Systems Modeling to Predict Mechano-Chemo Interactions In Cardiac Fibrosis

Cardiac fibrosis poses a central challenge in preventing heart failure for patients who have suffered a cardiac injury such as myocardial infarction or aortic valve stenosis. This chronic condition is characterized by a reduction in contractile function through combined hypertrophy and excessive scar formation, and although currently prescribed therapeutics targeting hypertrophy have shown improvements in patient outcomes, pathological fibrosis remains a leading cause of reduced cardiac function for patients long-term. Cardiac fibroblasts play a key role in regulating scar formation during heart failure progression, and interacting biochemical and biomechanical cues within the myocardium guide the activation of fibroblasts and expression of extracellular matrix proteins. While targeted experimental studies of fibroblast activation have elucidated the roles of individual pathways in fibroblast activation, intracellular crosstalk between mechanotransduction and chemotransduction pathways from multiple biochemical cues has largely confounded efforts to control overall cell behavior within the myocardial environment. Computational networks of intracellular signaling can account for complex interactions between signaling pathways and provide a promising approach for identifying influential mechanisms mediating cell behavior. The overarching goal of this dissertation is to improve our understanding of complex signaling in fibroblasts by investigating the role of mechano-chemo interactions in cardiac fibroblast-mediated fibrosis using a combination of experimental studies and systems-level computational models. Firstly, using an in vitro screen of cardiac fibroblast-secreted proteins in response to combinations of biochemical stimuli and mechanical tension, we found that tension modulated cell sensitivity towards biochemical stimuli, thereby altering cell behavior based on the mechanical context. Secondly, using a curated model of fibroblast intracellular signaling, we expanded model topology to include robust mechanotransduction pathways, improved accuracy of model predictions compared to independent experimental studies, and identified mechanically dependent mechanisms-of- ction and mechano-adaptive drug candidates in a post-infarction scenario. Lastly, using an inferred network of fibroblast transcriptional regulation and model fitting to patient-specific data, we showed the utility of model-based approaches in identifying influential pathways underlying fibrotic protein expression during aortic valve stenosis and predicting patient-specific responses to pharmacological intervention. Our work suggests that computational-based approaches can generate insight into influential mechanisms among complex systems, and such tools may be promising for further therapeutic development and precision medicine

Doctor of Philosophy

dissertationAngiogenesis is the process by which new blood vessels sprout from existing vessels, enabling new vascular elements to be added to an existing vasculature network. Mechanical interactions during angiogenesis, i.e., traction forces applied by neovessels and the corresponding deformation of the extracellular matrix (ECM), are important regulators of growth and neovascularization. However, the dynamic relationship between cell-generated forces, the deformation of the ECM, and the topology of the emerging vascular network are poorly understood. The goal of this research was to develop, implement, and validate a computational framework that simulates the dynamic mechanical interaction between angiogenic neovessels and the ECM. This dissertation presents a novel continuous-discrete finite element (FE) model with angiogenic growth coupled with matrix deformation. Angiogenesis was simulated using a discrete growth model. This model uses properties of the ECM, represented by a continuous FE mesh, to regulate angiogenic growth and branching and was capable of accurately predicting vascular morphometric data when simulating growth in various matrix conditions. To couple growth with matrix deformation, sprout forces were applied to the mesh and the corresponding deformation of the matrix was determined using the nonlinear FE software FEBio. This deformation was then used to update the ECM into the current configuration before calculating the next growth step. Data from vascularized gel experiments were used to both calibrate mechanisms within the model during implementation and compare with computational simulations to assess the validity of the simulations. In simulations of experiments involving vascularized collagen gels subjected to various mechanical boundary constraints, this coupled framework accurately predicted gel contraction and microvessel alignment for each condition. The primary mechanism for alignment occurs as microvessels passively align while moving with the deformation of the surrounding matrix. These results demonstrate how biomechanical cellular activity at the microscale during morphogenic processes such as angiogenesis can influence the macroenvironment and induce patterns and organization. These methods provide a flexible computational platform to investigate the mechanisms by which the biomechanical interaction between cells and the ECM regulates the structure and composition of the emerging tissue during morphogenesis

Mechanics of Biomaterials

The mechanical behavior of biomedical materials and biological tissues are important for their proper function. This holds true, not only for biomaterials and tissues whose main function is structural such as skeletal tissues and their synthetic substitutes, but also for other tissues and biomaterials. Moreover, there is an intimate relationship between mechanics and biology at different spatial and temporal scales. It is therefore important to study the mechanical behavior of both synthetic and livingbiomaterials. This Special Issue aims to serve as a forum for communicating the latest findings and trends in the study of the mechanical behavior of biomedical materials

Applications of Nanobiotechnology

This book is dedicated to the applications of nanobiotechnology, i.e. the way that nanotechnology is used to create devices to study biological systems and phenomena. It includes seven chapters, organized in two sections. The first section (Chapters 1–5) covers a large spectrum of issues associated with nanoparticle synthesis, nanoparticle toxicity, and the role of nanotechnology in drug delivery, tissue engineering, agriculture, and biosensing. The second section (Chapters 6 and 7) is devoted to the properties of nanofluids and the medical and biological applications of computational fluid dymanics modeling

USSR Space Life Sciences Digest, issue 1

The first issue of the bimonthly digest of USSR Space Life Sciences is presented. Abstracts are included for 49 Soviet periodical articles in 19 areas of aerospace medicine and space biology, published in Russian during the first quarter of 1985. Translated introductions and table of contents for nine Russian books on topics related to NASA's life science concerns are presented. Areas covered include: botany, cardiovascular and respiratory systems, cybernetics and biomedical data processing, endocrinology, gastrointestinal system, genetics, group dynamics, habitability and environmental effects, health and medicine, hematology, immunology, life support systems, man machine systems, metabolism, musculoskeletal system, neurophysiology, perception, personnel selection, psychology, radiobiology, reproductive system, and space biology. This issue concentrates on aerospace medicine and space biology

Biotechnology and Bioengineering

Biotechnology and Bioengineering presents the most up-to-date research on biobased technologies. It is designed to help scientists and researchers deepen their knowledge in this critical knowledge field. This solid resource brings together multidisciplinary research, development, and innovation for a wide study of Biotechnology and Bioengineering

Unveiling the Hidden Language of Extracellular Matrix Deformations: A tale of cellular whispers and unstable fibers

One of the key questions in cellular biology revolves around comprehending the intricate interplay between an individual cell and its neighboring counterparts within a tissue. Beyond the cell’s innate genetic blueprint, external influences, such as those exerted by its microenvironment, drive most of its functions. The main component of this microenvironment is the Extracellular Matrix (ECM), a convoluted network of fibrous proteins which interact directly with cells. The ECM serves as a scaffold that facilitates intercellular signal exchange, including biomechanical forces. Cells actively respond to mechanical action and induce deformation patterns which take the form of bands that interconnect neighbouring cells. These bands include tracts of elevated matrix densification and fiber alignment and orchestrate vital cellular processes like migration, invasion and proliferation, while there is strong evidence of their contribution to intercellular communication. Unraveling the mechanisms underpinning these phenomena equates to deciphering the mechanical properties of ECM and by that, the mechanical traits of its constituent fibers. Prior research into the mechanics of fibers has uncovered unusual mechanical phenomena driven in part by their inherent hierarchical structure. These phenomena encompass unique behaviors such as unstable responses of fibers when subjected to compressive loads. This instability is characterized by transitions from heightened fiber stiffness (in which the fiber becomes harder) to the loss of fiber stiffness (causing the fiber to become less stiff and buckle). In light of these findings, we have developed models that encompass the distinct intrinsic characteristics of fiber structure and mechanics, and investigate deformations of the Extracellular Matrix (ECM) induced by cells. We have analyzed and modelled the mechanical properties of the ECM from a macroscopic perspective. Our fundamental assumption is that individual fibers can withstand tension but buckle and collapse when subjected to compression. We compare two families of fiber mechanics models: Family 1, characterized by stable responses of individual fibers under compression, and Family 2, exhibiting unstable responses of individual fibers under compression. Our simulations expose diverse compression instabilities inherent to each Family. These instabilities lead to the formation of densely packed ECM regions, featuring strongly aligned fibers. These regions emanate either from individual contractile cells or join neighboring cells, mirroring observations from experiments. We show that both fiber alignment and ECM densification are prevented in the absence of elevated compression. Our models demonstrate that material instabilities wield a dominant role in the mechanical behavior of the fibrous ECM. Despite substantial disparities in the responses of the two model families, our research underscores the pivotal role played by compression instabilities in the behavior of fibrous biological tissues. This has implications to a number of cellular and tissue processes, particularly in understanding cancer invasion and metastasis. Our findings introduce novel perspectives for investigating how fibers respond to deformations induced by cells and the ensuing implications for biomechanical interactions between cells.Data-integrated multi-scale modelling of fibrous extracellular matrix materials (DIMMOFEMM