Dynamic Hydrogels Research Articles

Biocompatible hydrogels based on quaternary ammonium salts of chitosan with high antimicrobial activity as biocidal agents for disinfection

The paper reports new hydrogels based on quaternary ammonium salts of chitosan designed as biocidal products. The chitosan derivative was crosslinked with salicylaldehyde via reversible imine bonds and supramolecular self-assemble to give dynamic hydrogels which respond to environmental stimuli. The crosslinking mechanism was demonstrated by 1H NMR and FTIR spectroscopy, and X-ray diffraction and polarized light microscopy. The hydrogel nature, self-healing and thixotropy were proved by rheological investigation and visual observation, and their morphology was assessed by scanning electron microscopy. The relevant properties for application as biocidal products, such as swelling, dissolution, bioadhesiveness, antimicrobial activity and ex-vivo hemocompatibility and in vivo local toxicity and biocompatibility on experimental mice were measured and analyzed in relationship with the imination degree and the influence of each component. It was found that the hydrogels are superabsorbent, have good adhesivity to skin and various surfaces and antimicrobial activity against relevant gram-positive and gram-negative bacteria, while being hemocompatible and biocompatible. Besides, the hydrogels are easily biodegraded in soil. All these properties recommend the studied hydrogels as ecofriendly biocidal agents for living tissues and surfaces, but also open the perspectives of their use as platform for in vivo applications in tissue engineering, wound healing, or drug delivery systems.

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.

Biomimetic Non-ergodic Aging by Dynamic-to-covalent Transitions in Physical Hydrogels.

Hydrogels are soft materials engineered to suit a multitude of applications that exploit their tunable mechanochemical properties. Dynamic hydrogels employing noncovalent, physically cross-linked networks dominated by either enthalpic or entropic interactions enable unique rheological and stimuli-responsive characteristics. In contrast to enthalpy-driven interactions that soften with increasing temperature, entropic interactions result in largely temperature-independent mechanical properties. By engineering interfacial polymer-particle interactions, we can induce a dynamic-to-covalent transition in entropic hydrogels that leads to biomimetic non-ergodic aging in the microstructure without altering the network mesh size. This transition is tuned by varying temperature and formulation conditions such as pH, which allows for multivalent tunability in properties. These hydrogels can thus be designed to exhibit either temperature-independent metastable dynamic cross-linking or time-dependent stiffening based on formulation and storage conditions, all while maintaining structural features critical for controlling mass transport, akin to many biological tissues. Such robust materials with versatile and adaptable properties can be utilized in applications such as wildfire suppression, surgical adhesives, and depot-forming injectable drug delivery systems.

Mucus-Inspired Self-Healing Hydrogels: A Protective Barrier for Cells against Viral Infection.

Mucus is a dynamic biological hydrogel, composed primarily of the glycoprotein mucin, exhibits unique biophysical properties and forms a barrier protecting cells against a broad-spectrum of viruses. Here, this work develops a polyglycerol sulfate-based dendronized mucin-inspired copolymer (MICP-1) with ≈10% repeating units of activated disulfide as cross-linking sites. Cryo-electron microscopy (Cryo-EM)analysis of MICP-1 reveals an elongated single-chain fiber morphology. MICP-1 shows potential inhibitory activity against many viruses such as herpes simplex virus 1 (HSV-1) and SARS-CoV-2 (including variants such as Delta and Omicron). MICP-1 produces hydrogels with viscoelastic properties similar to healthy human sputum and with tuneable microstructures using linear and branched polyethylene glycol-thiol (PEG-thiol) as cross-linkers. Single particle tracking microrheology, electron paramagnetic resonance (EPR) and cryo-scanning electron microscopy (Cryo-SEM) are used to characterize the network structures. The synthesized hydrogels exhibit self-healing properties, along with viscoelastic properties that are tuneable through reduction. A transwell assay is used to investigate the hydrogel's protective properties against viral infection against HSV-1. Live-cell microscopy confirms that these hydrogels can protect underlying cells from infection by trapping the virus, due to both network morphology and anionic multivalent effects. Overall, this novel mucin-inspired copolymer generates mucus-mimetic hydrogels on a multi-gram scale. These hydrogels can be used as models for disulfide-rich airway mucus research, and as biomaterials.

Dynamic adaptive hydrogel facilitates neuroregeneration in segmental nerve deficits via immunomodulation and mitochondrial homeostasis

The clinical management of segmental nerve deficits faces significant challenges, particularly in achieving substantial neural structural reconstruction and functional recovery. Dynamic, adaptive smart hydrogels hold great promise for restoring tissue function by mimicking regenerative microenvironments and cytokine secretion. However, the influence of hydrogel structure on drug release behavior and its role in maintaining nerve bridging during repair remains underexplored and warrants attention. Here, we present a sequentially gel-forming nerve-guiding conduit (NC/DS@HPBGP) composed of bisphosphonates-modified hyaluronic acid (HA-PBA-BP) and Tannic acid-modified GelMA (GelMA-TA), which contains borate ester bonds and metal coordination bonds, allowing for a dual response to ROS and Ca2+ at nerve injury sites. After implantation, the conduit undergoes dynamic gel-sol–gel transitions, including ROS-responsive release of narciclasine (NC) and 5-iodoisoquinoline (DS) and Ca2+ cross-linking-induced 3D structural reorganization, resulting in enhancing nerve regeneration proximally through immunomodulation and ensuring structural integrity distally via mitochondrial autophagy. This multifaceted integration facilitates dynamic remodeling of the nerve regeneration microenvironment, markedly augmenting nerve regeneration and repair efficacy.

Crosslinker Architectures Impact Viscoelasticity in Dynamic Covalent Hydrogels.

Dynamic covalent crosslinked (DCC) hydrogels represent a significant advance in biomaterials for regenerative medicine and mechanobiology. These gels typically offer viscoelasticity and self-healing properties that more closely mimic in vivo tissue mechanics than traditional, predominantly elastic, covalent crosslinked hydrogels. Despite their promise, the effects of varying crosslinker architecture - side chain versus telechelic crosslinks - on the viscoelastic properties of DCC hydrogels have not been thoroughly investigated. This study introduces hydrazone-based alginate hydrogels and examines how side-chain and telechelic crosslinker architectures impact hydrogel viscoelasticity and stiffness. In hydrogels with side-chain crosslinking (SCX), higher polymer concentrations enhance stiffness and decelerates stress relaxation, while an off-stoichiometric hydrazine-to-aldehyde ratio leads to reduced stiffness and shorter relaxation time. In hydrogels with telechelic crosslinking, maximal stiffness and slowest stress relaxation occurs at intermediate crosslinker concentrations for both linear and star crosslinkers, with higher crosslinker valency further increasing stiffness and relaxation time. Our result suggested different ranges of stiffness and stress relaxation are accessible with the different crosslinker architectures, with SCX hydrogels leading to slower stress relaxation relative to the other architectures, and hydrogels with star crosslinking (SX) providing increased stiffness and slower stress relaxation relative to hydrogels with linear crosslinking (LX). The mechanical properties of SX hydrogels are more robust to changes induced by competing chemical reactions compared to LX hydrogels. Our research underscores the pivotal role of crosslinker architecture in defining hydrogel stiffness and viscoelasticity, providing crucial insights for the design of DCC hydrogels with tailored mechanical properties for specific biomedical applications.

Dynamic Covalent Hydrogel as a Single-Dose Vaccine Adjuvant for Sustained Antigen Release and Significantly Elevated Humoral Immunity.

Vaccine is the most important way for fighting against infection diseases. However, multiple injections and unsatisfied immune responses are the main obstacles for current vaccine application. Herein, a dynamic covalent hydrogel (DCH) is used as a single-dose vaccine adjuvant for eliciting robust and sustained humoral immunity. By adjusting the mass ratio of the DCH gel, 10-30 d constant release of the loaded recombinant protein antigens is successfully realized, and it is proved that sustained release of antigens can significantly improve the vaccine efficacy. When loading SARS-CoV-2 RBD (Wuhan and Omicron BA.1 strains) antigens into this DCH gel, an over 32000 times and 8000 times improvement is observed in antigen-specific antibody titers compared to conventional Aluminum adjuvanted vaccines. The universality of this DCH gel adjuvant is confirmed in a Nipah G antigen test as well as a H1N1 influenza virus antigen test, with much improved protection of C57BL/6 mice against H1N1 virus infection than conventional Aluminum adjuvanted vaccines. This sustainably released, single-dose DCH gel adjuvant provides a new promising option for designing next-generation infection vaccines.

Proanthocyanidins-based tandem dynamic covalent cross-linking hydrogel for diabetic wound healing

Wound healing in diabetic patients presents significant challenges in clinical wound care due to high oxidative stress, excessive inflammation, and a microenvironment prone to infection. In this study, we successfully developed a multifunctional tandem dynamic covalently cross-linked hydrogel dressing aimed at diabetic wound healing. This hydrogel was constructed using cyanoacetic acid functionalized dextran (Dex-CA), 2-formylbenzoylboric acid (2-FPBA) and natural oligomeric proanthocyanidins (OPC), catalyzed by histidine. The resulting Dex-CA/OPC/2-FPBA (DPOPC) hydrogel can be dissolved triggered by cysteine, thereby achieving “controllable and non-irritating" dressing change. Furthermore, the incorporation of OPC as a hydrogel building block endowed the hydrogel with antioxidant and anti-inflammatory properties. The cross-linked network of the DPOPC hydrogel circumvents the burst release of OPC, enhancing its biosafety. In vivo studies demonstrated that the DPOPC hydrogel significantly accelerated the wound healing process in diabetic mice compared to a commercial hydrogel, achieving an impressive wound closure rate of 98 % by day 14. The DPOPC hydrogel effectively balanced the disrupted inflammatory state during the healing process. This dynamic hydrogel based on natural polyphenols is expected to be an ideal candidate for dressings intended for chronic wounds.

Dynamic Schiff base linkage-based double-network hydrogels with injectable, self-healing, and pH-responsive properties for bacteria-infected wound healing

Dynamic Schiff base linkage-based double-network hydrogels with injectable, self-healing, and pH-responsive properties for bacteria-infected wound healing

Dynamic hydrogel–metal–organic framework system promotes bone regeneration in periodontitis through controlled drug delivery

Periodontitis is a prevalent chronic inflammatory disease, which leads to gradual degradation of alveolar bone. The challenges persist in achieving effective alveolar bone repair due to the unique bacterial microenvironment’s impact on immune responses. This study explores a novel approach utilizing Metal–Organic Frameworks (MOFs) (comprising magnesium and gallic acid) for promoting bone regeneration in periodontitis, which focuses on the physiological roles of magnesium ions in bone repair and gallic acid's antioxidant and immunomodulatory properties. However, the dynamic oral environment and irregular periodontal pockets pose challenges for sustained drug delivery. A smart responsive hydrogel system, integrating Carboxymethyl Chitosan (CMCS), Dextran (DEX) and 4-formylphenylboronic acid (4-FPBA) was designed to address this problem. The injectable self-healing hydrogel forms a dual-crosslinked network, incorporating the MOF and rendering its on-demand release sensitive to reactive oxygen species (ROS) levels and pH levels of periodontitis. We seek to analyze the hydrogel’s synergistic effects with MOFs in antibacterial functions, immunomodulation and promotion of bone regeneration in periodontitis. In vivo and in vitro experiment validated the system's efficacy in inhibiting inflammation-related genes and proteins expression to foster periodontal bone regeneration. This dynamic hydrogel system with MOFs, shows promise as a potential therapeutic avenue for addressing the challenges in bone regeneration in periodontitis.Graphical

Dynamically Cross-Linked Double-Network Hydrogels with Matched Mechanical Properties and Ideal Biocompatibility for Artificial Blood Vessels.

Vessel transplantation is currently considered the "gold standard" treatment for cardiovascular disease. However, ideal artificial vascular grafts should possess good biocompatibility and mechanical strength that match those of native autologous vascular tissue to promote in vivo tissue regeneration. In this study, a series of dynamic cross-linking double-network hydrogels and the resultant hydrogel tubes were prepared. The hydrogels (named PCO), composed of rigid poly(vinyl alcohol) (PVA), flexible carboxymethyl chitosan (CMCS), and a cross-linker of aldehyde-based β-cyclodextrin (OCD), were formed in a double-network structure with multiple dynamical cross-linking including dynamic imine bonds, hydrogen bonds, and microcrystalline regions. The PCO hydrogels exhibited superior mechanical strength, good network stability, and fatigue resistance. Additionally, it demonstrated excellent cell and blood compatibility. The results showed that the introduction of CMCS/OCD led to a significant increase in the proliferation rate of endothelial cells seeded on the surface of the hydrogel. The hemolysis rate in the test was lower than 0.3%, and both protein adsorption and platelet adhesion were reduced, indicating an excellent anticoagulant function. The plasma recalcification time test results showed that endogenous coagulation was alleviated to some extent. When formed into blood vessels and incubated with blood, no thrombus formation was observed, and there was minimal red blood cell aggregation. Therefore, this novel hydrogel tube, with excellent mechanical properties, exhibits antiadhesive characteristics toward blood cells and proteins, as well as antithrombotic properties, making it hold tremendous potential for applications in the biomedical and engineering fields.

Calmodulin‐Based Dynamic Protein Hydrogels with Three Distinct Mechanical Stiffness

AbstractStimuli‐responsive hydrogels that leverage protein conformational changes are of significant interest in the design of dynamic materials applicable in a myriad of fields, such as drug delivery, actuators, biosensors, and microfluidics. The small calcium binding protein calmodulin (CaM), which undergoes three‐stage conformational changes upon successive binding with Ca2+ and specific ligands, offers a mechanism to create dynamic hydrogels with three distinct physical states. In this work, a CaM‐based recombinant protein hydrogel is engineered using [Ru(bpy)3]2+‐mediated photo‐crosslinking. This hydrogel displays the ability to reversibly increase its Young's modulus by 1.5‐fold and ∼7‐fold, respectively, upon binding with Ca2+ and subsequent interaction with trifluoperazine. The magnitude of stiffness changes is tunable by adjusting the length proportion of dynamic and static domains and modifying protein content. This tunable and reversible control over hydrogel mechanics is further utilized to engineer shape‐morphing materials, highlighting the versatile potential of this CaM‐based protein hydrogel for diverse applications.

Ligand Dissociation of Metal-Complex Photocatalysts toward pH-Photomanipulation in Dynamic Covalent Hydrogels for Printing Reprocessable and Recyclable Devices.

Dynamic covalent hydrogels are gaining attention for their potential in smart materials, soft devices, electronics, and more thanks to their impressive mechanical properties, biomimetic structures, and dynamic behavior. However, a significant challenge lies in designing precise and efficient dynamic photochemistry for their preparation, allowing for complex structures and control over the dynamic process. Herein, we propose a general and straightforward orthogonal dynamic covalent photochemistry strategy for preparing high-performance printable dynamic covalent hydrogels, thereby broadening their advanced applications. This photochemical strategy uses a bifunctional photocatalyst to initiate radical polymerization and release ligands through a rapid light-mediated dissociation mechanism. This process leads to a controlled increase in system pH from mildly acidic to alkaline conditions within one hundred seconds, which in turn triggers the pH-sensitive model reactions of boronic acid/diol complexation and Knoevenagel condensation. The orthogonal photochemistry enables the formation of interpenetrated and conjoined networks, significantly enhancing the mechanical properties of the hydrogels. The reversible bonds formed during the process, i.e., boronic ester and unsaturated ketone bonds, confer excellent self-healing, reprocessable, and recyclable properties on the hydrogels through photochemical pH variations. Furthermore, this rapid, controlled fabrication process and dynamic behavior are highly compatible with printing techniques, enabling the design of adaptive and recyclable sensors with different structures. These advancements are promising for various material science, medicine, and engineering applications.

Dynamic Hydrogels against Infections: From Design to Applications.

Human defense against infection remains a global topic. In addition to developing novel anti-infection drugs, therapeutic drug delivery strategies are also crucial to achieving a higher efficacy and lower toxicity of these drugs for treatment. The application of hydrogels has been proven to be an effective localized drug delivery approach to treating infections without generating significant systemic adverse effects. The recent emerging dynamic hydrogels further show power as injectable formulations, giving new tools for clinical treatments. In this review, we delve into the potential applications of dynamic hydrogels in antibacterial and antiviral treatments and elaborate on their molecular designs and practical implementations. By outlining the chemical designs underlying these hydrogels, we discuss how the choice of dynamic chemical bonds affects their stimulus responsiveness, self-healing capabilities, and mechanical properties. Afterwards, we focus on how to endow dynamic hydrogels with anti-infection properties. By comparing different drug-loading methods, we highlight the advantages of dynamic chemical bonds in achieving sustained and controlled drug release. Moreover, we also include the design principles and uses of hydrogels that possess inherent anti-infective properties. Furthermore, we explore the design principles and applications of hydrogels with inherent anti-infective properties. Finally, we briefly summarize the current challenges faced by dynamic hydrogels and present a forward-looking vision for their future development. Through this review, we expect to draw more attention to these therapeutic strategies among scientists working with chemistry, materials, as well as pharmaceutics.

A novel red fluorescent and dynamic nanocomposite hydrogel based on chitosan and alginate doped with inclusion complex of carbon dots

Red fluorescent hydrogels possessing injectable and self-healing properties have widespread potential in biomedical field. It is still a challenge to achieve a biomacromolecules based dynamic hydrogels simultaneously combining with excellent red fluorescence, good mechanical properties, and biocompatibility. Here we first explore hydrophilic inclusion complex of (R-CDs@α-CD) derived from hydrophobic red fluorescent carbon dots (R-CDs) and α-cyclodextrin (α-CD), and then achieved a red fluorescent and dynamic polysaccharide R-CDs@α-CD/CEC-l-OSA hydrogel. The nanocomposite hydrogel can be fabricated through controlled doping of red fluorescent R-CDs@α-CD into dynamic polymer networks, taking reversibly crosslinked N-carboxyethyl chitosan (CEC) and oxidized sodium alginate (OSA) as an example. The versatile red fluorescent hydrogel simultaneously combines the features of injection, biocompatibility, and augmented mechanical properties and self-healing behavior, especially in rapid self-recovery even after integration. The R-CDs@α-CD uniformly dispersed into dynamic hydrogel played the role of killing two birds with one stone, that is, endowing red emission of a hydrophilic fluorescent substance, and improving mechanical and self-healing properties as a dynamic nano-crosslinker, via forming hydrogen bonds as reversible crosslinkings. The novel red fluorescent and dynamic hydrogel based on polysaccharides is promising for using as biomaterials in biomedical field.

Hydrogen bond‐reinforced double‐network hydrogels with enhanced mechanical strength: Preparation, characterization and swelling behavior

AbstractRecently, double network (DN) gels with dynamic non‐covalent interaction such as hydrogen bonds has drawn much attention as an innovative material having both high water content and high mechanical strength. Research efforts have identified DN gels as a promising class of materials due to their unique network architecture. These gels comprise two interpenetrating networks formed by different types of polymer. Herein, we report a tough DN hydrogel with high mechanical strength and high swelling ability. The DN gel is synthesized via a two‐step network formation. The first network gel was synthesized via frontal polymerization. Then, the first gel is immersed in an aqueous solution of a second monomer and carrying out a second polymerization in the presence of first network. The spectroscopic analysis and thermal behavior with differential scanning calorimeter measurements corroborated the existence of hydrogen bonds. The mechanical test and microscopic morphology were further explored to explain the strength and high imbibing characteristics. We expect that this facile strategy may explore a dynamic and tunable hydrogel to expand its potential applications in biomedical field.

Internal Catalysis in Dynamic Hydrogels with Associative Thioester Cross-Links.

Thioesters are an essential functional group in biosynthetic pathways, which has motivated their development as reactive handles in probes and peptide assembly. Thioester exchange is typically accelerated by catalysts or elevated pH. Here, we report the use of bifunctional aromatic thioesters as dynamic covalent cross-links in hydrogels, demonstrating that at physiologic pH in aqueous conditions, transthioesterification facilitates stress relaxation on the time scale of hundreds of seconds. We show that intramolecular hydrogen bonding is responsible for accelerated exchange, evident in both molecular kinetics and macromolecular stress relaxation. Drawing from concepts in the vitrimer literature, this system exemplifies how dynamic cross-links that exchange through an associative mechanism enable tunable stress relaxation without altering stiffness.

Photoactivated Formation of an Extravascular Dynamic Hydrogel as an Intelligent Blood Flow Regulator to Reprogram the Immunogenic Landscape.

Long-term tumor starvation may be a potential strategy to elevate the antitumor immune response by depriving nutrients. However, combining long-term starvation therapy with immunotherapy often yields limited efficacy due to the blockage of immune cell migration pathways. Herein, an intelligent blood flow regulator (BFR) is first established through photoactivated in situ formation of the extravascular dynamic hydrogel to compress blood vessels, which can induce long-term tumor starvation to elicit metabolic stress in tumor cells without affecting immune cell migration pathways. By leveraging methacrylate-modified nanophotosensitizers (HMMAN) and biodegradable gelatin methacrylate (GelMA), the developed extravascular hydrogel dynamically regulates blood flow via enzymatic degradation. Additionally, aPD-L1 loaded into HMMAN continuously blocks immune checkpoints. Systematic in vivo experiments demonstrate that the combination of immune checkpoint blockade (ICB) and BFR-induced metabolic stress (BIMS) significantly delays the progression of Lewis lung and breast cancers by reshaping the tumor immunogenic landscape and enhancing antitumor immune responses.

Black Phosphorus-Based Dynamic Self-Healing Hydrogel to Integrate Demineralized Bone Matrix and Noggin-Targeting siRNA for Synergistic Osteogenesis.

Although a demineralized bone matrix (DBM) is often used as an alternative to an autologous bone graft, its clinical application is still hampered by easy dispersion of DBM particles and insufficient osteoinductivity in the defect site. Herein, we designed a self-healing hydrogel for DBM that can rapidly restore its structural integrity after damage based on amino-rich black phosphorus (BP) nanosheets and aldehyde-functionalized hyaluronic acid (AHA). Given the increased expression of bone morphogenetic protein (BMP) antagonists by DBM stimulation, the osteogenic potency of DBM in the hydrogel carrier was further enhanced by abrogating the BMP antagonism. The BP/AHA hydrogel provided dynamic polymer-nanosheet networks that combine injectability, modability, and physical stability with high DBM loading, where the BP nanosheets served as osteogenic cross-linkers to promote biomineralization and deliver siRNA to suppress undesirable expression of BMP antagonist noggin by DBM. As a result, the BP/AHA hydrogel integrated with DBM and noggin-targeting siRNA synergistically promoted osteogenic differentiation of mesenchymal stem cells by enhancing BMP/Smad signaling. This work demonstrates a promising strategy to improve the efficacy of bone regeneration using bone graft.

Schiff base crosslinked hyaluronic acid hydrogels with tunable and cell instructive time-dependent mechanical properties

The dynamic interplay between cells and their native extracellular matrix (ECM) influences cellular behavior, imposing a challenge in biomaterial design. Dynamic covalent hydrogels are viscoelastic and show self-healing ability, making them a potential scaffold for recapitulating native ECM properties. We aimed to implement kinetically and thermodynamically distinct crosslinkers to prepare self-healing dynamic hydrogels to explore the arising properties and their effects on cellular behavior. To do so, aldehyde-substituted hyaluronic acid (HA) was synthesized to generate imine, hydrazone, and oxime crosslinked dynamic covalent hydrogels. Differences in equilibrium constants of these bonds yielded distinct properties including stiffness, stress relaxation, and self-healing ability. The effects of degree of substitution (DS), polymer concentration, crosslinker to aldehyde ratio, and crosslinker functionality on hydrogel properties were evaluated. The self-healing ability of hydrogels was investigated on samples of the same and different crosslinkers and DS to obtain hydrogels with gradient properties. Subsequently, human dermal fibroblasts were cultured in 2D and 3D to assess the cellular response considering the dynamic properties of the hydrogels. Moreover, assessing cell spreading and morphology on hydrogels having similar modulus but different stress relaxation rates showed the effects of matrix viscoelasticity with higher cell spreading in slower relaxing hydrogels.