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

Breast cancer becomes invasive when carcinoma cells collectively invade through the basement membrane (BM), a nanoporous layer of matrix that physically separates the primary tumor from the stroma, in a first step towards metastasis. Single cells can invade through nanoporous three-dimensional (3D) matrices via protease-mediated degradation or, when the matrix exhibits sufficient mechanical plasticity, force-mediated widening of pores. However, how cells invade collectively through physiological BM layers in cancer remains unclear. Here, we developed a 3D in vitro model of collective invasion of the BM during breast cancer. We show that cells utilize both proteases and forces to breach the BM. Forces are generated from a combination of global cell volume expansion that stretch the BM with local contractile forces that act in the plane of the BM to breach it, allowing invasion. These results uncover a mechanism by which cells collectively interact to overcome a critical barrier to metastasis.

Collective invasion of the basement membrane in breast cancer driven by forces from cell volume expansion and local contractility

Circulating monocytes are recruited to the tumor microenvironment, where they can differentiate into macrophages that mediate tumor progression. To reach the tumor microenvironment, monocytes must first extravasate and migrate through the type-1 collagen rich stromal matrix. The viscoelastic stromal matrix around tumors not only stiffens relative to normal stromal matrix, but often exhibits enhanced viscous characteristics, as indicated by a higher loss tangent or faster stress relaxation rate. Here, we studied how changes in matrix stiffness and viscoelasticity, impact the three-dimensional migration of monocytes through stromal-like matrices. Interpenetrating networks of type-1 collagen and alginate, which enable independent tunability of stiffness and stress relaxation over physiologically relevant ranges, were used as confining matrices for three-dimensional culture of monocytes. Increased stiffness and faster stress relaxation independently enhanced the 3D migration of monocytes. Migrating monocytes have an ellipsoidal or rounded wedge-like morphology, reminiscent of amoeboid migration, with accumulation of actin at the trailing edge. Matrix adhesions and Rho-mediated contractility were dispensable for monocyte migration in 3D, but migration did require actin polymerization and myosin contractility. Mechanistic studies indicate that actin polymerization at the leading edge generates protrusive forces that open a path for the monocytes to migrate through in the confining viscoelastic matrices. Taken together, our findings implicate matrix stiffness and stress relaxation as key mediators of monocyte migration and reveal how monocytes use pushing forces at the leading edge mediated by actin polymerization to generate migration paths in confining viscoelastic matrices. Significance Statement Cell migration is essential for numerous biological processes in health and disease, including for immune cell trafficking. Monocyte immune cells migrate through extracellular matrix to the tumor microenvironment where they can play a role in regulating cancer progression. Increased extracellular matrix (ECM) stiffness and viscoelasticity have been implicated in cancer progression, but the impact of these changes in the ECM on monocyte migration remains unknown. Here, we find that increased ECM stiffness and viscoelasticity promote monocyte migration. Interestingly, we reveal a previously undescribed adhesion-independent mode of migration whereby monocytes generate a path to migrate through pushing forces at the leading edge. These findings help elucidate how changes in the tumor microenvironment impact monocyte trafficking and thereby disease progression.

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Monocytes use protrusive forces to generate migration paths in viscoelastic collagen-based extracellular matrices

A hydrogel composition includes: (1) a polymer network including a first water-soluble polymer and a second water-soluble polymer that are crosslinked through dynamic bonds; and (2) a catalyst to modulate a rate of exchange of crosslinking of the polymer network.

Injectable and stable hydrogels with dynamic properties modulated by biocompatible catalysts

Lumens or fluid-filled cavities are a ubiquitous feature of mammals and are often evolutionarily linked to the origin of body-plan complexity. Post-implantation, the pluripotent epiblast in a human embryo forms a central lumen, paving the way for gastrulation. While osmotic pressure gradients drive lumen formation in many developmental contexts, mechanisms of human epiblast lumenogenesis are unknown. Here, we study lumenogenesis in a pluripotent-stem-cell-based model of the epiblast using engineered hydrogels that model the confinement faced by the epiblast in the blastocyst. Actin polymerization into a dense mesh-like network at the apical surface generates forces to drive early lumen expansion, as leaky junctions prevent osmotic pressure gradients. Theoretical modeling reveals that apical actin polymerization into a stiff network drives lumen opening, but predicts that a switch to pressure driven lumen growth at larger lumen sizes is required to avoid buckling of the cell layer. Consistent with this prediction, once the lumen reaches a radius of around 12 μm, tight junctions mature, and osmotic pressure gradients develop to drive further lumen growth. Human epiblasts show a transcriptional signature of actin polymerization during early lumenogenesis. Thus, actin polymerization drives lumen opening in the human epiblast, and may serve as a general mechanism of lumenogenesis.

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Actin polymerization drives lumen formation in a human epiblast model

In this issue of Bioengineering and Translational Medicine, we are pleased to introduce our Editorial Board Member, Professor David J. Mooney (Figure 1). Professor Mooney is the Robert P. Pinkas Family Professor of Bioengineering at the John A. Paulson School of Engineering and Applied Sciences at Harvard University. He is a founding member of the Wyss Institute for Biologically Inspired Engineering at Harvard University, in which he serves as a core faculty member. He is a member of both the National Academy of Engineering and the National Academy of Medicine, and he is a fellow of the National Academy of Inventors. Professor Mooney is widely recognized for his influential work in biomaterials, drug delivery, tissue engineering and regenerative medicine, mechanotransduction, and immunotherapy. His publications have been cited over 90,000 times and include 13 papers with over 1,000 citations, his h-index is 150, and he has given over 400 invited lectures. In 2019, Nature Biotechnology named him one of the top 10 translational researchers in biotechnology. Professor Mooney earned his BS in Chemical Engineering at the University of Wisconsin, Madison. He then went on to conduct his PhD work in Chemical Engineering at the Massachusetts Institute of Technology, under the mentorship of Professor Robert Langer. After finishing his PhD, he worked as a postdoctoral fellow at Harvard University under the guidance of Dr Joseph Vacanti and Professor Donald Ingber. He started his career as a professor at the University of Michigan in 1994 and then moved to Harvard University in 2004. In his early work, Professor Mooney made major advances in the use of biomaterials for regenerative medicine and tissue engineering. At the time, the paradigm in regenerative medicine had been the bolus delivery of single growth factors, which had limited efficacy. To address these limitations, Professor Mooney and others developed approaches to use biomaterial carriers for localized and sustained delivery of growth factors and other bioactive agents. His group demonstrated that modified, porous poly(lactide-co-glycolide) (PLG) scaffolds could deliver multiple growth factors with distinct kinetics to drive angiogenesis and bone formation, as well as deliver DNA-encoding growth factors intracellularly to promote angiogenesis in vivo. They also developed a number of in vitro applications using these materials, including tissue-engineered bone and models of tumors. Professor Mooney's early efforts also pioneered the use of alginate hydrogels for various biomedical applications. Alginate is a polysaccharide derived fromalgae, which forms a three-dimensional (3D) nanoporous hydrogel when crosslinked with calcium that has similar structural characteristics to extracellular matrix. Alginate hydrogels are biocompatible, gel under mild conditions, and are injectable. Professor Mooney recognized and exploited these useful properties both in vivo and in vitro. His group showed how tuning various parameters, such as degradation and crosslinking, or applying mechanical perturbation can be used to control the spatiotemporal release of single or multiple bioactive molecules. They utilized alginate gels to deliver a wide variety of bioactive molecules, including vascular endothelial growth factor and other heparin-binding growth factors that naturally bind to alginate, as well as other bioactive molecules that must first be packaged or tethered to control their release. These approaches were used to promote angiogenesis, bone formation, and smoothmuscle tissue formation in vivo. In parallel, they demonstrated that coupling the RGD (Arginine-Glycine-Aspartate) cell adhesion peptide sequence to the alginate allows cells to adhere to the otherwise inert gels. This enabled in vivo regenerative medicine applications involving infiltration of host cells into gels or delivery of exogenous cells, as well as twodimensional (2D) and 3D culture of adherent cells in vitro. Professor Mooney's group continues to work on applying alginate toward therapeutic angiogenesis and regeneration of musculoskeletal tissues. Furthermore, they have continued to innovate with alginate, introducing various ways to modify the gels chemically and physically and expanding their use to new applications. Recent developments include alginate-based tough gels and tough adhesives. Professor Mooney is also a leader in the field of mechanotransduction, the process by which cells sense and respond to mechanical cues. Professor Mooney's group has extensively characterized the mechanical properties of alginate gels and elucidated their underlying mechanisms; based on this knowledge, they have devised various approaches to modulate the mechanical properties of alginate-based materials. In their early studies, they discovered that the stiffness of RGD-coupled alginate hydrogels impacts cell proliferation, apoptosis, and differentiation in 2D culture, and they identified integrin clustering as a key mediator of mechanotransduction. They went on to show that hydrogel stiffness regulates the differentiation of mesenchymal stem cells in 3D culture and applied this finding to design a material that optimally promotes bone regeneration in vivo. Professor Mooney also recognized that tissues and extracellular matrices are typically not elastic but viscoelastic. His group developed alginate hydrogels with tunable viscoelasticity and showed that Received: 22 April 2020 Accepted: 22 April 2020

https://aiche.onlinelibrary.wiley.com/doi/pdf/10.1002/btm2.10162

Ovijit Chaudhuri

Papers

Collective invasion of the basement membrane in breast cancer driven by forces from cell volume expansion and local contractility

Monocytes use protrusive forces to generate migration paths in viscoelastic collagen-based extracellular matrices

Injectable and stable hydrogels with dynamic properties modulated by biocompatible catalysts

Actin polymerization drives lumen formation in a human epiblast model

Introduction to Editorial Board Member: Professor David J. Mooney