Catch bond kinetics are instrumental to cohesion of fire ant rafts under load.

Dynamic networks composed of constituents that break and reform bonds reversibly are ubiquitous in nature owing to their modular architectures that enable functions like energy dissipation, self-healing, and even activity. While bond breaking depends only on the current configuration of attachment in these networks, reattachment depends also on the proximity of constituents. Therefore, dynamic networks composed of macroscale constituents (not benefited by the secondary interactions cohering analogous networks composed of molecular-scale constituents) must rely on primary bonds for cohesion and self-repair. Toward understanding how such macroscale networks might adaptively achieve this, we explore the uniaxial tensile response of 2D rafts composed of interlinked fire ants (S. invicta). Through experiments and discrete numerical modeling, we find that ant rafts adaptively stabilize their bonded ant-to-ant interactions in response to tensile strains, indicating catch bond dynamics. Consequently, low-strain rates that should theoretically induce creep mechanics of these rafts instead induce elastic-like response. Our results suggest that this force-stabilization delays dissolution of the rafts and improves toughness. Nevertheless, above 35[Formula: see text] strain low cohesion and stress localization cause nucleation and growth of voids whose coalescence patterns result from force-stabilization. These voids mitigate structural repair until initial raft densities are restored and ants can reconnect across defects. However mechanical recovery of ant rafts during cyclic loading suggests that-even upon reinstatement of initial densities-ants exhibit slower repair kinetics if they were recently loaded at faster strain rates. These results exemplify fire ants' status as active agents capable of memory-driven, stimuli-response for potential inspiration of adaptive structural materials.

Material assembly from collective action of shape-changing polymers.

Some animals form transient, responsive and solid-like ensembles through dynamic structural interactions. These ensembles demonstrate emergent responses such as spontaneous self-assembly, which are difficult to achieve in synthetic soft matter. Here we use shape-morphing units comprising responsive polymers to create solids that self-assemble, modulate their volume and disassemble on demand. The ensemble is composed of a responsive hydrogel, liquid crystal elastomer or semicrystalline polymer ribbons that reversibly bend or twist. The dispersions of these ribbons mechanically interlock, inducing reversible aggregation. The aggregated liquid crystal elastomer ribbons have a 12-fold increase in the yield stress compared with cooled dispersion and contract by 34% on heating. Ribbon type, concentration and shape dictate the aggregation and govern the global mechanical properties of the solid that forms. Coating liquid crystal elastomer ribbons with a liquid metal begets photoresponsive and electrically conductive aggregates, whereas seeding cells on hydrogel ribbons enables self-assembling three-dimensional scaffolds, providing a versatile platform for the design of dynamic materials.

Nonsteady fracture of transient networks: The case of vitrimer.

We have discovered a peculiar form of fracture that occurs in polymer network formed by covalent adaptable bonds. Due to the dynamic feature of the bonds, fracture of this network is rate dependent, and the crack propagates in a highly nonsteady manner. These phenomena cannot be explained by the existing fracture theories, most of which are based on steady-state assumption. To explain these peculiar characteristics, we first revisit the fundamental difference between the transient network and the covalent network in which we highlighted the transient feature of the cracks. We extend the current fracture criterion for crack initiation to a time-evolution scheme that allows one to track the nonsteady propagation of a crack. Through a combined experimental modeling effort, we show that fracture in transient networks is governed by two parameters: the Weissenberg number [Formula: see text] that defines the history path of crack-driving force and an extension parameter Z that tells how far a crack can grow. We further use our understanding to explain the peculiar experimental observation. To further leverage on this understanding, we show that one can "program" a specimen's crack extension dynamics by tuning the loading history.

Computational exploration of treadmilling and protrusion growth observed in fire ant rafts.

Collective living systems regularly achieve cooperative emergent functions that individual organisms could not accomplish alone. The rafts of fire ants (Solenopsis invicta) are often studied in this context for their ability to create aggregated structures comprised entirely of their own bodies, including tether-like protrusions that facilitate exploration of and escape from flooded environments. While similar protrusions are observed in cytoskeletons and cellular aggregates, they are generally dependent on morphogens or external gradients leaving the isolated role of local interactions poorly understood. Here we demonstrate through an ant-inspired, agent-based numerical model how protrusions in ant rafts may emerge spontaneously due to local interactions. The model is comprised of a condensed structural network of agents that represents the monolayer of interconnected worker ants, which floats on the water and gives ant rafts their form. Experimentally, this layer perpetually contracts, which we capture through the pairwise contraction of all neighboring structural agents at a strain rate of [Formula: see text]. On top of the structural layer, we model a dispersed, on-lattice layer of motile agents that represents free ants, which walk on top of the floating network. Experimentally, these self-propelled free ants walk with some mean persistence length and speed that we capture through an ant-inspired phenomenological model. Local interactions occur between neighboring free ants within some radius of detection, R, and the persistence length of freely active agents is tuned through a noise parameter, η as introduced by the Vicsek model. Both R and η where fixed to match the experimental trajectories of free ants. Treadmilling of the raft occurs as agents transition between the structural and free layers in accordance with experimental observations. Ultimately, we demonstrate how phases of exploratory protrusion growth may be induced by increased ant activity as characterized by a dimensionless parameter, [Formula: see text]. These results provide an example in which functional morphogenesis of a living system may emerge purely from local interactions at the constituent length scale, thereby providing a source of inspiration for the development of decentralized, autonomous active matter and swarm robotics.

Coupled bond dynamics alters relaxation in polymers with multiple intrinsic dissociation rates.

Dynamic networks containing multiple bond types within a continuous network grant engineers another design parameter - relative bond fraction - by which to tune storage and dissipation of mechanical energy. However, the mechanisms governing emergent properties are difficult to deduce experimentally. Therefore, we here employ a network model with prescribed fractions of dynamic and stable bonds to predict relaxation characteristics of hybrid networks. We find that during stress relaxation, predominantly dynamic networks can exhibit long-term moduli through conformationally inhibited relaxation of stable bonds due to exclusion interactions with neighboring chains. Meanwhile, predominantly stable networks exhibit minor relaxation through non-affine reconfiguration of dynamic bonds. Given this, we introduce a single fitting parameter, ξ, to Transient Network Theory via a coupled rule of mixture, that characterizes the extent of stable bond relaxation. Treating ξ as a fitting parameter, the coupled rule of mixture's predicted stress response not only agrees with the network model's, but also unveils likely micromechanical traits of gels hosting multiple bond dissociation timescales.

Poroviscoelasto-plasticity of agarose-based hydrogels.

Agarose gels are excellent candidates for tissue engineering as they are tunable, viscoelastic, and show a pronounced strain-stiffening response. These characteristics make them ideal to create in vitro environments to grow cells and develop tissues. As in many other biopolymers, viscoelasticity and poroelasticity coexist as time-dependent behaviors in agarose gels. While the viscoelastic behavior of these hydrogels has been considered using both phenomenological and continuum models, there remains a lack of connection between the underlying physics and the macroscopic material response. Through a finite element analysis and complimentary experiments, we evaluated the complex time-dependent mechanical response of agarose gels in various conditions. We then conceptualized these gels as a dynamic network where the global dissociation/association rate of intermolecular bonds is described as a combination of a fast rate native to double helices forming between aligned agarose molecules and a slow rate of the agarose molecules present in the clusters. Using the foundation of the transient network theory, we developed a physics-based constitutive model that accurately describes agarose behavior. Integrating experimental results and model prediction, we demonstrated that the fast dissociation/association rate follows a nonlinear force-dependent response, whose exponential evolution agrees with Eyring's model based on the transition state theory. Overall, our results establish a more accurate understanding of the time-dependent mechanics of agarose gels and provide a model that can inform design of a variety of biopolymers with a similar network topology.

Mechanics of 3D Cell-Hydrogel Interactions: Experiments, Models, and Mechanisms.

Hydrogels are highly water-swollen molecular networks that are ideal platforms to create tissue mimetics owing to their vast and tunable properties. As such, hydrogels are promising cell-delivery vehicles for applications in tissue engineering and have also emerged as an important base for ex vivo models to study healthy and pathophysiological events in a carefully controlled three-dimensional environment. Cells are readily encapsulated in hydrogels resulting in a plethora of biochemical and mechanical communication mechanisms, which recapitulates the natural cell and extracellular matrix interaction in tissues. These interactions are complex, with multiple events that are invariably coupled and spanning multiple length and time scales. To study and identify the underlying mechanisms involved, an integrated experimental and computational approach is ideally needed. This review discusses the state of our knowledge on cell-hydrogel interactions, with a focus on mechanics and transport, and in this context, highlights recent advancements in experiments, mathematical and computational modeling. The review begins with a background on the thermodynamics and physics fundamentals that govern hydrogel mechanics and transport. The review focuses on two main classes of hydrogels, described as semiflexible polymer networks that represent physically cross-linked fibrous hydrogels and flexible polymer networks representing the chemically cross-linked synthetic and natural hydrogels. In this review, we highlight five main cell-hydrogel interactions that involve key cellular functions related to communication, mechanosensing, migration, growth, and tissue deposition and elaboration. For each of these cellular functions, recent experiments and the most up to date modeling strategies are discussed and then followed by a summary of how to tune hydrogel properties to achieve a desired functional cellular outcome. We conclude with a summary linking these advancements and make the case for the need to integrate experiments and modeling to advance our fundamental understanding of cell-matrix interactions that will ultimately help identify new therapeutic approaches and enable successful tissue engineering.

Thermosensitive P(AAc-co-NIPAm) Hydrogels Display Enhanced Toughness and Self-Healing via Ion-Ligand Interactions.

Hydrogels containing thermosensitive polymers such as poly(N-isopropylacrylamide) (P(NIPAm)) may contract during heating and show great promise in fields ranging from soft robotics to thermosensitive biosensors. However, these gels often exhibit low stiffness, tensile strength, and mechanical toughness, limiting their applicability. Through copolymerization of P(NIPAm) with poly(Acrylic acid) (P(AAc)) and introduction of ferric ions (Fe3+ ) that coordinate with functional groups along the P(AAc) chains, here a thermoresponsive hydrogel with enhanced mechanical extensibility, strength, and toughness is introduced. Using both experimentation and constitutive modeling, it is found that increasing the ratio of m(AAc):m(NIPAm) in the prepolymer decreases strength and toughness but improves extensibility. In contrast, increasing Fe3+ concentration generally improves strength and toughness with little decrease in extensibility. Due to reversible coordination of the Fe3+ bonds, these gels display excellent recovery of mechanical strength during cyclic loading and self-healing ability. While thermosensitive contraction imbued by the underlying P(NIPAm) decreases slightly with increased Fe3+ concentration, the temperature transition range is widened and shifted upward toward that of human body temperature (between 30 and 40 °C), perhaps rendering these gels suitable as in vivo biosensors. Finally, these gels display excellent adsorptive properties with a variety of materials, rendering them possible candidates in adhesive applications.

Recellularization and Integration of Dense Extracellular Matrix by Percolation of Tissue Microparticles.

Cells embedded in the extracellular matrix of tissues play a critical role in maintaining homeostasis while promoting integration and regeneration following damage or disease. Emerging engineered biomaterials utilize decellularized extracellular matrix as a tissue-specific support structure; however, many dense, structured biomaterials unfortunately demonstrate limited formability, fail to promote cell migration, and result in limited tissue repair. Here, we developed a reinforced composite material of densely packed acellular extracellular matrix microparticles in a hydrogel, termed tissue clay, that can be molded and crosslinked to mimic native tissue architecture. We utilized hyaluronic acid-based hydrogels, amorphously packed with acellular articular cartilage tissue particulated to ~125-250 microns in diameter and defined a percolation threshold of 0.57 (v/v) beyond which the compressive modulus exceeded 300kPa. Remarkably, primary chondrocytes recellularized particles within 48 hours, a process driven by chemotaxis, exhibited distributed cellularity in large engineered composites, and expressed genes consistent with native cartilage repair. We additionally demonstrated broad utility of tissue clays through recellularization and persistence of muscle, skin, and cartilage composites in a subcutaneous in vivo mouse model. Our findings suggest optimal strategies and material architectures to balance concurrent demands for large-scale mechanical properties while also supporting recellularization and integration of dense musculoskeletal and connective tissues. TABLE OF CONTENTS ENTRY: We present a new design framework for regenerative articular cartilage scaffolds using acellular extracellular matrix particles, packed beyond a percolation threshold, and crosslinked within chondroinductive hydrogels. Our results suggest that the architecture and the packing, rather than altering the individual components, creates a composite material that can balance mechanics, porosity to enable migration, and tissue specific biochemical interactions with cells. Moreover, we provide a technique that we show is applicable to other tissue types.

A network model of transient polymers: exploring the micromechanics of nonlinear viscoelasticity.

Dynamic networks contain crosslinks that re-associate after disconnecting, imparting them with viscoelastic properties. While continuum approaches have been developed to analyze their mechanical response, these approaches can only describe their evolution in an average sense, omitting local, stochastic mechanisms that are critical to damage initiation or strain localization. To address these limitations, we introduce a discrete numerical model that mesoscopically coarse-grains the individual constituents of a dynamic network to predict its mechanical and topological evolution. Each constituent consists of a set of flexible chains that are permanently cross-linked at one end and contain reversible binding sites at their free ends. We incorporate nonlinear force-extension of individual chains via a Langevin model, slip-bond dissociation through Eyring's model, and spatiotemporally-dependent bond attachment based on scaling theory. Applying incompressible, uniaxial tension to representative volume elements at a range of constant strain rates and network connectivities, we then compare the mechanical response of these networks to that predicted by the transient network theory. Ultimately, we find that the idealized continuum approach remains suitable for networks with high chain concentrations when deformed at low strain rates, yet the mesoscale model proves necessary for the exploration of localized stochastic events, such as variability of the bond kinetics, or the nucleation of micro-cavities that likely conceive damage and fracture.

Force-dependent bond dissociation explains the rate-dependent fracture of vitrimers.

We investigate the rate-dependent fracture of vitrimers by conducting a tear test. Based on the relationship between the fracture energy and the thickness of vitrimer films, we, for the first time, obtain the intrinsic fracture energy and bulk dissipation of vitrimers during crack extension. The intrinsic fracture energy strongly depends on tear speed, and such dependence can be well explained by Eyring theory. In contrast, the bulk dissipation only weakly depends on tear speed, which is drastically different from observations on traditional viscoelastic polymers. We ascribe such a weak rate-dependence to the strong force-sensitivity of the exchange reaction of the dynamic covalent bond in the vitrimer.

Moving while you're stuck: a macroscopic demonstration of an active system inspired by binding-mediated transport in biology.

Diffusive motion is typically constrained when particles bind to the medium through which they move. However, when binding is transient and the medium is made of flexible filaments, each association or dissociation event produces a stochastic force that can overcome the medium stickiness and enable motion. This mechanism is amply used by biological systems where the act of balancing binding and displacement robustly achieves key functionalities, including bacterial locomotion or selective active filtering in cells. Here we demonstrate the feasibility of making a dynamic system with macroscopic features, in which analogous binding-mediated motion can be actively driven, precisely tuned, and conveniently studied. We find an optimal binding affinity and number of binding sites for diffusive motion, and an inverse relationship between viscosity and diffusivity.

Dynamic competition of inflation and delamination in the finite deformation of thin membranes.

The mechanics of blister delamination and growth plays a major role in a diversity of areas including medicine (skin pathology and mechanics of cell membranes), materials (adhesive and fracture) or soft robotics (actuation and morphing). The behavior of a blister in this context is typically difficult to grasp as it arises from the interplay of two highly nonlinear and time-dependent processes: membrane attachment and decohesion from a substrate. In the present work, we device a simplified approach, based on experimental systems, to predict the deformation path of a blister under various conditions. For this, we consider the problem of a growing blister made of a rubber-like membrane adhered on a rigid substrate, and develop a theoretical and experimental framework to study its stability and growth. We start by constructing a theoretical model of viscoelastic blister growth which we later validate with an experimental setup. We show that blister growth is controlled by the competition between two instabilities: one inherent to the rubber, and a second one pertaining to the adhesion with the substrate. Using these concepts, we show that a "targeted" stable blister shape can be achieved by controlling two parameters: the thickness of the film and the inflation rate.

On the blistering of thermo-sensitive hydrogel: the volume phase transition and mechanical instability.

This paper explores the physical mechanisms responsible for the appearance of small blisters on the surface of temperature sensitive hydrogels as they deswell rapidly during their volume phase transition. For this, we develop a numerical model that couples the processes of hydrogel deswelling and blister growth due to the existence of a thin quasi-impermeable layer on its surface. The model points out that blister inflation originates at defects point under the gel's surface, under the effect of the increasing osmotic pressure in the gel as it undergoes its phase transition. Due to their large deformation, these blisters often experience a mechanical instability that triggers a sudden increase in their growth rate at the expense of their closest neighbors. Using a simple computational model, we then show that blisters are able to communicate via internal pressure and that these interactions are mediated by two characteristic time scales related to solvent transport within and between adjacent blisters. Our study finally indicates that these mechanisms can be controlled by temperature and the gel's cross-link density to achieve diversity of blister patterns on the gel's surface. The proposed analysis provides predictions that agree well with experimental observations of NiPAm gels which deswell in various conditions.

A Statistical Model of Expansive Growth in Plant and Fungal Cells: The Case of Phycomyces.

Expansive growth is a process by which walled cells of plants, algae, and fungi use turgor pressure to mediate irreversible wall deformation and regulate their shape and volume. The molecular structure of the primary cell wall must therefore perform multiple functions simultaneously, including providing structural support by combining elastic and irreversible deformation and facilitating the deposition of new material during growth. This is accomplished by a network of microfibrils and tethers composed of complex polysaccharides and proteins that can dynamically mediate the network topology via periodic detachment and reattachment events. Lockhart and Ortega have provided crucial macroscopic understanding of the expansive growth process through global biophysical models, but these models lack the connection to molecular processes that trigger network rearrangements in the wall. Interestingly, the helical growth of the fungal sporangiophores of Phycomyces blakesleeanus is attributed to a limited region (called the growth zone) where microfibrils are deposited, followed by reorientation and slip. Based on past evidence of dominant shear strain between microfibrils (slippage), we propose a mechanistic model of a network of sliding fibrils connected by tethers. A statistical approach is introduced to describe the population behavior of tethers that have elastic properties and the ability to break and reform in time. These properties are responsible for global cell wall mechanics such as creep and stress relaxation. Model predictions are compared with experiments from literature on stress relaxation and turgor pressure step up for the growing cells of P. blakesleeanus, which are later extended to incised pea (Pisum sativus L.) and the algae Chara corallina using the unique dimensionless number Πpe for each species. To our knowledge, this research is the first attempt to use a statistical approach to model the cell wall during expansive growth, and we believe it provides critical insights on cell wall dynamics at a molecular level.

Transient response of nonlinear polymer networks: A kinetic theory.

Dynamic networks are found in a majority of natural materials, but also in engineering materials, such as entangled polymers and physically cross-linked gels. Owing to their transient bond dynamics, these networks display a rich class of behaviors, from elasticity, rheology, self-healing, or growth. Although classical theories in rheology and mechanics have enabled us to characterize these materials, there is still a gap in our understanding on how individuals (i.e., the mechanics of each building blocks and its connection with others) affect the emerging response of the network. In this work, we introduce an alternative way to think about these networks from a statistical point of view. More specifically, a network is seen as a collection of individual polymer chains connected by weak bonds that can associate and dissociate over time. From the knowledge of these individual chains (elasticity, transient attachment, and detachment events), we construct a statistical description of the population and derive an evolution equation of their distribution based on applied deformation and their local interactions. We specifically concentrate on nonlinear elastic response that follows from the strain stiffening response of individual chains of finite size. Upon appropriate averaging operations and using a mean field approximation, we show that the distribution can be replaced by a so-called chain distribution tensor that is used to determine important macroscopic measures such as stress, energy storage and dissipation in the network. Prediction of the kinetic theory are then explored against known experimental measurement of polymer responses under uniaxial loading. It is found that even under the simplest assumptions of force-independent chain kinetics, the model is able to reproduce complex time-dependent behaviors of rubber and self-healing supramolecular polymers.

Effects of soft interactions and bound mobility on diffusion in crowded environments: a model of sticky and slippery obstacles.

Crowded environments modify the diffusion of macromolecules, generally slowing their movement and inducing transient anomalous subdiffusion. The presence of obstacles also modifies the kinetics and equilibrium behavior of tracers. While previous theoretical studies of particle diffusion have typically assumed either impenetrable obstacles or binding interactions that immobilize the particle, in many cellular contexts bound particles remain mobile. Examples include membrane proteins or lipids with some entry and diffusion within lipid domains and proteins that can enter into membraneless organelles or compartments such as the nucleolus. Using a lattice model, we studied the diffusive movement of tracer particles which bind to soft obstacles, allowing tracers and obstacles to occupy the same lattice site. For sticky obstacles, bound tracer particles are immobile, while for slippery obstacles, bound tracers can hop without penalty to adjacent obstacles. In both models, binding significantly alters tracer motion. The type and degree of motion while bound is a key determinant of the tracer mobility: slippery obstacles can allow nearly unhindered diffusion, even at high obstacle filling fraction. To mimic compartmentalization in a cell, we examined how obstacle size and a range of bound diffusion coefficients affect tracer dynamics. The behavior of the model is similar in two and three spatial dimensions. Our work has implications for protein movement and interactions within cells.

Heterogeneity is key to hydrogel-based cartilage tissue regeneration.

Degradable hydrogels have been developed to provide initial mechanical support to encapsulated cells while facilitating the growth of neo-tissues. When cells are encapsulated within degradable hydrogels, the process of neo-tissue growth is complicated by the coupled phenomena of transport of large extracellular matrix macromolecules and the rate of hydrogel degradation. If hydrogel degradation is too slow, neo-tissue growth is hindered, whereas if it is too fast, complete loss of mechanical integrity can occur. Therefore, there is a need for effective modelling techniques to predict hydrogel designs based on the growth parameters of the neo-tissue. In this article, hydrolytically degradable hydrogels are investigated due to their promise in tissue engineering. A key output of the model focuses on the ability of the construct to maintain overall structural integrity as the construct transitions from a pure hydrogel to engineered neo-tissue. We show that heterogeneity in cross-link density and cell distribution is the key to this successful transition and ultimately to achieve tissue growth. Specifically, we find that optimally large regions of weak cross-linking around cells in the hydrogel and well-connected and dense cell clusters create the optimum conditions needed for neo-tissue growth while maintaining structural integrity. Experimental observations using cartilage cells encapsulated in a hydrolytically degradable hydrogel are compared with model predictions to show the potential of the proposed model.

A simple statistical approach to model the time-dependent response of polymers with reversible cross-links.

A new class of polymers characterized by dynamic cross-links is analyzed from a mechanical point of view. A thermodynamically consistent model is developed within the Lagrangian framework for polymers that can rearrange their internal cross-links. Such a class of polymers has the capability to reset their internal microstructure and the microscopic remodeling mechanism leads to a behavior similar to that of an elastic fluid. These materials can potentially be used in several fields, such as in biomechanics, smart materials, morphing materials to cite e few. However, a comprehensive understanding is necessary before we can predict their behavior and perform material design for advanced technologies. The proposed formulation-following a statistical approach adapted from classical rubber elasticitye is based on the evolution of the molecular chains' end-to-end distance distribution function. This distribution is allowed here to evolve with time, starting from an initial stress-free state and depending on the deformation history and the cross-link attachment/detachment kinetics. Some simple examples are finally presented and discussed to illustrate the capability and generality of the developed approach.

Tuning tissue growth with scaffold degradation in enzyme-sensitive hydrogels: a mathematical model.

Despite tremendous advances in the field of tissue engineering, a number of obstacles remain that hinder its successful translation to the clinic. One challenge that relates to the use of cells encapsulated in a hydrogel is identifying a hydrogel design that can provide an appropriate environment for cells to successfully synthesize and deposit new matrix molecules while providing a mechanical support that can resist physiological loads at the early stage of implementation. A solution to this problem has been to balance tissue growth and hydrogel degradation. However, identifying this balance is difficult due to the complexity of coupling diffusion, deposition, and degradation mechanisms. Very little is known about the complex behavior of these mechanisms, emphasizing the need for a rigorous mathematical approach that can assist and guide experimental advances. To address this issue, this paper discusses a model for interstitial growth based on mixture theory, that can capture the coupling between cell-mediated hydrogel degradation (i.e., hydrogels containing enzyme-sensitive crosslinks) and the transport of extracellular matrix (ECM) molecules released by encapsulated cells within a hydrogel. Taking cartilage tissue engineering as an example, the model investigates the role of enzymatic degradation on ECM diffusion and its impact on two important outcomes: the extent of ECM transport (and deposition) and the evolution of the hydrogel's mechanical integrity. Numerical results based on finite element analysis show that if properly tuned, enzymatic degradation yields the appearance of a highly localized degradation front propagating away from the cell, which can be immediately followed by a front of growing neotissue. We show that this situation is key to maintaining mechanical properties (e.g., stiffness) while allowing for deposition of new ECM molecules. Overall, our study suggests a hydrogel design that could enable successful tissue engineering (e.g., of cartilage, bone, etc.) where mechanical integrity is important.