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

Abstract

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.

3D Bioprinted GelMA‐Nanoclay Hydrogels Induce Colorectal Cancer Stem Cells Through Activating Wnt/β‐Catenin Signaling

“…This result suggested that the GelMA hydrogel may stimulate some signaling involved in stemness regulation but not enough to successfully induce CSCs. Nanoclay addition may induce the ECM organization and reconstruction of CSCs, which may be due to the suitable mechanical environment [55] or the negative charge of the nanoclay allowing the hydrogel to sequester water and divalent cations, conferring space-filling and biomolecule diffusion, [55,56] thus leading to good cell-cell or cell-hydrogel-cell communication within the microenvironment. Among these interactions, the GelMA-nanoclay hydrogel may interact with cell surface proteins, including inte-grin, and generate the differential spatiotemporal activation of tyrosine kinases, inducing the expression of proteins related to cell stemness, such as SHH [29] and LGR5 (Figure 4b,c).…”

4D Printing of Extrudable and Degradable Poly(Ethylene Glycol) Microgel Scaffolds for Multidimensional Cell Culture

“…[ 10 ] Incorporation of cells in the interstitial space between connected microgels, often described as 2.5D culture (as cells are in a 3D scaffold without being fully confined by matrix), addresses important cytocompatibility limitations of bulk encapsulation due to pore sizes (microns‐millimeters) orders of magnitude larger than the mesh size of polymer networks (nanometers). [ 11 ] This interstitial space acts not only as a thoroughfare for nutrient diffusion but also as an important environment for cellular colonization by spreading, growth, and migration, [ 12 ] which can collectively be influenced by chemical, mechanical, and topological cues from the microgel substrate. [ 13 ] Recently, matrices of fibrous granular hydrogels were demonstrated to undergo programmable contraction and cell‐driven reorganization, marking the potential for microgel scaffolds to evolve over time in response to both intrinsic and extrinsic cues.…”

Development of Organogels for Live Yarrowia lipolytica Encapsulation

“…To date, various organic and inorganic encapsulation materials have been explored, including hydrogels, 7 hydrogel− elastomer hybrids, 8 polydopamine, 9 polyelectrolytes, polyelectrolyte/oxidized carbon nanotube hybrids, 10 silica, 11 and calcium phosphate/carbonate. 12,13 All of them are hydrophilic materials because, on one hand, hydrophilic biocompatible materials have been well studied and can ensure the survival of encapsulated cells/microorganisms; 7 on the other hand, the design of hydrophobic biocompatible encapsulation materials is still challenging. 14 Oleaginous microorganisms capable of using hydrophobic substances have attracted extensive attention in various fields.…”