Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel-drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

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Designing hydrogels for controlled drug delivery.

The ability of a eukaryotic cell to resist deformation, to transport intracellular cargo and to change shape during movement depends on the cytoskeleton, an interconnected network of filamentous polymers and regulatory proteins. Recent work has demonstrated that both internal and external physical forces can act through the cytoskeleton to affect local mechanical properties and cellular behaviour. Attention is now focused on how cytoskeletal networks generate, transmit and respond to mechanical signals over both short and long timescales. An important insight emerging from this work is that long-lived cytoskeletal structures may act as epigenetic determinants of cell shape, function and fate.

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Cell mechanics and the cytoskeleton

Soft robotics: a bioinspired evolution in robotics.

BACKGROUND Hydrogels are formed through the cross-linking of hydrophilic polymer chains within an aqueous microenvironment. The gelation can be achieved through a variety of mechanisms, spanning physical entanglement of polymer chains, electrostatic interactions, and covalent chemical cross-linking. The water-rich nature of hydrogels makes them broadly applicable to many areas, including tissue engineering, drug delivery, soft electronics, and actuators. Conventional hydrogels usually possess limited mechanical strength and are prone to permanent breakage. The lack of desired dynamic cues and structural complexity within the hydrogels has further limited their functions. Broadened applications of hydrogels, however, require advanced engineering of parameters such as mechanics and spatiotemporal presentation of active or bioactive moieties, as well as manipulation of multiscale shape, structure, and architecture. ADVANCES Hydrogels with substantially improved physicochemical properties have been enabled by rational design at the molecular level and control over multiscale architecture. For example, formulations that combine permanent polymer networks with reversibly bonding chains for energy dissipation show strong toughness and stretchability. Similar strategies may also substantially enhance the bonding affinity of hydrogels at interfaces with solids by covalently anchoring the polymer networks of tough hydrogels onto solid surfaces. Shear-thinning hydrogels that feature reversible bonds impart a fluidic nature upon application of shear forces and return back to their gel states once the forces are released. Self-healing hydrogels based on nanomaterial hybridization, electrostatic interactions, and slide-ring configurations exhibit excellent abilities in spontaneously healing themselves after damages. Additionally, harnessing techniques that can dynamically and precisely configure hydrogels have resulted in flexibility to regulate their architecture, activity, and functionality. Dynamic modulations of polymer chain physics and chemistry can lead to temporal alteration of hydrogel structures in a programmed manner. Three-dimensional printing enables architectural control of hydrogels at high precision, with a potential to further integrate elements that enable change of hydrogel configurations along prescribed paths. OUTLOOK We envision the continuation of innovation in new bioorthogonal chemistries for making hydrogels, enabling their fabrication in the presence of biological species without impairing cellular or biomolecule functions. We also foresee opportunities in the further development of more sophisticated fabrication methods that allow better-controlled hydrogel architecture across multiple length scales. In addition, technologies that precisely regulate the physicochemical properties of hydrogels in spatiotemporally controlled manners are crucial in controlling their dynamics, such as degradation and dynamic presentation of biomolecules. We believe that the fabrication of hydrogels should be coupled with end applications in a feedback loop in order to achieve optimal designs through iterations. In the end, it is the combination of multiscale constituents and complementary strategies that will enable new applications of this important class of materials.

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Advances in engineering hydrogels

Natural extracellular matrices (ECMs) are viscoelastic and exhibit stress relaxation. However, hydrogels used as synthetic ECMs for three-dimensional (3D) culture are typically elastic. Here, we report a materials approach to tune the rate of stress relaxation of hydrogels for 3D culture, independently of the hydrogel's initial elastic modulus, degradation, and cell-adhesion-ligand density. We find that cell spreading, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) are all enhanced in cells cultured in gels with faster relaxation. Strikingly, MSCs form a mineralized, collagen-1-rich matrix similar to bone in rapidly relaxing hydrogels with an initial elastic modulus of 17 kPa. We also show that the effects of stress relaxation are mediated by adhesion-ligand binding, actomyosin contractility and mechanical clustering of adhesion ligands. Our findings highlight stress relaxation as a key characteristic of cell-ECM interactions and as an important design parameter of biomaterials for cell culture.

https://biblio.ugent.be/publication/8692536/file/8692544.pdf

Hydrogels with tunable stress relaxation regulate stem cell fate and activity

As cells migrate through the extracellular matrix (ECM), they can sense the mechanical properties of their environment and remodel the matrix. Most ECMs are known to be dissipative, exhibiting viscoelastic and often plastic behaviors. However, the influence of dissipation on cell motility, in particular the plasticity in 3D confining microenvironments that endows matrix with intrinsic long-term mechanical memory, is not clear. In this study, we develop a chemo-mechanical model to predict the impact of matrix plasticity on the dynamics of invadopodia, the protrusive structures that cancer cells use to facilitate invasion and motility. By considering myosin dynamics, actin polymerization, adhesion formation, and biochemical signaling, we demonstrate that matrix dissipation facilitates invadopodia oscillations by softening the ECM over repeated cycles, during which plastic deformation gradually accumulates via cyclic ratcheting. Our model reveals that distinct patterns of protrusion behavior, oscillatory or monotonic, emerge from the interplay between timescales of extension-associated viscosity and signaling-associated myosin recruitment; oscillations are only observed when these timescales are comparable. Further, we predict and experimentally validate the influence of pharmacological treatments that target myosin activity, adhesions and Rho and Rho kinase (ROCK) pathways on invadopodia dynamics. More importantly, our model provides a quantitative framework to understand how the matrix can serve as a memory storage mechanism for protrusions that is “written on” or “read” by cells.

Recursive Feedback between Matrix Dissipation and Chemo-Mechanical Signaling Drives Oscillatory Growth of Cancer Cell Invadopodia

https://research.tue.nl/files/257498148/s43586_022_00179_7.pdf

Engineered hydrogels for mechanobiology

Mechanical regulation of cell-cycle progression and division.

Epithelial cells undergo striking morphological changes during division to ensure proper segregation of genetic and cytoplasmic materials. These morphological changes occur despite dividing cells being mechanically restricted by neighboring cells, indicating the need for extracellular force generation. Beyond driving cell division itself, forces associated with division have been implicated in tissue-scale processes, including development, tissue growth, migration, and epidermal stratification. While forces generated by mitotic rounding are well understood, forces generated after rounding remain unknown. Here, we identify two distinct stages of division force generation that follow rounding: (1) Protrusive forces along the division axis that drive division elongation, and (2) outward forces that facilitate postdivision spreading. Cytokinetic ring contraction of the dividing cell, but not activity of neighboring cells, generates extracellular forces that propel division elongation and contribute to chromosome segregation. Forces from division elongation are observed in epithelia across many model organisms. Thus, division elongation forces represent a universal mechanism that powers cell division in confining epithelia.

The nature of cell division forces in epithelial monolayers.

A few decades ago, the notion that a patient's own immune system could recognize and eliminate tumor cells was highly controversial; now, it is the basis for a thriving new field of cancer research, cancer immunology. With these new immune-based cancer treatments come the need for new complex preclinical models to assess their efficacy. Traditional therapeutics have often targeted the intrinsic growth of cancer cells and could, thus, be modeled with 2D monoculture. However, the next generation of therapeutics necessitates significantly greater complexity to model the ability of immune cells to infiltrate, recognize, and eliminate tumor cells. Modeling the physical and chemical barriers to immune infiltration requires consideration of extracellular matrix composition, architecture, and mechanobiology in addition to interactions between multiple cell types. Here, we give an overview of the unique properties of the tumor immune microenvironment, the challenges of creating physiologically relevant 3D culture models for drug discovery, and a perspective on future opportunities to meet this significant challenge.

Ovijit Chaudhuri

Papers

Recursive Feedback between Matrix Dissipation and Chemo-Mechanical Signaling Drives Oscillatory Growth of Cancer Cell Invadopodia

Engineered hydrogels for mechanobiology

Mechanical regulation of cell-cycle progression and division.

The nature of cell division forces in epithelial monolayers.

Modeling the tumor immune microenvironment for drug discovery using 3D culture.