Dynamic Hydrogels Research Articles

Dynamic cell-adaptable hydrogels with a moderate level of elasticity promote 3D development of encapsulated cells

Hydrogels stabilized by dynamic reversible crosslinks provide a more permissive three-dimensional (3D) microenvironment to support various behaviors of encapsulated cells. Compared with hydrogels based on dynamic covalent crosslinks, supramolecular hydrogels based on host–guest interactions generally possess higher structural dynamics but lower elasticity due to the highly dynamic nature of the host–guest interactions. Herein, we first preassemble thiolated β-cyclodextrin (CD-SH) with adamantane-grafted hyaluronic acid (HA-Ada) before reacting with maleimide-grafted HA (HA-Mal) via the thiol–ene click reaction to fabricate host–guest hydrogels (HAHG) with a highly dynamic network. Furthermore, a minor fraction of covalent crosslinking can be easily incorporated into the hydrogel network by using multivalent CD-SH as the crosslinker to produce HAHG hydrogels with varying residual elasticity (RE) while keeping the hydrogel chemical composition unchanged. We demonstrated that HAHG hydrogels with a moderate level of RE best support the 3D spreading and intercellular interactions of encapsulated stem cells. This work provides an easy strategy to prepare cell-adaptable dynamic hydrogels with tunable network elasticity to study the effects of biophysical properties of hydrogel networks on cellular behavior in 3D environments.

Anti-bacterial dynamic hydrogels prepared from O-carboxymethyl chitosan by dual imine bond crosslinking for biomedical applications

Imine dynamic hydrogels are synthesized via dual-imine bond crosslinking from O-carboxymethyl chitosan (CMCS) and a water soluble dynamer using a ‘green’ approach. Three dynamers are prepared through reaction of benzene-1,3,5-tricarbaldehyde and di-amino Jeffamine with molar mass of 500, 800 and 1900, respectively. Hydrogels, namely H500, H800 and H1900 are then obtained by mixing CMCS and dynamer aqueous solutions. FT-IR confirms the formation of hydrogels via imine bonding. H1900 presents larger pore size and higher storage modulus as compared to H500 and H800 due to the higher molar mass of Jeffamine linker. The hydrogels exhibit pH sensitive swelling behavior due to electrostatic attraction or repulsion in the pH range from 3 to 10. The highest swelling ratio is obtained at pH 8, reaching 7500% for H800. Self-healing of hydrogels is evidenced by rheological measurements with alternatively applied low and high strains, and by using a macroscopic approach with re-integration of injected filaments. Furthermore, the H1900 membrane exhibits outstanding antibacterial activity against an E. coli suspension at 108 CFU mL−1. Therefore, dynamic hydrogels synthesized from CMCS and Jeffamine present outstanding rheological, swelling, self-healing and antibacterial properties, and are most promising as healthcare material in wound dressing, drug delivery and tissue engineering.

Dynamic Hydrogels for Investigating Vascularization.

Extracellular matrix is known to regulate vascularization by a sequence of multiple factors including mechanical forces. In this issue of Cell Stem Cell, Wei etal. (2020) investigate the roles of matrix biomechanics on early stages of vasculogenesis by using hydrogels with tunable stiffness and stress relaxation.

Facile Synthesis of Poly(ethylene oxide)-Based Self-Healable Dynamic Triblock Copolymer Hydrogels.

Stimuli-responsive smart hydrogels have garnered considerable interest for their potential in biomedical applications. While widely utilized, little is known about the rheological and mechanical properties of the hydrogels with respect to the type of cross-linker in a systematic manner. In this study, we present a facile synthetic route toward ABA triblock copolymer hydrogels based on poly(ethylene oxide) (PEO). Two classes of hydrogels were prepared by employing the functional allyl glycidyl ether (AGE) monomer during the polymerization followed by the subsequent post-polymerization modification of prepared PAGE-b-PEO-b-PAGE via respective hydrogenation or thiol-ene reaction: (1) chemically cross-linked hydrogels responsive to redox stimuli and (2) physically cross-linked hydrogels responsive to temperature. A series of dynamic mechanical analyses revealed the relaxation dynamics of the associative A block. Most interestingly, the redox-responsive hydrogels demonstrated a highly tunable nature by introducing reducing and oxidizing agents, which provided the self-healing property and injectability. Together with superior biocompatibility, these smart hydrogels offer the prospect of advancing biomedical applications.

Antibacterial Hydrogels: Injectable and Self‐Healing Hydrogel with Anti‐Bacterial and Anti‐Inflammatory Properties for Acute Bacterial Rhinosinusitis with Micro Invasive Treatment (Adv. Healthcare Mater. 20/2020)

In article number 2001032 by Haihong Tang, Hongliang Zheng, and co-workers, an injectable and self-healing hydrogel is first developed to treat acute bacterial rhinosinusitis based on high affinity and reversible combination between thiol and Ag+. This dynamic hydrogel with antibacterial and anti-inflammatory properties is suitable for sinus micro invasive treatment which not only effectively eliminates pathogens, but also reduces mucosal edema. This approach provides a new strategy for avoiding systemic abuse of antibiotics.

Sustained Release of Magnesium Ions Mediated by a Dynamic Mechanical Hydrogel to Enhance BMSC Proliferation and Differentiation.

Hydrogel scaffolds are promising and widely applicable platforms for various therapeutic agents to facilitate bone tissue regeneration due to their biocompatibility and low immunogenicity. Nevertheless, the improvement of local administration efficiency and on-demand release of drugs from a hydrogel system is still an obstacle. In this work, we reported that a novel injectable hydrogel system was fabricated based on coordination of multiarm thiolated polyethylene glycol (PEG-SH) and magnesium ions for bone marrow-derived mesenchymal stem cell (BMSC) proliferation and differentiation. The dynamic nature coordination bond of Mg–S and the dynamic disulfide bond of S–S provide hydrogels with good mechanical performance and typical rheological behavior and thus endow the hydrogels with a satisfactory swelling rate and degradation property. Mg2+ was incorporated in the system not only to act as an effective cross-linker to enhance the hydrogel network structure but also to mediate the sustained release of Mg2+. Due to the controlled release of Mg2+, the PEG-SH/Mg2+ hydrogel can effectively improve BMSC proliferation and osteoblastic activity via the PI3K/Akt/GSK3β/β-catenin signal pathway in vitro. These findings indicated that the novel hydrogel controlled release of a Mg2+ ion is viewed as a promising and flexible platform for bone regeneration clinically.

Dual-crosslinked hyaluronan hydrogels with rapid gelation and high injectability for stem cell protection

Injectable dynamic hydrogels play a key role in cell transplantation to protect the cells from shear stress during injection. However, it still remains challenging to design dynamic hydrogels with fast gelation and high stability for protecting cells under flow due to the slow formation and exchange of most dynamic bonds. Here, a novel dual-crosslinked hydrogel system with fast dynamic crosslinks is developed by using methacrylate chitosan (CHMA) and aldehyde functionalized hyaluronate (oxidized HA, OHA). Based on the cooperation of electrostatic interaction between cationic amino of chitosan and anionic carboxyl of HA and Schiff-based crosslinking through amino and aldehyde groups, the dynamic CHMA-OHA hydrogel shows rapid gelation and high injectability. Further, the CHMA-OHA hydrogel is photopolymerized for achieving a high modulus and stability. Importantly, such hydrogels loaded with stem cells remains a cell viability (~ 92%) after extrusion. These results indicate that the CHMA-OHA hydrogel is a promising tissue engineering biomaterial for therapeutic cell delivery and 3D printing of encapsulated cell scaffolds.

Hydrogel Network Dynamics Regulate Vascular Morphogenesis.

Matrix dynamics influence how individual cells develop into complex multicellular tissues. Here, we develop hydrogels with identical polymer components but different crosslinking capacities to enable the investigation of mechanisms underlying vascular morphogenesis. We show that dynamic (D) hydrogels increase the contractility of human endothelial colony-forming cells (hECFCs), promote the clustering of integrin β1, and promote the recruitment of vinculin, leading to the activation of focal adhesion kinase (FAK) and metalloproteinase expression. This leads to the robust assembly of vasculature and the deposition of new basement membrane. We also show that non-dynamic (N) hydrogels do not promote FAK signaling and that stiff D- and N-hydrogels are constrained for vascular morphogenesis. Furthermore, D-hydrogels promote hECFC microvessel formation and angiogenesis invivo. Our results indicate that cell contractility mediates integrin signaling via inside-out signaling and emphasizes the importance of matrix dynamics in vascular tissue formation, thus informing future studies of vascularization and tissue engineering applications.

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.

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.

Dynamic Hydrogels Based on Double Imine Connections and Application for Delivery of Fluorouracil.

Dynamic hydrogels have been prepared by cross-linking of O-carboxymethyl chitosan (O-CMCS) with reversibly connected imino-PEGylated dynamers. The double imine chitosan/dynamer and dynamer bonds and were used to provide tighter structures and adaptive drug release behaviors of the hydrogels. The structural and physical properties of the resulted hydrogels were examined, showing good thermal stability and higher swelling behaviors (up to 3,000%). When hydrogels with various composition ratios were further applied for delivery of anti-cancer drug fluorouracil (5-FU), high drug encapsulation rates were recorded, up to 97%. The release profile of 5-FU showed fast rate at the beginning, followed by slow increase to the maximum amount within 12 h, demonstrating potential as drug carriers for efficient drug delivery.

Photoconfigurable, Cell-Remodelable Disulfide Cross-linked Hyaluronic Acid Hydrogels.

Dynamic photoresponsive synthetic hydrogels offer important advantages for biomaterials design, from the ability to cure hydrogels and encapsulate cells in situ to the light-mediated control of cell-spreading and tissue formation. We report the facile and effective photocuring and photoremodeling of disulfide-cross-linked hyaluronic acid hydrogels, based on photo-oxidation of corresponding thiol residues and their radical-mediated photodegradation. We find that the mechanical properties of disulfide hydrogels and the extent of their photoremodeling can be tuned by controlling the photo-oxidation and photodegradation reactions, respectively. This enables not only the photopatterning of the mechanical properties of hydrogels but also their self-healing and photomediated healing. Finally, we demonstrate the ability to encapsulate mesenchymal stromal cells within these materials and to regulate their protrusion and spreading in 3D matrices by controlling the mechanical properties of the disulfide networks. Therefore, synthetically accessible photoconfigurable disulfide hydrogels offer interesting opportunities for the design of soft biomaterials and the regulation of cell encapsulation and matrix remodeling for tissue engineering.

Environment Controls Biomolecule Release from Dynamic Covalent Hydrogels.

Moldable hydrogels composed of dynamic covalent bonds are attractive biomaterials for controlled release, as the dynamic exchange of bonds in these networks enables minimally invasive application via injection. Despite the growing interest in the biomedical application of dynamic covalent hydrogels, there is a lack of fundamental understanding as to how the network design and local environment control the release of biomolecules from these materials. In this work, we fabricated boronic-ester-based dynamic covalent hydrogels for the encapsulation and in vitro release of a model biologic (β-galactosidase). We systematically investigated the role of network properties and of the external environment (temperature and presence of competitive binders) on release from these dynamic covalent hydrogels. We observed that surface erosion (and associated mass loss) governed biomolecule release. In addition, we developed a statistical model of surface erosion based on the binding equilibria in a boundary layer that described the rates of release. In total, our results will guide the design of dynamic covalent hydrogels as biomaterials for drug delivery applications.

Linking Molecular Behavior to Macroscopic Properties in Ideal Dynamic Covalent Networks.

Dynamic covalent networks (DCvNs) are increasingly used in advanced materials design with applications ranging from recyclable thermosets to self-healing hydrogels. However, the relationship between the underlying chemistry at the junctions of DCvNs and their macroscopic properties is still not fully understood. In this work, we constructed a robust framework to predict how complex network behavior in DCvNs emerges from the chemical landscape of the dynamic chemistry at the junction. Ideal dynamic covalent boronic ester-based hydrogels were used as model DCvNs. We developed physical models that describe how viscoelastic properties, as measured by shear rheometry, are linked to the molecular behavior of the dynamic junction, quantified via fluorescence and NMR spectroscopy and DFT calculations. Additionally, shear rheometry was combined with Transition State Theory to quantify the kinetics and thermodynamics of network rearrangements, enabling a mechanistic understanding including preferred reaction pathways for dynamic covalent chemistries. We applied this approach to corroborate the "loose-bolt" postulate for the reaction mechanism in Wulff-type boronic acids. These findings, grounded in molecular principles, advance our understanding and rational design of dynamic polymer networks, improving our ability to predict, design, and leverage their unique properties for future applications.

Modeling of dynamic hydrogel swelling within the pore space of a porous medium

Aim of this work is to model a multiphasic porous material modified with a hydrogel made from a granulate of Superabsorbent Polymers (SAP). The void space of the material is simultaneously filled with two interacting phases, namely a chemically active hydrogel and a multi-component aqueous pore fluid. The hydrogel has the ability to absorb and retain large amounts of the pore fluid. Depending on the pore fluid chemistry, the hydrogel is also able to reverse the absorption process by releasing absorbed solution. The overall material is finally classified as a functional porous material since the macroscopic material properties depend on the interaction within the pore space. For instance, swelling of the hydrogel within the pore space changes the morphology of the porous media and influences the hydraulic permeability and the mechanical stiffness. Absorption and desorption processes are modeled in a thermodynamic-consistent framework, while constitutive equations for mass transfer are proposed in accordance to polymer chemistry. Experiments have been carried out and inherent model parameters are identified by a Monte-Carlo method. The predicted results of the derived model are in good accordance to experimental findings. Through the reversibility of the phase transition process, the material becomes an excellent candidate of a functional porous media, e. g. a sophisticated filter, which adapts its hydraulic permeability to the pore fluid chemistry.

Boronate-ester crosslinked hyaluronic acid hydrogels for dihydrocaffeic acid delivery and fibroblasts protection against UVB irradiation

Herein, we exploit the dynamic nature and pH dependence of complexes between phenylboronic acid and diol-containing molecules to control the release of an anti-photoaging agent, dihydrocaffeic acid (DHCA), from a dynamic covalent hydrogel (HG). The HG is prepared by reversible formation of boronate ester crosslinks between hyaluronic acid (HA) modified with saccharide (GLU) residues and HA functionalized with 3-aminophenylboronic acid (APBA), part of which is involved in complexation with DHCA. The hydrogel exhibited increased dynamic moduli and a lower relaxation time at pH 7.4 in comparison to pH 6, and greater amount of DHCA was incorporated at pH 7.4. Moreover, this hydrogel prolonged DHCA release at pH 7.4 through drug reversible complexation/decomplexation, while the rate of release was fastest in acidic (skin) conditions. Very interestingly, the incorporation of DHCA into the network enhances its protection against UVB-induced L929 fibroblast death. Therefore, this smart hydrogel can contribute to photoaging prevention.

Injectable multi-responsive micelle/nanocomposite hybrid hydrogel for bioenzyme and photothermal augmented chemodynamic therapy of skin cancer and bacterial infection

Activatable theranostic strategy with high specificity and sensitivity for simultaneous skin cancer therapy and anti-infection remains a major challenge. Here, we developed an injectable multi-responsive micelle/nanocomposite hybrid hydrogel (CFMG) for bioenzyme and photothermal augmented chemodynamic therapy (CDT) of both skin tumor and bacterial invasion. The multifunctional hybrid hydrogel was successfully fabricated through incorporating MoS2@MnFe2O4 nanocomposites into a dynamic Schiff-based chemical cross-linked hydrogel of chitosan-grafted-dihydrocaffeic acid (CS-DA) and aldehyde Pluronic F127 (F127-CHO) micelles loaded with glucose oxidase (GOx). The sustained release of GOx induced by the pH-responsive biodegradation of the hybrid hydrogel could continuously consume the intratumoral glucose, produce H2O2, and increase acidity. In the gradually enhanced acidic environment, the accelerated release of catalytic iron ions from MoS2@MnFe2O4 nanocomposites catalyzed the decomposition of H2O2 into highly toxic OH via Fenton-like reaction to induce cell death. Remarkably, by combining with a spatiotemporal controllable photothermal hyperthermia, the CFMG hydrogel exhibited bioenzyme and photothermal synergistically enhanced CDT of skin tumor, and demonstrated an almost complete tumor suppression both in vitro (98.8%) and in vivo (97.6%). Moreover, due to the cationic chitosan and the augmented production of OH, the CFMG hydrogel also demonstrated an effective bacterial eradication (≥99%) both in vitro and in vivo. Taken together, the CFMG hydrogel indicated a great potential for simultaneous skin cancer treatment and antibacterial infection.

Bioinspired Hydrogels with Muscle-Like Structure for AIEgen-Guided Selective Self-Healing

Living systems, including human beings, animals, and plants, display the power to self-heal spontaneously after being damaged. The self-healing is usually selective, which means that the healing ef...

Granular hydrogels for 3D bioprinting applications

AbstractGranular hydrogels are the conglomerations of micrometer‐sized hydrogel particles that have recently become promising in tissue growth and three‐dimensional (3D) bioprinting. Recent advances in the use of jamming transition of granular hydrogels represent a potential paradigm shift in the extrusion‐based 3D bioprinting. These dynamic granular hydrogels are shear thinning and self‐healing, enable higher printing performance, and the creation of better physiological conditions for heterocellular constructs. Here, we review the current efforts to explore materials to produce granular hydrogels with novel functional properties, focusing on the granular hydrogels that can be used for supporting baths and bioinks in the extrusion‐based 3D bioprinting. The recent advances, benefits, and challenges in this emerging area are highlighted.

On-Demand Dissoluble Diselenide-Containing Hydrogel.

On-demand dissolution of hydrogels is being increasingly studied for their potential use in burn wound dressing applications. Herein, a dynamic diselenide-containing hydrogel is developed through a very simple one-pot and two-step process starting from the selenol functionalization of a partially hydrolyzed poly(2-ethyl-2-oxazoline) with γ-butyroselenolactone. The hydrogel spontaneously cross-links via an in situ oxidation of the selenol functionalities in air. The gelation process and the final viscoelastic properties of the gel are characterized by rheological experiments. The mechanical properties of those new diselenide-containing hydrogels are easily tuned by varying the concentration of γ-butyroselenolactone. The materials also show good skin adhesion and UV light responsiveness. A unique feature of the hydrogel is its capability to be fully and rapidly dissolved on-demand, via oxidation or reduction of the diselenide cross-links, making them particularly attractive for burn wound dressing applications.