches often break down when applied to real world mechanics problems with unknown test environments and data distribution shifts. In contrast, out-of-distribution (OOD) generalization assumes that the test data may shift (i.e., violate the i.i.d. assumption). To date, multiple methods have been proposed to improve the OOD generalization of ML methods. However, because of the lack of benchmark datasets for OOD regression problems, the efficiency of these OOD methods on regression problems, which dominate the mechanics field, remains unknown. To address this, we investigate the performance of OOD generalization methods for regression problems in mechanics. Specifically, we identify three OOD problems: covariate shift, mechanism shift, and sampling bias. For each problem, we create two benchmark examples that extend the Mechanical MNIST dataset collection, and we investigate the performance of popular OOD generalization methods on these mechanics-specific regression problems. Our numerical experiments show that in most cases, while the OOD generalization algorithms perform better compared to traditional ML methods on these OOD problems, there is a compelling need to develop more robust OOD generalization methods that are effective across multiple OOD scenarios. Overall, we expect that this study, as well as the associated open access benchmark datasets, will enable further development of OOD generalization methods for mechanics specific regression problems.

Modeling biological soft tissue is complex in part due to material heterogeneity. Microstructural patterns, which play a major role in defining the mechanical behavior of these tissues, are both challenging to characterize, and difficult to simulate. Recently, machine learning-based methods to predict the mechanical behavior of heterogeneous materials have made it possible to more thoroughly explore the massive input parameter space associated with heterogeneous blocks of material. Specifically, we can train machine learning (ML) models to closely approximate computationally expensive heterogeneous material simulations where the ML model is trained on a dataset of simulations that capture the range of spatial heterogeneity present in the material of interest. However, when it comes to applying these techniques to biological tissue more broadly, there is a major limitation: the relevant microstructural patterns are both challenging to obtain and difficult to analyze. Consequently, the number of useful examples available to characterize the input domain under study is limited. In this work, we investigate the efficacy of ML-based generative models as well as procedural methods as a tool for augmenting limited input pattern datasets. We find that a Style-based Generative Adversarial Network with adaptive discriminator augmentation is able to successfully leverage just 1,000 example patterns to create the most authentic generated patterns. In general, diverse generated patterns with adequate resemblance to the real patterns can be used as inputs to finite element simulations to meaningfully augment the training dataset. To enable this methodological contribution, we have created an open access dataset of Finite Element Analysis simulations based on Cahn-Hilliard patterns. We anticipate that future researchers will be able to leverage this dataset and build on the work presented here., Comment: 13 pages, 6 figures

From designing architected materials to connecting mechanical behavior across scales, computational modeling is a critical tool in solid mechanics. Recently, there has been a growing interest in using machine learning to reduce the computational cost of physics-based simulations. Notably, while machine learning approaches that rely on Graph Neural Networks (GNNs) have shown success in learning mechanics, the performance of GNNs has yet to be investigated on a myriad of solid mechanics problems. In this work, we examine the ability of GNNs to predict a fundamental aspect of mechanically driven emergent behavior: the connection between a column's geometric structure and the direction that it buckles. To accomplish this, we introduce the Asymmetric Buckling Columns (ABC) dataset, a dataset comprised of three sub-datasets of asymmetric and heterogeneous column geometries where the goal is to classify the direction of symmetry breaking (left or right) under compression after the onset of instability. Because of complex local geometry, the "image-like" data representations required for implementing standard convolutional neural network based metamodels are not ideal, thus motivating the use of GNNs. In addition to investigating GNN model architecture, we study the effect of different input data representation approaches, data augmentation, and combining multiple models as an ensemble. While we were able to obtain good results, we also showed that predicting solid mechanics based emergent behavior is non-trivial. Because both our model implementation and dataset are distributed under open-source licenses, we hope that future researchers can build on our work to create enhanced mechanics-specific machine learning pipelines for capturing the behavior of complex geometric structures., Comment: 24 pages, 14 figures; added section 3.5 and Appendix C; fixed minor typos; edited figures

A better fundamental understanding of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has the potential to advance applications ranging from drug discovery to cardiac repair. Automated quantitative analysis of beating hiPSC-CMs is an important and fast developing component of the hiPSC-CM research pipeline. Here we introduce "Sarc-Graph," a computational framework to segment, track, and analyze sarcomeres in fluorescently tagged hiPSC-CMs. Our framework includes functions to segment z-discs and sarcomeres, track z-discs and sarcomeres in beating cells, and perform automated spatiotemporal analysis and data visualization. In addition to reporting good performance for sarcomere segmentation and tracking with little to no parameter tuning and a short runtime, we introduce two novel analysis approaches. First, we construct spatial graphs where z-discs correspond to nodes and sarcomeres correspond to edges. This makes measuring the network distance between each sarcomere (i.e., the number of connecting sarcomeres separating each sarcomere pair) straightforward. Second, we treat tracked and segmented components as fiducial markers and use them to compute the approximate deformation gradient of the entire tracked population. This represents a new quantitative descriptor of hiPSC-CM function. We showcase and validate our approach with both synthetic and experimental movies of beating hiPSC-CMs. By publishing Sarc-Graph, we aim to make automated quantitative analysis of hiPSC-CM behavior more accessible to the broader research community., Comment: Link to SI: https://github.com/elejeune11/Sarc-Graph/tree/main/Supplementary_Information

From the nano-scale to the macro-scale, biological tissue is spatially heterogeneous. Even when tissue behavior is well understood, the exact subject specific spatial distribution of material properties is often unknown. And, when developing computational models of biological tissue, it is usually prohibitively computationally expensive to simulate every plausible spatial distribution of material properties for each problem of interest. Therefore, one of the major challenges in developing accurate computational models of biological tissue is capturing the potential effects of this spatial heterogeneity. Recently, machine learning based metamodels have gained popularity as a computationally tractable way to overcome this problem because they can make predictions based on a limited number of direct simulation runs. These metamodels are promising, but they often still require a high number of direct simulations to achieve an acceptable performance. Here we show that transfer learning, a strategy where knowledge gained while solving one problem is transferred to solving a different but related problem, can help overcome this limitation. Critically, transfer learning can be used to leverage both low-fidelity simulation data and simulation data that is the outcome of solving a different but related mechanical problem. In this paper, we extend Mechanical MNIST, our open source benchmark dataset of heterogeneous material undergoing large deformation, to include a selection of low-fidelity simulation results that require 2-4 orders of magnitude less CPU time to run. Then, we show that transferring the knowledge stored in metamodels trained on these low-fidelity simulation results can vastly improve the performance of metamodels used to predict the results of high-fidelity simulations., Comment: 9 figures, 35 pages