Focus on the Physics of Cancer

Despite the spectacular achievements of molecular biology in the second half of the twentieth century and the crucial advances it permitted in cancer research, the fight against cancer has brought some disillusions. It is nowadays more and more apparent that getting a global picture of the very diverse and interlinked aspects of cancer development necessitates, in synergy with these achievements, other perspectives and investigating tools. In this undertaking, multidisciplinary approaches that include quantitative sciences in general and physics in particular play a crucial role. This `focus on' collection contains 19 articles representative of the diversity and state-of-the-art of the contributions that physics can bring to the field of cancer research.Comment: Invited editorial review for the `Focus on the Physics of Cancer' published by the New journal of Physics in 2011--201

Leveraging Microtechnology to Study Multicellular Microvascular Systems and Macromolecular Interaction

Biological systems are large-scale, complex systems comprised of many hierarchical subsystems interacting physico-chemically in a dynamic and coordinated fashion. The complex interactions of subsystems (in micro-scale) lead to the formation of emergent properties (in macro-scale); these are properties that are not visible if individual subsystems are studied. The inherent high-throughput characteristics of microfabrication technology (microtechnology) along with its ability to manipulate biological species at the micro-scale makes it an ideal tool to elucidate the mechanisms leading to the formation of emergent properties at the macro-scale. In this dissertation, by combining microtechnologies with advanced computational algorithms, we demonstrate system-level analysis of biological systems in development and disease. The abundance of high quality molecular and genetic data along with the drastic increase in computational power resulted in considerable progress in genomics, epigenomics and proteomics, but not for the so-called cellomics as we define it here: high-throughput study of single-cell phenotype and heterotypic cell-cell interaction via micromanipulation and bioinformatics analysis. Lack of high-throughput robust experimental tools is the major roadblock to cellomics. Using microtechnologies, in the context of developmental biology we studied vascular tissue morphogenesis (vasculogenesis). Formation of microvessels is of critical significance in development and for vascularizing newly engineered tissues in regenerative medicine. First, we sought to map the heterogeneous morphodynamic behavior of individual clonal cells in the process of capillary-like structure (CLS) formation (Chapter 2 and 3). Then we looked into deciphering the role of extracellular matrix (ECM) mediated mechanical signals in deriving the process of CLS formation (Chapter 4). In the second half of this thesis, we demonstrated the capabilities of microtechnologies and advanced computational algorithms in tackling the challenging problems in disease: global health diagnostics and cancer drug screening. First, we studied the performance of microfluidic-based diagnostic as a large-scale complex system under real-world constraints (Chapter 5). Then, we present the development of two microfluidic-based platforms to study the heterotypic interaction of cells in both a biomimetic in vitro and a realistic in vivo setting. We developed an implantable construct carrying a densely-packed heterogeneous panel of tumor cells. This platform could ultimately be used to test anti-cancer drug efficacy against a large number of genotypes in an in vivo setting (Appendices A and B). Together, these methods provide a powerful suite of tools for high-throughput analysis of biological species at the micro-scale and could potentially unlock the mysteries behind the emergent properties observed at the macro-scale

A Review of Mathematical Models for the Formation of\ud Vascular Networks

Mainly two mechanisms are involved in the formation of blood vasculature: vasculogenesis and angiogenesis. The former consists of the formation of a capillary-like network from either a dispersed or a monolayered population of endothelial cells, reproducible also in vitro by specific experimental assays. The latter consists of the sprouting of new vessels from an existing capillary or post-capillary venule. Similar phenomena are also involved in the formation of the lymphatic system through a process generally called lymphangiogenesis.\ud \ud A number of mathematical approaches have analysed these phenomena. This paper reviews the different modelling procedures, with a special emphasis on their ability to reproduce the biological system and to predict measured quantities which describe the overall processes. A comparison between the different methods is also made, highlighting their specific features

Mechanical testing of metallic foams for 3d model and simulation of cell distribution effects

Cellular materials have a bulk matrix with a larger number of voids named also cells. Metallic foams made by powder technology represent stochastic closed cells. The related inhomogeneity leads to a scattering of results both in terms of stress–strain curves and maximum strength. Scattering is attributed to relative density variations and local cell discontinuities and it is confirmed also in case of dynamic loading. Finite element simulations through geometrical models that are able to capture the void morphology (named “mesoscale models”), confirm these results and some efforts have been already done to quantify the relationship between shape irregularities and mechanical behavior. The aim of this paper is to present the dynamic characterization of an AA7075 closed cell material and to calibrate its mesoscale finite element model according to the related cell shape distribution. Specimens have been derived from a small ingot (45x45x100 mm) divided along sections so that morphological analysis and experimental tests have been carried out. Specimens extracted from a half of the ingot have been used for dynamic compression tests by means of a split Hopkinson bar, meanwhile specimens extracted from the other half of the ingot have been dissected for porosity distribution analyses carried out by means of image analysis. Stress-strain curves obtained from the mechanical tests have been discussed in terms of strain rate and statistical descriptors of the porosity. Successively a 3D-model of the specimen has been generated starting from the Voronoi algorithm, assigning as input the above-mentioned statistical distribution of the porosity. Due to the peculiarity of the cell morphology (e.g. single larger cells), stress-strain localization has been demonstrated as one of the reasons of the scattering found during the experiments. A material model, to reproduce the investigated foam mechanical behavior, has been calibrated. Despite the difference among experiments the material model is able to reproduce all of them. Difference between the model coefficients quantifies roughly the difference due to the local geometry of the cells

An active poroelastic model for mechanochemical patterns in protoplasmic droplets of Physarum polycephalum

Motivated by recent experimental studies, we derive and analyze a twodimensional model for the contraction patterns observed in protoplasmic droplets of Physarum polycephalum. The model couples a model of an active poroelastic two-phase medium with equations describing the spatiotemporal dynamics of the intracellular free calcium concentration. The poroelastic medium is assumed to consist of an active viscoelastic solid representing the cytoskeleton and a viscous fluid describing the cytosol. The model equations for the poroelastic medium are obtained from continuum force-balance equations that include the relevant mechanical fields and an incompressibility relation for the two-phase medium. The reaction-diffusion equations for the calcium dynamics in the protoplasm of Physarum are extended by advective transport due to the flow of the cytosol generated by mechanical stresses. Moreover, we assume that the active tension in the solid cytoskeleton is regulated by the calcium concentration in the fluid phase at the same location, which introduces a chemomechanical feedback. A linear stability analysis of the homogeneous state without deformation and cytosolic flows exhibits an oscillatory Turing instability for a large enough mechanochemical coupling strength. Numerical simulations of the model equations reproduce a large variety of wave patterns, including traveling and standing waves, turbulent patterns, rotating spirals and antiphase oscillations in line with experimental observations of contraction patterns in the protoplasmic droplets.Comment: Additional supplemental material is supplie

Structural characterization and statistical-mechanical model of epidermal patterns

In proliferating epithelia of mammalian skin, cells of irregular polygonal-like shapes pack into complex nearly flat two-dimensional structures that are pliable to deformations. In this work, we employ various sensitive correlation functions to quantitatively characterize structural features of evolving packings of epithelial cells across length scales in mouse skin. We find that the pair statistics in direct and Fourier spaces of the cell centroids in the early stages of embryonic development show structural directional dependence, while in the late stages the patterns tend towards statistically isotropic states. We construct a minimalist four-component statistical-mechanical model involving effective isotropic pair interactions consisting of hard-core repulsion and extra short-ranged soft-core repulsion beyond the hard core, whose length scale is roughly the same as the hard core. The model parameters are optimized to match the sample pair statistics in both direct and Fourier spaces. By doing this, the parameters are biologically constrained. Our model predicts essentially the same polygonal shape distribution and size disparity of cells found in experiments as measured by Voronoi statistics. Moreover, our simulated equilibrium liquid-like configurations are able to match other nontrivial unconstrained statistics, which is a testament to the power and novelty of the model. We discuss ways in which our model might be extended so as to better understand morphogenesis (in particular the emergence of planar cell polarity), wound-healing, and disease progression processes in skin, and how it could be applied to the design of synthetic tissues

To Be, or Not to Be: Cellular Homeostasis to Mechanical Perturbations

Mechanical homeostasis is an emerging mechanobiology concept that describes the critical biological process to maintain whole-cell/tissue physiology against forces and deformation arising both intra- and extracellularly. Dysregulation of mechanical homeostasis has important implications in pathophysiological conditions such as developmental defect, cardiovascular and pulmonary diseases, and cancer. Mechanical homeostasis has been commonly investigated at molecular, cellular, tissue levels and beyond. However, in mechanical homeostasis collective dynamics at smaller scales and its functional relationship with emergent system-level properties at larger scales remains elusive. The major contribution of this dissertation is to provide a detailed picture of the functional link between molecular and subcellular events and apparent cellular behaviors under mechanical perturbations. A novel suite of technologies, involving microfabrication, live-cell imaging, high-throughput and multidimensional image processing, and mechanical characterization, have been developed and implemented in this research for the live-cell study of both subcellular and cellular aspects of mechanical homeostasis. By utilizing these techniques, we performed cell stretch experiments and quantitative measurements of biomechanical and biochemical responses with a spatiotemporal resolution to examine cell behaviors upon mechanical perturbation. Our data have revealed that cellular mechanical homeostasis is an emergent phenomenon driven by collective and graduated, yet non-homeostatic, subcellular behaviors (“subcellular rheostasis”) that follow distinct mechanosensitive compensatory paths. We have for the first time shown that subcellular dynamics would observe patterns different from that at the single-cell level. Further investigations have revealed that impairment to the extracellular matrix (ECM) – focal adhesion (FA) – cytoskeleton (CSK) mechanical linkage can lead to an effective exit from cellular mechanical homeostasis by skewing the subcellular rheostasis pattern of FAs, which might be a sensitive gating mechanism of cellular homeostasis. Lastly, a mechano-biophysical model has been constructed in this work to quantitatively recapitulate experimental observations of subcellular rheostasis and its perturbation by different drug treatments. Cross-examination of experimental and theoretical modeling results has unveiled the regulatory roles of different mechanosensitive machineries including catch-slip bonds and myosin motor activity in governing the emergence of cellular mechanical homeostasis.PHDMechanical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/135780/1/shinuow_1.pd