pH-Responsive and Recyclable Hydrogels for Gas Releasing and Scavenging.

Gas-releasing/scavenging hydrogels have wide applications in biomedical and industrial fields. However, the covalently crosslinked nature of these existing materials makes them difficult to degrade or recycle, leading to a waste of raw materials and aggravating environmental pollution. Herein, a new class of pH-responsive and recyclable hydrogels with versatile gas-releasing and scavenging properties is reported, utilizing pH changes to reversibly control disassembly and reassembly of the hydrogel network. The initial hydrogels are constructed via the one-pot radical polymerization and contain dynamic molecular networks based on hydrophobic interactions, which can disassemble when the materials are placed in low pH solutions. The disassembled copolymer chains can reform hydrogels, following supplementation with fresh mineral salts and micelle monomers in neutral solutions. Moreover, the mineral salts used to reform hydrogels can function as gas donors or scavengers, endowing these hydrogels with versatile gas-releasing and consuming properties. Overall, this research provides a facile and environmentally friendly method to recycle hydrogels with gas-releasing and gas-scavenging properties, which have potential applications in diverse fields, including wound healing, wastewater management, and gas therapy for diseases.

Acetic Acid Enables Precise Tailoring of the Mechanical Behavior of Protein-Based Hydrogels.

Engineering viscoelastic and biocompatible materials with tailored mechanical and microstructure properties capable of mimicking the biological stiffness (<17 kPa) or serving as bioimplants will bring protein-based hydrogels to the forefront in the biomaterials field. Here, we introduce a method that uses different concentrations of acetic acid (AA) to control the covalent tyrosine-tyrosine cross-linking interactions at the nanoscale level during protein-based hydrogel synthesis and manipulates their mechanical and microstructure properties without affecting protein concentration and (un)folding nanomechanics. We demonstrated this approach by adding AA as a precursor to the preparation buffer of a photoactivated protein-based hydrogel mixture. This strategy allowed us to synthesize hydrogels made from bovine serum albumin (BSA) and eight repeats protein L structure, with a fine-tailored wide range of stiffness (2-35 kPa). Together with protein engineering technologies, this method will open new routes in developing and investigating tunable protein-based hydrogels and extend their application toward new horizons.

3D Printable Dynamic Hydrogel: As Simple as it Gets!

3D printing technology offers a vast range of applications for tissue engineering applications. Over the past decade a vast range of new equipment has been developed; while, 3D printable biomaterials, especially hydrogels, are investigated to fit the printability requirements. The current candidates for bioprinting often require post-printing cross-linking to maintain their shape. On the other hand, dynamic hydrogels are considered as the most promising candidate for this application with their extrudability and self-healing properties. However, it proves to be very difficult to match the required rheological in a simple material. Here, this study presents for the first time the simplest formulation of a dynamic hydrogel based on thiol-functionalized hyaluronic acid formulated with gold ions that fulfill all the requirements to be printed without the use of external stimuli, as judged by the rheological studies. The printability is also demonstrated with a 3D printer allowing for the printing of the dynamic hydrogel as it is, achieving 3D construct with a relatively good precision and up to 24 layers, corresponding to 10 mm high. This material is the simplest 3D printable hydrogel and its mixture with cells and biological compounds is expected to open a new era in 3D bioprinting.

Double-Network Heparin Dynamic Hydrogels: Dynagels as Anti-bacterial 3D Cell Culture Scaffolds.

Double cross-linked dynamic hydrogels, dynagels, have been prepared through reversible imine bonds and supramolecular interactions, which showed good pH responsiveness, injectability, self-healing property and biocompatibility. With the further encapsulation of heparin, the obtained hydrogels exhibited good anti-bacterial activity and promotion effects for 3D cell culture.

Dynamic Nanohybrid-Polysaccharide Hydrogels for Soft Wearable Strain Sensing.

Electroconductive hydrogels with stimuli-free self-healing and self-recovery (SELF) properties and high mechanical strength for wearable strain sensors is an area of intensive research activity at the moment. Most electroconductive hydrogels, however, consist of static bonds for mechanical strength and dynamic bonds for SELF performance, presenting a challenge to improve both properties into one single hydrogel. An alternative strategy to successfully incorporate both properties into one system is via the use of stiff or rigid, yet dynamic nano-materials. In this work, a nano-hybrid modifier derived from nano-chitin coated with ferric ions and tannic acid (TA/Fe@ChNFs) is blended into a starch/polyvinyl alcohol/polyacrylic acid (St/PVA/PAA) hydrogel. It is hypothesized that the TA/Fe@ChNFs nanohybrid imparts both mechanical strength and stimuli-free SELF properties to the hydrogel via dynamic catecholato-metal coordination bonds. Additionally, the catechol groups of TA provide mussel-inspired adhesion properties to the hydrogel. Due to its electroconductivity, toughness, stimuli-free SELF properties, and self-adhesiveness, a prototype soft wearable strain sensor is created using this hydrogel and subsequently tested.

Rational Design of Mussel-Inspired Hydrogels with Dynamic Catecholato-Metal Coordination Bonds.

Nature has often been the main source of inspiration for designing smart functional materials. As an example, mussels can attach to almost any wet surfaces, for example, wood, rocks, metal, etc., due to the presence of catechols containing amino acid 3,4-dihydroxyphenyl-l-alanine (DOPA). Fabrication of mussel-inspired hydrogels using dynamic catecholato-metal coordination bonds has recently been in the limelight because of the hydrogels' ease of gelation, interesting self-healing, self-recovery, adhesiveness, and pH-responsiveness, as well as shear-thinning and mechanical properties. Mussel inspired hydrogels take advantage of catechols, for example, DOPA in the blue mussel, to undergo catecholatometal gelation through coordination chemistry. This review explores the latest developments in the fabrication of such hydrogels using catecholato-metal coordination bonds, and discusses their potential applications in sensors, flexible electronics, tissue engineering, and wound dressing. Moreover, current challenges and prospects of such hydrogels are discussed. The main focus of this paper is on providing a deeper understanding of this growing field in terms of chemistry, physics, and associated properties.

Bioactive Metal Ion-Coordinated Dynamic Hydrogel with Antibacterial, Immunomodulatory, and Angiogenic Activities for Infected Wound Repair.

The repair of infected wounds is a complex physiopathologic process. Current studies on infected wound treatment have predominantly focused on infection treatment, while the factors related to delayed healing caused by vascular damage and immune imbalance are commonly overlooked. In this study, an extracellular matrix (ECM)-like dynamic and multifunctional hyaluronic acid (HA) hydrogel with antimicrobial, immunomodulatory, and angiogenic capabilities was designed as wound dressing for the treatment of infected skin wounds. The dynamic network in the hydrogel dressing was based on reversible metal-ligand coordination formed between sulfhydryl groups and bioactive metal ions. In our design, antibacterial silver and immunomodulatory zinc ions were employed to coordinate with sulfhydrylated HA and a vasculogenic peptide. In addition to the desired bioactivities for infected wounds, the hydrogel could also exhibit self-healing and injectable abilities. Animal experiments with infected skin wound models indicated that the hydrogel dressings enabled minimally invasive injection and seamless skin wound covering and then facilitated wound healing by efficient bacterial killing, continuous inflammation inhibition, and improved blood vessel formation. In conclusion, the metal ion-coordinated hydrogels with wound-infection-desired bioactivities and ECM-like dynamic structures represent a class of tissue bionic wound dressings for the treatment of infected and chronic inflammation wounds.

Extracellular Matrix-Mimetic Immunomodulatory Hydrogel for Accelerating Wound Healing.

Macrophages play a crucial role in the complete processes of tissue repair and regeneration, and the activation of M2 polarization is an effective approach to provide a pro-regenerative immune microenvironment. Natural extracellular matrix (ECM) has the capability to modulate macrophage activities via its molecular, physical, and mechanical properties. Inspired by this, an ECM-mimetic hydrogel strategy to modulate macrophages via its dynamic structural characteristics and bioactive cell adhesion sites is proposed. The LZM-SC/SS hydrogel is in situ formed through the amidation reaction between lysozyme (LZM), 4-arm-PEG-SC, and 4-arm-PEG-SS, where LZM provides DGR tripeptide for cell adhesion, 4-arm-PEG-SS provides succinyl ester for dynamic hydrolysis, and 4-arm-PEG-SC balances the stability and dynamics of the network. In vitro and subcutaneous tests indicate the dynamic structural evolution and cell adhesion capacity promotes macrophage movement and M2 polarization synergistically. Comprehensive bioinformatic analysis further confirms the immunomodulatory ability, and reveals a significant correlation between M2 polarization and cell adhesion. A full-thickness wound model is employed to validate the induced M2 polarization, vessel development, and accelerated healing by LZM-SC/SS. This study represents a pioneering exploration of macrophage modulation by biomaterials' structures and components rather than drug or cytokines and provides new strategies to promote tissue repair and regeneration.

In Situ Covalent Reinforcement of a Benzene-1,3,5-Tricarboxamide Supramolecular Polymer Enables Biomimetic, Tough, and Fibrous Hydrogels and Bioinks.

Synthetic hydrogels often lack the load-bearing capacity and mechanical properties of native biopolymers found in tissue, such as cartilage. In natural tissues, toughness is often imparted via the combination of fibrous noncovalent self-assembly with key covalent bond formation. This controlled combination of supramolecular and covalent interactions remains difficult to engineer, yet can provide a clear strategy for advanced biomaterials. Here, a synthetic supramolecular/covalent strategy is investigated for creating a tough hydrogel that embodies the hierarchical fibrous architecture of the extracellular matrix (ECM). A benzene-1,3,5-tricarboxamide (BTA) hydrogelator is developed with synthetically addressable norbornene handles that self-assembles to form a and viscoelastic hydrogel. Inspired by collagen's covalent cross-linking of fibrils, the mechanical properties are reinforced by covalent intra- and interfiber cross-links. At over 90% water, the hydrogels withstand up to 550% tensile strain, 90% compressive strain, and dissipated energy with recoverable hysteresis. The hydrogels are shear-thinning, can be 3D bioprinted with good shape fidelity, and can be toughened via covalent cross-linking. These materials enable the bioprinting of human mesenchymal stromal cell (hMSC) spheroids and subsequent differentiation into chondrogenic tissue. Collectively, these findings highlight the power of covalent reinforcement of supramolecular fibers, offering a strategy for the bottom-up design of dynamic, yet tough, hydrogels and bioinks.

Photoinduced Dithiolane Crosslinking for Multiresponsive Dynamic Hydrogels.

While many hydrogels are elastic networks crosslinked by covalent bonds, viscoelastic hydrogels with adaptable crosslinks are increasingly being developed to better recapitulate time and position-dependent processes found in many tissues. In this work, 1,2-dithiolanes are presented as dynamic covalent photocrosslinkers of hydrogels, resulting in disulfide bonds throughout the hydrogel that respond to multiple stimuli. Using lipoic acid as a model dithiolane, disulfide crosslinks are formed under physiological conditions, enabling cell encapsulation via an initiator-free light-induced dithiolane ring-opening photopolymerization. The resulting hydrogels allow for multiple photoinduced dynamic responses including stress relaxation, stiffening, softening, and network functionalization using a single chemistry, which can be supplemented by permanent reaction with alkenes to further control network properties and connectivity using irreversible thioether crosslinks. Moreover, complementary photochemical approaches are used to achieve rapid and complete sample degradation via radical scission and post-gelation network stiffening when irradiated in the presence of reactive gel precursor. The results herein demonstrate the versatility of this material chemistry to study and direct 2D and 3D cell-material interactions. This work highlights dithiolane-based hydrogel photocrosslinking as a robust method for generating adaptable hydrogels with a range of biologically relevant mechanical and chemical properties that are varied on demand.

Nano-crosslinked dynamic hydrogels for biomedical applications.

Hydrogels resemble natural extracellular matrices and have been widely studied for biomedical applications. Nano-crosslinked dynamic hydrogels combine the injectability and self-healing property of dynamic hydrogels with the versatility of nanomaterials and exhibit unique advantages. The incorporation of nanomaterials as crosslinkers can improve the mechanical properties (strength, injectability, and shear-thinning properties) of hydrogels by reinforcing the skeleton and endowing them with multifunctionality. Nano-crosslinked functional hydrogels that can respond to external stimuli (such as pH, heat, light, and electromagnetic stimuli) and have photothermal properties, antimicrobial properties, stone regeneration abilities, or tissue repair abilities have been constructed through reversible covalent crosslinking strategies and physical crosslinking strategies. The possible cytotoxicity of the incorporated nanomaterials can be reduced. Nanomaterial hydrogels show excellent biocompatibility and can facilitate cell proliferation and differentiation for biomedical applications. This review introduces different nano-crosslinked dynamic hydrogels in the medical field, from fabrication to application. In this review, nanomaterials for dynamic hydrogel fabrication, such as metals and metallic oxides, nanoclays, carbon-based nanomaterials, black phosphorus (BP), polymers, and liposomes, are discussed. We also introduce the dynamic crosslinking method commonly used for nanodynamic hydrogels. Finally, the medical applications of nano-crosslinked hydrogels are presented. We hope that this summary will help researchers in the related research fields quickly understand nano-crosslinked dynamic hydrogels to develop more preparation strategies and promote their development and application.

Soft, Dynamic Hydrogel Confinement Improves Kidney Organoid Lumen Morphology and Reduces Epithelial-Mesenchymal Transition in Culture.

Pluripotent stem cell-derived kidney organoids offer a promising solution to renal failure, yet current organoid protocols often lead to off-target cells and phenotypic alterations, preventing maturity. Here, various dynamic hydrogel architectures are created, conferring a controlled and biomimetic environment for organoid encapsulation. How hydrogel stiffness and stress relaxation affect renal phenotype and undesired fibrotic markers are investigated. The authors observe that stiff hydrogel encapsulation leads to an absence of certain renal cell types and signs of an epithelial-mesenchymal transition (EMT), whereas encapsulation in soft, stress-relaxing hydrogels leads to all major renal segments, fewer fibrosis or EMT associated proteins, apical proximal tubule polarization, and primary cilia formation, representing a significant improvement over current approaches to culture kidney organoids. The findings show that engineering hydrogel mechanics and dynamics have a decided benefit for organoid culture. These structure-property-function relationships can enable the rational design of materials, bringing us closer to functional engraftments and disease-modeling applications.

Photoswitchable Microgels for Dynamic Macrophage Modulation.

Dynamic manipulation of supramolecular self-assembled structures is achieved irreversibly or under non-physiological conditions, thereby limiting their biomedical, environmental, and catalysis applicability. In this study, microgels composed of azobenzene derivatives stacked via π-cation and π-π interactions are developed that are electrostatically stabilized with Arg-Gly-Asp (RGD)-bearing anionic polymers. Lateral swelling of RGD-bearing microgels occurs via cis-azobenzene formation mediated by near-infrared-light-upconverted ultraviolet light, which disrupts intermolecular interactions on the visible-light-absorbing upconversion-nanoparticle-coated materials. Real-time imaging and molecular dynamics simulations demonstrate the deswelling of RGD-bearing microgels via visible-light-mediated trans-azobenzene formation. Near-infrared light can induce in situ swelling of RGD-bearing microgels to increase RGD availability and trigger release of loaded interleukin-4, which facilitates the adhesion structure assembly linked with pro-regenerative polarization of host macrophages. In contrast, visible light can induce deswelling of RGD-bearing microgels to decrease RGD availability that suppresses macrophage adhesion that yields pro-inflammatory polarization. These microgels exhibit high stability and non-toxicity. Versatile use of ligands and protein delivery can offer cytocompatible and photoswitchable manipulability of diverse host cells.

Dynamic nanocellulose hydrogels: Recent advancements and future outlook.

Nanocellulose is of great interest in material science nowadays mainly because of its hydrophilic, renewable, biodegradable, and biocompatible nature, as well as its excellent mechanical strength and tailorable surface ready for modification. Currently, nanocellulose is attracting attention to overcome the current challenges of dynamic hydrogels: robustness, autonomous self-healing, and self-recovery (SELF) properties simultaneously occurring in one system. In this regard, this review aims to explore current advances in design and fabrication of dynamic nanocellulose hydrogels and elucidate how incorporating nanocellulose with dynamic motifs simultaneously improves both SELF and robustness of hydrogels. Finally, current challenges and prospects of dynamic nanocellulose hydrogels are discussed.

Biomimetic stiffening of cell-laden hydrogels via sequential thiol-ene and hydrazone click reactions.

Hydrogels with dynamically tunable crosslinking are invaluable for directing stem cell fate and mimicking a stiffening matrix during fibrosis or tumor development. The increases in matrix stiffness during tissue development are often accompanied by the accumulation of extracellular matrices (e.g., collagen, hyaluronic acid (HA)), a phenomenon that has received little attention in the development of dynamic hydrogels. In this contribution, we present a gelatin-based cell-laden hydrogel system capable of being dynamically stiffened while accumulating HA, a key glycosaminoglycans (GAG) increasingly deposited by stromal cells during tumor progression. Central to this strategy is the synthesis of a dually-modified gelatin macromer - gelatin-norbornene-carbohydrazide (GelNB-CH), which is susceptible to both thiol-norbornene photopolymerization and hydrazone click chemistry. We demonstrate that the crosslinking density of cell-laden thiol-norbornene hydrogels can be dynamically tuned via simple incubation with aldehyde-bearing macromers (e.g., oxidized dextran (oDex) or oHA). The GelNB-CH hydrogel system is highly cytocompatible, as demonstrated by in situ encapsulation of pancreatic cancer cells (PCC) and cancer-associated fibroblasts (CAF). This unique dynamic stiffening scheme provides a platform to study tandem accumulation of HA and elevation in matrix stiffness in the pancreatic tumor microenvironment. STATEMENT OF SIGNIFICANCE: Hydrogels permitting on-demand and secondary crosslinking are ideal for mimicking a stiffening tumor microenvironment (TME). However, none of the current dynamic hydrogels account for both stiffening and accumulation of hyaluronic acid (HA), a major extracellular matrix component increasingly deposited in tumor stromal tissues, including pancreatic ductal adenocarcinoma (PDAC). The current work addresses this gap by developing a dynamic hydrogel system capable of simultaneously increasing stiffness and HA accumulation. This is achieved by a new gelatin macromer permitting sequential thiol-norbornene (for primary network crosslinking) and hydrazone click chemistry (for bioinert or biomimetic stiffening with oxidized dextran (oDex) or oHA, respectively). The results of this study provide new insights into how dynamically changing physicochemical matrix properties guide cancer cell fate processes.

Engineering the Dynamics of Cell Adhesion Cues in Supramolecular Hydrogels for Facile Control over Cell Encapsulation and Behavior.

The extracellular matrix (ECM) forms through hierarchical assembly of small and larger polymeric molecules into a transient, hydrogel-like fibrous network that provides mechanical support and biochemical cues to cells. Synthetic, fibrous supramolecular networks formed via non-covalent assembly of various molecules are therefore potential candidates as synthetic mimics of the natural ECM, provided that functionalization with biochemical cues is effective. Here, combinations of slow and fast exchanging molecules that self-assemble into supramolecular fibers are employed to form transient hydrogel networks with tunable dynamic behavior. Obtained results prove that modulating the ratio between these molecules dictates the extent of dynamic behavior of the hydrogels at both the molecular and the network level, which is proposed to enable effective incorporation of cell-adhesive functionalities in these materials. Excitingly, the dynamic nature of the supramolecular components in this system can be conveniently employed to formulate multicomponent supramolecular hydrogels for easy culturing and encapsulation of single cells, spheroids, and organoids. Importantly, these findings highlight the significance of molecular design and exchange dynamics for the application of supramolecular hydrogels as synthetic ECM mimics.

Dynamic Bioinks to Advance Bioprinting.

The development of bioinks for bioprinting of cell-laden constructs remains a challenge for tissue engineering, despite vigorous investigation. Hydrogels to be used as bioinks must fulfill a demanding list of requirements, mainly focused around printability and cell function. Recent advances in the use of supramolecular and dynamic covalent chemistry (DCvC) provide paths forward to develop bioinks. These dynamic hydrogels enable tailorability, higher printing performance, and the creation of more life-like environments for ultimate tissue maturation. This review focuses on the exploration and benefits of dynamically cross-linked bioinks for bioprinting, highlighting recent advances, benefits, and challenges in this emerging area. By incorporating internal dynamics, many benefits can be imparted to the material, providing design elements for next generation bioinks.

Dynamic Click Hydrogels for Xeno-Free Culture of Induced Pluripotent Stem Cells.

Xeno-free, chemically defined poly(ethylene glycol) (PEG)-based hydrogels are being increasingly used for in vitro culture and differentiation of human induced pluripotent stem cells (hiPSCs). These synthetic matrices provide tunable gelation and adaptable material properties crucial for guiding stem cell fate. Here, sequential norbornene-click chemistries are integrated to form synthetic, dynamically tunable PEG-peptide hydrogels for hiPSCs culture and differentiation. Specifically, hiPSCs are photoencapsulated in thiol-norbornene hydrogels crosslinked by multiarm PEG-norbornene (PEG-NB) and proteaselabile crosslinkers. These matrices are used to evaluate hiPSC growth under the influence of extracellular matrix properties. Tetrazine-norbornene (Tz-NB) click reaction is then employed to dynamically stiffen the cell-laden hydrogels. Fast reactive Tz and its stable derivative methyltetrazine (mTz) are tethered to multiarm PEG, yielding mono-functionalized PEG-Tz, PEG-mTz, and dualfunctionalized PEG-Tz/mTz that react with PEG-NB to form additional crosslinks in the cell-laden hydrogels. The versatility of Tz-NB stiffening is demonstrated with different Tz-modified macromers or by intermittent incubation of PEG-Tz for temporal stiffening. Finally, the Tz-NB-mediated dynamic stiffening is explored for 4D culture and definitive endoderm differentiation of hiPSCs. Overall, this dynamic hydrogel platform affords exquisite controls of hydrogel crosslinking for serving as a xeno-free and dynamic stem cell niche.

Dynamic Mussel-Inspired Chitin Nanocomposite Hydrogels for Wearable Strain Sensors.

It is an ongoing challenge to fabricate an electroconductive and tough hydrogel with autonomous self-healing and self-recovery (SELF) for wearable strain sensors. Current electroconductive hydrogels often show a trade-off between static crosslinks for mechanical strength and dynamic crosslinks for SELF properties. In this work, a facile procedure was developed to synthesize a dynamic electroconductive hydrogel with excellent SELF and mechanical properties from starch/polyacrylic acid (St/PAA) by simply loading ferric ions (Fe3+) and tannic acid-coated chitin nanofibers (TA-ChNFs) into the hydrogel network. Based on our findings, the highest toughness was observed for the 1 wt.% TA-ChNF-reinforced hydrogel (1.43 MJ/m3), which is 10.5-fold higher than the unreinforced counterpart. Moreover, the 1 wt.% TA-ChNF-reinforced hydrogel showed the highest resistance against crack propagation and a 96.5% healing efficiency after 40 min. Therefore, it was chosen as the optimized hydrogel to pursue the remaining experiments. Due to its unique SELF performance, network stability, superior mechanical, and self-adhesiveness properties, this hydrogel demonstrates potential for applications in self-wearable strain sensors.

Poly-Epsilon-Lysine Hydrogels with Dynamic Crosslinking Facilitates Cell Proliferation.

The extracellular matrix (ECM) is a three-dimensional network within which fundamental cell processes such as cell attachment, proliferation, and differentiation occur driven by its inherent biological and structural cues. Hydrogels have been used as biomaterials as they possess many of the ECM characteristics that control cellular processes. However, the permanent crosslinking often found in hydrogels fails to recapitulate the dynamic nature of the natural ECM. This not only hinders natural cellular migration but must also limit cellular expansion and growth. Moreover, there is an increased interest in the use of new biopolymers to create biomimetic materials that can be used for biomedical applications. Here we report on the natural polymer poly-ε-lysine in forming dynamic hydrogels via reversible imine bond formation, with cell attachment promoted by arginine-glycine-aspartic acid (RGD) incorporation. Together, the mechanical properties and cell behavior of the dynamic hydrogels with low poly-ε-lysine quantities indicated good cell viability and high metabolic activity.