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Studies on pattern formation in coculture cell systems can provide insights into many physiological and pathological processes. Here, we investigate how the extracellular matrix (ECM) may influence the patterning in coculture systems. The model coculture system we use is composed of highly motile invasive breast cancer cells, initially mixed with inert nonmetastatic cells on a 2D substrate and covered with a Matrigel layer introduced to mimic ECM. We observe that the invasive cells exhibit persistent centripetal motion and yield abnormal aggregation, rather than random spreading, due to a "collective pulling" effect resulting from ECM-mediated transmission of active contractile forces generated by the polarized migration of the invasive cells along the vertical direction. The mechanism we report may open a new window for the understanding of biological processes that involve multiple types of cells.

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Disordered hyperuniformity (DHU) is a recently proposed new state of matter, which has been observed in a variety of classical and quantum many-body systems. DHU systems are characterized by vanishing infinite-wavelength normalized density fluctuations and are endowed with unique novel physical properties. Here, we report the discovery of disordered hyperuniformity in atomic-scale two-dimensional materials, i.e., amorphous silica composed of a single layer of atoms, based on spectral-density analysis of high-resolution transmission electron microscopy images. Moreover, we show via large-scale density functional theory calculations that DHU leads to almost complete closure of the electronic bandgap compared to the crystalline counterpart, making the material effectively a metal. This is in contrast to the conventional wisdom that disorder generally diminishes electronic transport and is due to the unique electron wave localization induced by the topological defects in the DHU state.

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Metastasis of mesenchymal tumor cells is traditionally considered as a single-cell process. Here, we report an emergent collective phenomenon in which the dissemination rate of mesenchymal breast cancer cells from three-dimensional tumors depends on the tumor geometry. Combining experimental measurements and computational modeling, we demonstrate that the collective dynamics is coordinated by the mechanical feedback between individual cells and their surrounding extracellular matrix (ECM). We find the tissue-like fibrous ECM supports long-range physical interactions between cells, which turn geometric cues into regulated cell dissemination dynamics. Our results suggest that migrating cells in three-dimensional ECM represent a distinct class of an active particle system in which the collective dynamics is governed by the remodeling of the environment rather than direct particle-particle interactions.

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Cell migration in fibrous extracellular matrix (ECM) is crucial to many physiological and pathological processes such as tissue regeneration, immune response, and cancer progression. During migration, individual cells can generate active pulling forces via actomyosin contraction, which are transmitted to the ECM fibers through focal adhesion complexes, remodel the ECM, and eventually propagate to and can be sensed by other cells in the system. The microstructure and physical properties of the ECM can also significantly influence cell migration, e.g., via durotaxis and contact guidance. Here, we develop a computational model for two-dimensional cell migration regulated by cell-ECM micromechanical coupling. Our model explicitly takes into account a variety of cellular-level processes, including focal adhesion formation and disassembly, active traction force generation and cell locomotion due to actin filament contraction, transmission and propagation of tensile forces in the ECM, as well as the resulting ECM remodeling. We validate our model by accurately reproducing single-cell dynamics of MCF-10A breast cancer cells migrating on collagen gels and show that the durotaxis and contact guidance effects naturally arise as a consequence of the cell-ECM micromechanical interactions considered in the model. Moreover, our model predicts strongly correlated multicellular migration dynamics, which are resulted from the ECM-mediated mechanical coupling among the migrating cell and are subsequently verified in in vitro experiments using MCF-10A cells. Our computational model provides a robust tool to investigate emergent collective dynamics of multicellular systems in complex in vivo microenvironment and can be utilized to design in vitro microenvironments to guide collective behaviors and self-organization of cells.

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Collective cell migration in 3D extracellular matrix (ECM) is crucial to many physiological and pathological processes. Migrating cells can generate active pulling forces via actin filament contraction, which are transmitted to the ECM fibers and lead to a dynamically evolving force network in the system. Here, we elucidate the role of this force network in regulating collective cell behaviors using a minimal active-particle-on-network (APN) model, in which active particles can pull the fibers and hop between neighboring nodes of the network following local durotaxis. Our model reveals a dynamic transition as the particle number density approaches a critical value, from an "absorbing" state containing isolated stationary small particle clusters, to an "active" state containing a single large cluster undergoing constant dynamic reorganization. This reorganization is dominated by a subset of highly dynamic "radical" particles in the cluster, whose number also exhibits a transition at the same critical density. The transition is underlaid by the percolation of "influence spheres" due to the particle pulling forces. Our results suggest a robust mechanism based on ECM-mediated mechanical coupling for collective cell behaviors in 3D ECM.

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Understanding the mechanisms underlying the diversity of tumor invasion dynamics, including single-cell migration, multicellular streaming, and the emergence of various collective migration patterns, is a long-standing problem in cancer research. Here we have designed and fabricated a series of microchips containing high-throughput microscale tracks using protein repelling coating technology, which were then covered with a thin Matrigel layer. By varying the geometrical confinement (track width) and microenvironment factors (Matrigel concentration), we have reproduced a diversity of collective migration patterns in the chips, which were also observed in vivo. We have further classified the collective patterns and quantified the emergence probability of each class of patterns as a function of microtrack width and Matrigel concentration to devise a quantitive "collective pattern diagram." To elucidate the mechanisms behind the emergence of various collective patterns, we employed cellular automaton simulations, incorporating the effects of both direct cell-cell interactions and microenvironment factors (e.g., chemical gradient and extracellular matrix degradation). Our simulations suggest that tumor cell phenotype heterogeneity, and the associated dynamic selection of a favorable phenotype via cell-microenivronment interactions, are key to the emergence of the observed collective patterns in vitro.

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Accurately resolving the traction forces on active cells in 3D extra-cellular matrix (ECM) is crucial to understanding stress homeostasis in cellularized ECM systems and the resulting collective cellular behavior. The majority of 3D traction force microscopy techniques, which compute the stress distribution in ECM as well as cellular traction forces from experimentally measured deformation field in the ECM using dispersed tracing particles or fluorescently-tagged matrix proteins, have assumed a spatially homogeneous ECM with constant material properties at every location in the system. Recent studies have shown that ECM can exhibit significant heterogeneity due to the disordered nature of collagen network as well as cell remodeling. In this paper, we develop a novel inverse finite-element formulation for accurately resolving the cellular traction forces by explicitly reconstructing the relative local elastic modulus values of the heterogeneous ECM containing an arbitrary shaped cell from a measured displacement field in the ECM. Our formulation does not require any a priori knowledge of the boundary conditions, and simultaneously results in the distribution of the heterogeneous modulus values and stress field in the ECM, as well as the traction forces on the cell, given experimentally measured average modulus of the ECM. We first validate our procedure in artifical model cell-ECM systems, and then employ the procedure to compute the distribution of elastic modulus in a heterogeneous type-I collagen gel as well as the traction force on a rounded breast cancer cell in the gel, based on the deformation field data obtained via 3D reflectance force microscopy. Our results indicate that the majority part of the cell is in a tensile state, while a local region on the cell is in a tri-axial compressive state, indicating the possible development of a local protrusion in this region. This is further verified by tracking the subsequent evolution of the cell morphology.

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Three-dimensional (3D) collective cell migration in a collagen-based extracellular matrix (ECM) is among one of the most significant topics in developmental biology, cancer progression, tissue regeneration, and immune response. Recent studies have suggested that collagen-fiber mediated force transmission in cellularized ECM plays an important role in stress homeostasis and regulation of collective cellular behaviors. Motivated by the recent in vitro observation that oriented collagen can significantly enhance the penetration of migrating breast cancer cells into dense Matrigel which mimics the intravasation process in vivo [Han et al. Proc. Natl. Acad. Sci. USA 113, 11208 (2016)PNASA60027-842410.1073/pnas.1610347113], we devise a procedure for generating realizations of highly heterogeneous 3D collagen networks with prescribed microstructural statistics via stochastic optimization. Specifically, a collagen network is represented via the graph (node-bond) model and the microstructural statistics considered include the cross-link (node) density, valence distribution, fiber (bond) length distribution, as well as fiber orientation distribution. An optimization problem is formulated in which the objective function is defined as the squared difference between a set of target microstructural statistics and the corresponding statistics for the simulated network. Simulated annealing is employed to solve the optimization problem by evolving an initial network via random perturbations to generate realizations of homogeneous networks with randomly oriented fibers, homogeneous networks with aligned fibers, heterogeneous networks with a continuous variation of fiber orientation along a prescribed direction, as well as a binary system containing a collagen region with aligned fibers and a dense Matrigel region with randomly oriented fibers. The generation and propagation of active forces in the simulated networks due to polarized contraction of an embedded ellipsoidal cell and a small group of cells are analyzed by considering a nonlinear fiber model incorporating strain hardening upon large stretching and buckling upon compression. Our analysis shows that oriented fibers can significantly enhance long-range force transmission in the network. Moreover, in the oriented-collagen-Matrigel system, the forces generated by a polarized cell in collagen can penetrate deeply into the Matrigel region. The stressed Matrigel fibers could provide contact guidance for the migrating cell cells, and thus enhance their penetration into Matrigel. This suggests a possible mechanism for the observed enhanced intravasation by oriented collagen.

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We have developed a novel method to synthesize a hyper-branched biomimetic hydrogel network across a soil matrix to improve the mechanical strength of the loose soil and simultaneously mitigate potential contamination due to excessive ammonium. This method successfully yielded a hierarchical structure that possesses the water retention, ion absorption, and soil aggregation capabilities of plant root systems in a chemically controllable manner. Inspired by the robust organic-inorganic composites found in many living organisms, we have combined this hydrogel network with a calcite biomineralization process to stabilize soil. Our experiments demonstrate that poly(acrylic acid) (PAA) can work synergistically with enzyme-induced carbonate precipitation (EICP) to render a versatile, high-performance soil stabilization method. PAA-enhanced EICP provides multiple benefits including lengthening of water supply time, localization of cementation reactions, reduction of harmful byproduct ammonium, and achievement of ultrahigh soil strength. Soil crusts we have obtained can sustain up to 4.8 × 103 kPa pressure, a level comparable to cementitious materials. An ammonium removal rate of 96% has also been achieved. These results demonstrate the potential for hydrogel-assisted EICP to provide effective soil improvement and ammonium mitigation for wind erosion control and other applications.

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The efficient extraction of (bio)molecules from fluid mixtures is vital for applications ranging from target characterization in (bio)chemistry to environmental analysis and biomedical diagnostics. Inspired by biological processes that seamlessly synchronize the capture, transport and release of biomolecules, we designed a robust chemomechanical sorting system capable of the concerted catch and release of target biomolecules from a solution mixture. The hybrid system is composed of target-specific, reversible binding sites attached to microscopic fins embedded in a responsive hydrogel that moves the cargo between two chemically distinct environments. To demonstrate the utility of the system, we focus on the effective separation of thrombin by synchronizing the pH-dependent binding strength of a thrombin-specific aptamer with volume changes of the pH-responsive hydrogel in a biphasic microfluidic regime, and show a non-destructive separation that has a quantitative sorting efficiency, as well as the system's stability and amenability to multiple solution recycling.

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