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Review
. 2021 Dec 16;6(1):426.
doi: 10.1038/s41392-021-00830-x.

Current hydrogel advances in physicochemical and biological response-driven biomedical application diversity

Huan Cao #  1   2   3 , Lixia Duan #  2 , Yan Zhang  2 , Jun Cao  4 , Kun Zhang  5
Affiliations
Review

Current hydrogel advances in physicochemical and biological response-driven biomedical application diversity

Huan Cao et al. Signal Transduct Target Ther. .

Abstract

Hydrogel is a type of versatile platform with various biomedical applications after rational structure and functional design that leverages on material engineering to modulate its physicochemical properties (e.g., stiffness, pore size, viscoelasticity, microarchitecture, degradability, ligand presentation, stimulus-responsive properties, etc.) and influence cell signaling cascades and fate. In the past few decades, a plethora of pioneering studies have been implemented to explore the cell-hydrogel matrix interactions and figure out the underlying mechanisms, paving the way to the lab-to-clinic translation of hydrogel-based therapies. In this review, we first introduced the physicochemical properties of hydrogels and their fabrication approaches concisely. Subsequently, the comprehensive description and deep discussion were elucidated, wherein the influences of different hydrogels properties on cell behaviors and cellular signaling events were highlighted. These behaviors or events included integrin clustering, focal adhesion (FA) complex accumulation and activation, cytoskeleton rearrangement, protein cyto-nuclei shuttling and activation (e.g., Yes-associated protein (YAP), catenin, etc.), cellular compartment reorganization, gene expression, and further cell biology modulation (e.g., spreading, migration, proliferation, lineage commitment, etc.). Based on them, current in vitro and in vivo hydrogel applications that mainly covered diseases models, various cell delivery protocols for tissue regeneration and disease therapy, smart drug carrier, bioimaging, biosensor, and conductive wearable/implantable biodevices, etc. were further summarized and discussed. More significantly, the clinical translation potential and trials of hydrogels were presented, accompanied with which the remaining challenges and future perspectives in this field were emphasized. Collectively, the comprehensive and deep insights in this review will shed light on the design principles of new biomedical hydrogels to understand and modulate cellular processes, which are available for providing significant indications for future hydrogel design and serving for a broad range of biomedical applications.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Schematic images for indicating the interactions between cell and hydrogel matrix, uncovering the influences of hydrogel physicochemical properties on cell biology via correspondingly triggering signaling cascades (e.g., inside-out and outside-in signaling), and illustrating various hydrogel biomedical applications of cell-free and cell-loaded hydrogels
Fig. 2
Fig. 2
Rheological characterization of solution to gelation (sol–gel) transition process of hydrogel precursor. Modified from ref. . Copyright 2006, Elsevier
Fig. 3
Fig. 3
The outlined image for indicating the representative cellular mechanosignaling pathways induced by varied hydrogel stiffness. Hydrogel stiffness was demonstrated to correlate with many activations of focal adhesion kinase (FAK) signaling, RhoA signaling, and Wnt signaling and simultaneously regulate cell morphology, proliferation, migration, invasiveness, differentiation, and stemness., The figure is made with biorender (https://biorender.com/)
Fig. 4
Fig. 4
The influences of the pore size of hydrogel scaffolds on cell biology. a Influence summary of pore size on cellular compartment, molecular function, cytoskeleton arrangement, etc. The figure is made with biorender (https://biorender.com/). b–e Pore size (volume, V1 > V2 > V3 > V4)-dependent cell stress fiber formation (b, c) and YAP cytoplasm–nuclei translocation (d, e). *p < 0.05, **p < 0.01. Reproduced with permission. Copyright 2015, Springer nature. f, g A case focusing on how pore size (pore diameters: 47.0 ± 2.2 μm (Group i), 84.8 ± 11.0 μm (Group ii), 147.9 ± 7.2 μm (Group iii), and 198.7 ± 9.1 μm (Group iv)) affected F-actin (f) and Vinculin (g) expression in mesenchymal stromal cells. Reproduced with permission. Copyright 2016, Springer nature
Fig. 5
Fig. 5
Clarifications and evidences on how hydrogel viscoelasticity regulated cell biology. a Schematic image of the interaction between cells and elastic/viscoelastic hydrogel via activating Rho and Rac1 signaling pathways. Reproduced with permission. Copyright 2015, Springer nature. b A case depicting how hydrogel with fast stress relaxation promoted stem cell spreading and β1 expression and led to integrin clustering. Reproduced with permission. Copyright 2015, Springer nature. c Protease-independent invasion way in cancer cells when cultured in viscoelastic hydrogels with slow, immediate, and fast relaxation rates, and d schematic on the migration mode of cancer cells via progressively widening surrounding hydrogel matrix with invadopodia rather than proteases. Reproduced with permission. Copyright 2018, Springer nature
Fig. 6
Fig. 6
The effects of hydrogel architecture on cell activities. a–d Schematic image of the interaction between cell and hydrogel scaffolds with different topographies. Cells generally exhibited a spindle-shaped morphology on microfibers (b, d) or aligned fibers (a, b), while evolved into the rounded morphology on nanofibers or randomly oriented fibers (c). Reproduced with permission., Copyright 2013, Wiley-VCH. The figure is made with biorender (https://biorender.com/). e–h Fibroblast F-actin staining (green) on glass (e), microfiber (f), and nanofiber (g), as well as the quantification analysis of focal plaque area (h). The arrows represent membrane protrusions (“cork-screw” ruffles). Reproduced with permission. Copyright 2011, Wolters Kluwer Health, Inc. i, j Evidences on how the architecture of hydrogel scaffolds regulated macrophage morphology (i) and cytokine expression (j), where microfibers (1–50 μm) induced M1 microphage activations and more proinflammatory cytokine secretions compared to fibers with a diameter of 200–600 nm. Adapted with permission. Copyright 2011, American Chemical Society
Fig. 7
Fig. 7
The influences of hydrogel degradability on cell biology. a Schematic image of the interaction between entrapped cell and degradable/non-degradable hydrogels. The figure is made with biorender (https://biorender.com/). b–d Explorations on how hydrogel degradability promoted stem cell spreading and β1 integrin activation within 3D PEG-based hydrogels (b) and induced distinctive differentiation preference (c, d), e.g., osteogenesis and adipogenesis within the degradable and non-degradable hydrogel, respectively. **p < 0.01. Reproduced with permission. Copyright 2013, Elsevier. e, f Tests indicating how hydrogel degradability enhanced neural stem cells’ stemness (e) via permitting cell–cell contact and inducing Nestin and Sox2 expression (f). Reproduced with permission. Copyright 2017, Springer nature
Fig. 8
Fig. 8
Different cell attachment site (chemical surface)-induced signaling pathways. Information is collected from published works.,– The figure is made with biorender (https://biorender.com/)
Fig. 9
Fig. 9
The effects of other hydrogel properties on cell biology and biomedical applications. a–d Hypoxia-inducible hydrogel design (a) could enhance blood vessel morphogenesis (b, c) with increased correlated gene expression levels (d). *p < 0.05, **p < 0.01 and ***p < 0.001. Reproduced with permission. Copyright 2014, Springer nature. e–h D- and L-chiral hydrogel preparation (e) and the induced immuno-responses (f–h), where hydrogels with D-chirality induced adaptive immune responses with CD11b+ myeloid cell recruitment compared to the L-chiral hydrogel in mice. (g *p = 0.0455, ***p = 0.0006; h ****p < 0.001). Reproduced with permission. Copyright 2020, Springer nature. i, j Self-healing hydrogel construction (i) and the enhanced angiogenesis via a series of signaling cascades, including integrin clustering, FAK activation, and MMP expression (j). Reproduced with permission. Copyright 2020, Elsevier
Fig. 10
Fig. 10
Influence recapitulation of stimulus-responsive hydrogels on dynamic cell microenvironment, spatiotemporal cell spreading control, target gene expression, myofibroblast activation, and stem cell differentiation. Adapted with permission from ref. Copyright 2014, American Chemical Society. Reproduced with permission. Copyright 2015, Springer nature. Reproduced with permission. Copyright 2016, Springer nature. Reproduced with permission. Copyright 2012, Springer nature
Fig. 11
Fig. 11
The preclinical studies of hydrogel applications. a–c Preparation of a hyaluronic acid (HA)-based hydrogel that released CAR-T cells to target the human chondroitin sulfate proteoglycan 4 (a) and anti-PDL1-conjugated platelets for inhibiting post-surgery melanoma tumor recurrence (b, c). *p = 0.0486, ***p < 0.001 Copyright 2021, Springer nature. d–f Pufferfish-inspired ingestible hydrogel device (d, e) for long-term gastric retention and physiological monitoring like porcine gastric temperature (f). Copyright 2019, Springer nature. g–m A photoinduced imine-cross-linking hydrogel (g) with pulsatile TGF-beta inhibitor release characteristic (h–k) for promoting scarless wound healing in rabbit ear scar (l) and porcine skin (m). Copyright 2021, Springer nature
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