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.

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, 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 is developed. Hyaluronic acid-based hydrogels are utilized, amorphously packed with acellular 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 300 kPa. Remarkably, primary chondrocytes recellularize particles within 48 h, a process driven by chemotaxis, exhibit distributed cellularity in large engineered composites, and express genes consistent with native cartilage repair. In addition, broad utility of tissue clays through recellularization and persistence of muscle, skin, and cartilage composites in an in vivo mouse model is demonstrated. The findings suggest optimal material architectures to balance concurrent demands for large-scale mechanical properties while also supporting recellularization and integration of dense musculoskeletal and connective tissues.

Hydrolytically degradable poly(ethylene glycol) (PEG) hydrogels are promising platforms for cell encapsulation and tissue engineering. However, hydrolysis leads to bulk degradation and a decrease in hydrogel mechanical integrity. Despite these challenges, hydrolytically degradable hydrogels have supported macroscopic neotissue growth. The goal of this study was to combine experimental methods with a multiscale mathematical model to analyze hydrogel degradation concomitant with neocartilage growth in PEG hydrogels. Primary bovine chondrocytes were encapsulated at increasing densities (50, 100, and 150 million cells/mL of precursor solution) in a radical-mediated photoclickable hydrogel formed from 8-arm PEG-co-caprolactone end-capped with norbornene and cross-linked with PEG dithiol. Two observations were made in the experimental system: (1) the cell distribution was not uniform and cell clustering was evident, which increased with increasing cell density and (2) a significant decrease in the initial hydrogel compressive modulus was observed with increasing cell concentration. By introducing heterogeneities in the form of cell clusters and spatial variations in the network structure around cells, the mathematical model explained the drop in initial modulus and captured the experimentally observed spatial evolution of ECM and the construct modulus as a function of cell density and culture time. Overall, increasing cell density led to improved ECM formation, ECM connectivity, and overall modulus. This study strongly points to the importance of heterogeneities within a cell-laden hydrogel in retaining mechanical integrity as the construct transitions from hydrogel to neotissue.

Active networks are omnipresent in nature, from the molecular to the macro-scale. In this study, we explore the mechanical behaviour of fire ant aggregations, closely knit swarms that display impressive dynamics culminating with the aggregations’ capacity to self-heal and adapt to the environment. Although the combined elasticity and rheology of the ant aggregation can be characterized by phenomenological mechanical models (e.g. linear Maxwell or Kelvin–Voigt model), it is not clear how the behaviour of individual ants affects the aggregations’ emerging responses. Here, we explore an alternative way to think about these materials, describing them as a collection of individuals connected via elastic chains that associate and dissociate over time. Using our knowledge of these connections—e.g. their elasticity and attachment/dissociation rates—we construct a statistical description of connection stretch and derive an evolution equation for the corresponding stretch distribution. This time-evolving stretch distribution is then used to determine important macroscopic measures, e.g. stress, energy storage and energy dissipation, in the network. In this context, we show how the physical characteristics and activities of individual ants can explain the elasticity, flow and shear thinning of the aggregation. In particular, we find that experimental results are matched if the detachment rate between two individuals increases with tension in the connection.

Enzyme-sensitive hydrogels are promising cell delivery vehicles for cartilage tissue engineering. However, a better understanding of their spatiotemporal degradation behavior and its impact on tissue growth is needed. The goal of this study was to combine experimental and computational approaches to provide new insights into spatiotemporal changes in hydrogel crosslink density and extracellular matrix (ECM) growth and how these changes influence the evolving macroscopic properties as a function of time. Hydrogels were designed from aggrecanase-sensitive peptide crosslinks using a simple and robust thiol-norbornene photoclick reaction. To study the influence of variations in cellular activity of different donors, chondrocytes were isolated from either juvenile or adult bovine donors. Initial studies were performed to validate and calibrate the model against experiments. Through this process, two key features were identified. These included spatial variations in the hydrogel crosslink density in the immediate vicinity of the cell and the presence of cell clustering within the construct. When these spatial heterogeneities were incorporated into the computational model along with model inputs of initial hydrogel properties and cellular activity (i.e., enzyme and ECM production rates), the model was able to capture the spatial and temporal evolution of ECM growth that was observed experimentally for both donors. In this study, the juvenile chondrocytes produced an interconnected matrix within the cell clusters leading to overall improved ECM growth, while the adult chondrocytes resulted in poor ECM growth. Overall, the computational model was able to capture the spatiotemporal ECM growth of two different donors and provided new insights into the importance of spatial heterogeneities in facilitating ECM growth. Our long-term goal is to use this model to predict optimal hydrogel designs for a wide range of donors and improve cartilage tissue engineering.

Degradable hydrogels have been developed to provide initial mechanical support to encapsulated cells while facilitating 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 pure hydrogel to an engineered neo-tissue. We show that heterogeneity in cross-link density and cell distribution are key elements for 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.

No abstract

No abstract