Covalent Hydrogels Research Articles

Cross-Linker Architectures Impact Viscoelasticity in Dynamic Covalent Hydrogels.

Dynamic covalent cross-linked (DCC) hydrogels represent a significant advance in biomaterials for regenerative medicine and mechanobiology, offering viscoelasticity, and self-healing properties that more closely mimic in vivo tissue mechanics than traditional, predominantly elastic, covalent hydrogels. However, the effects of varying cross-linker architecture on DCC hydrogel viscoelasticity have not been thoroughly investigated. This study introduces hydrazone-based alginate hydrogels to explore how cross-linker architectures impact stiffness and viscoelasticity. In hydrogels with side-chain cross-linker (SCX), higher cross-linker concentrations enhance stiffness and decelerate stress relaxation, while an off-stoichiometric hydrazine-to-aldehyde ratio reduces stiffness and shortens relaxation time. In hydrogels with telechelic cross-linking, maximal stiffness and relaxation time occurs at intermediate cross-linker mixing ratio for both linear cross-linker (LX) and star cross-linker (SX), with higher cross-linker valency further enhancing these properties. Further, the ranges of stiffness and viscoelasticity accessible with the different cross-linker architectures are found to be distinct, with SCX hydrogels leading to slower stress relaxation relative to the other architectures, and SX hydrogels providing increased stiffness and slower stress relaxation versus LX hydrogels. This research underscores the pivotal role of cross-linker architecture in defining hydrogel stiffness and viscoelasticity, providing insights for designing DCC hydrogels with tailored mechanical properties for specific biomedical applications.

Structure-Reactivity Relationships in a Small Library of Imine-Type Dynamic Covalent Materials: Determination of Rate and Equilibrium Constants Enables Model Prediction and Validation of a Unique Mechanical Softening in Dynamic Hydrogels.

The development of next generation soft and recyclable materials prominently features dynamic (reversible) chemistries such as host-guest, supramolecular, and dynamic covalent. Dynamic systems enable injectability, reprocessability, and time-dependent mechanical properties. These properties arise from the inherent relationship between the rate and equilibrium constants (RECs) of molecular junctions (cross-links) and the resulting macroscopic behavior of dynamic networks. However, few examples explicitly measure RECs while exploring this connection between molecular and material properties, particularly for polymeric hydrogel systems. Here we use dynamic covalent imine formation to study how single-point compositional changes in NH2-terminated nucleophiles affect binding constants and resulting hydrogel mechanical properties. We explored both model small molecule studies and model polymeric macromers, and found >3-decade change in RECs. Leveraging established relationships in the literature, we then developed a simple model to describe the cross-linking equilibrium and predict changes in hydrogel mechanical properties. Interestingly, we observed that a narrow ≈2-decade range of Keq's determine the bound fraction of imines. Our model allowed us to uncover a regime where adding cross-linker before saturation can decrease the cross-link density of a hydrogel. We then demonstrated the veracity of this predicted behavior experimentally. Notably this emergent behavior is not accounted for in covalent hydrogel theory. This study expands upon structure-reactivity relationships for imine formation, highlighting how quantitative determination of RECs facilitates predicting macroscopic behavior. Furthermore, while the present study focuses on dynamic covalent imine formation, the underlying principles of this work are applicable to the general bottom-up design of soft and recyclable dynamic materials.

Stable and antibacterial tannic acid-based covalent polymeric hydrogel for highly selective Pb2+ recovery from lead-acid battery industrial wastewater

The resource of trace lead (Pb2+) from wastewater bearing intricate components is imperative for sustainable progression of the lead-acid battery industry. Herein, we fabricated a tannic acid-based covalent polymeric hydrogel (TA@PMAM) with antimicrobial properties and stability via facile Michael addition reaction. The incorporation of tannic acid (TA) through robust covalent bond leads to a stable porous 3D covalent polymer network with almost no loss of mechanical properties even after 20 compression cycles. Batch adsorption experiments of TA@PMAM revealed an extraordinary adsorption capacity of Pb2+(Qe =196.6 mg/g), achieving 87.2 % of Pb2+ adsorption within the first 5 min owing to porous structure, numerous adsorption sites and good hydrophilicity. Moreover, TA@PMAM demonstrated a strong affinity for Pb2+ in the presence of the interfere metal ions (Cu2+, Co2+, Mn2+etc.) due to the carbonyl and phenolic hydroxyl that can specifically pair with Pb2+. Stable adsorption properties of TA@PMAM were confirmed in fixed bed column adsorption experiment using lead-acid batteries wastewater, retaining 79.56 % of initial adsorption capacity even after 10 times’ reuse. Besides, TA@PMAM possesses a broad spectrum of antimicrobial properties. This study sheds novel light on the design and fabrication of adsorbent, which holds great potential for commercialization in recovering lead from battery industrial wastewater.

Dehydration regulates structural reorganization of dynamic hydrogels

The dehydration process is widely recognized as a significant phenomenon in nature. Hydrogels, which are important functional materials with high water content and crosslinked networks, encounter the issue of dehydration in their practical applications. Here, we report the distinctive anisotropic dehydration modality of dynamic hydrogels, which is fundamentally different from the more commonly observed isotropic dehydration of covalent hydrogels. Xerogels derived from dynamic hydrogel dehydration will fully cover a curved substrate surface and exhibit hollow structures with internal knots, in contrast to the bulk xerogels produced by covalent hydrogel dehydration. Depending on the competing cohesion of polymer chains and the adhesion at the hydrogel-substrate interface, the previously overlooked reorganization of polymer networks within dynamic hydrogels, triggered by dehydration-induced stress, has been discovered to regulate such macroscopic structural reconstruction for dynamic hydrogel dehydration. With the attached hydrogel-substrate interface, the surface microstructures of substrates can also be engraved onto xerogels with high resolution and on a large scale. This work will greatly enhance our understanding of the soft matter dehydration process and broaden the applications of dehydration technologies using water-containing materials.

Chitosan/Poly(maleic acid-alt-vinyl acetate) Hydrogel Beads for the Removal of Cu2+ from Aqueous Solution.

Covalent cross-linked hydrogels based on chitosan and poly(maleic acid-alt-vinyl acetate) were prepared as spherical beads. The structural modifications of the beads during the preparation steps (dropping in liquid nitrogen and lyophilization, thermal treatment, washing with water, and treatment with NaOH) were monitored by FT-IR spectroscopy. The hydrogel beads have a porous inner structure, as shown by SEM microscopy; moreover, they are stable in acidic and basic pH due to the covalent crosslinking. The swelling degree is strongly influenced by the pH since the beads possess ionizable amine and carboxylic groups. The binding capacity for Cu2+ ions was examined in batch mode as a function of sorbent composition, pH, contact time, and the initial concentration of Cu2+. The kinetic data were well-fitted with the pseudo-second-order kinetic, while the sorption equilibrium data were better fitted with Langmuir and Sips isotherms. The maximum equilibrium sorption capacity was higher for the beads obtained with a 3:1 molar ratio between the maleic copolymer and chitosan (142.4 mg Cu2+ g-1), compared with the beads obtained using a 1:1 molar ratio (103.7 mg Cu2+ g-1). The beads show a high degree of reusability since no notable decrease in the sorption capacity was observed after five consecutive sorption/desorption cycles.

Enzymatically cross-linked arabinoxylan hydrogel: Effect of glucose oxidase on the gel characteristics and oral colon-targeted delivery for Naja atra neurotoxin

Water-extracted arabinoxylan (WEAX) can form covalent hydrogels and has potential applications in colon-targeted drug delivery. However, it is not clear which structural characteristics of WEAX gels can better facilitate drug release in the colon as a microbial triggered system. In this study, different rheological properties of WEAX gels were prepared through oxidative cross-linking using glucose oxidase (GOX) with varying amounts for oral colon-targeted released Naja atra neurotoxin (NANT). It was found that the WEAX hydrogel with an adequate strong cross-linking degree minimized NANT loss in the gastrointestinal tract and improved its release in the colon in vitro. Moreover, NANT was fixed to the wall of the gel network by noncovalent binding and could maintain its secondary structure in the WEAX–NANT hydrogel. The WEAX–NANT hydrogel had an obvious analgesic effect in the in vivo mice test. The results revealed that the WEAX–NANT hydrogel with a strong cross-linking degree was better at releasing NANT.

Tuning on passive interfacial cooling of covalent organic framework hydrogel for enhancing freshwater and electricity generation

AbstractDeveloping an efficient freshwater and electricity co‐generation device (FECGD) can solve the shortage of freshwater and electricity. However, the poor salt resistance and refrigeration properties of the materials for FECGD put big challenges in the efficient and stable operation of these devices. To address these issues, we propose the covalent organic framework (COF) confined co‐polymerization strategy to prepare COF‐modified acrylamide cationic hydrogels (ACH‐COF), where hydrogen bonding interlocking between negatively charged polymer chains and COF pores can form a salt resistant hydrogel for stabilizing tunable passive interfacial cooling (TPIC). The FECPDs based on the TPIC and salt resistance of ACH‐COF display a maximum output power density of 2.28 W m−2, which is 4.3 times higher than that of a commercial thermoelectric generator under one solar radiation. The production rate of freshwater can reach 2.74 kg m−2 h−1. Our results suggest that the high efficiency and scalability of the FECGD can hold the promise of alleviating freshwater and power shortages.

Hyaluronic Acid/Chondroitin Sulfate-Based Dynamic Thiol-Aldehyde Addition Hydrogel: An Injectable, Self-Healing, On-Demand Dissolution Wound Dressing.

Frequent removal and reapplication of wound dressings can cause mechanical disruption to the healing process and significant physical discomfort for patients. In response to this challenge, a dynamic covalent hydrogel has been developed to advance wound care strategies. This system comprises aldehyde functionalized chondroitin sulfate (CS-CHO) and thiolated hyaluronic acid (HA-SH), with the distinct ability to form in situ via thiol-aldehyde addition and dissolve on-demand via the thiol-hemithioacetal exchange reaction. Although rarely reported, the dynamic covalent reaction of thiol-aldehyde addition holds great promise for the preparation of dynamic hydrogels due to its rapid reaction kinetics and easy reversible dissociation. The thiol-aldehyde addition chemistry provides the hydrogel system with highly desirable characteristics of rapid gelation (within seconds), self-healing, and on-demand dissolution (within 30 min). The mechanical and dissolution properties of the hydrogel can be easily tuned by utilizing CS-CHO materials of different aldehyde functional group contents. The chemical structure, rheology, self-healing, swelling profile, degradation rate, and cell biocompatibility of the hydrogels are characterized. The hydrogel possesses excellent biocompatibility and proves to be significant in promoting cell proliferation in vitro when compared to a commercial hydrogel (HyStem® Cell Culture Scaffold Kit). This study introduces the simple fabrication of a new dynamic hydrogel system that can serve as an ideal platform for biomedical applications, particularly in wound care treatments as an on-demand dissolvable wound dressing.

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.

Chitosan-based hydrogels: Influence of crosslinking strategy on rheological properties

The effect of two crosslink strategies on the preparation of chitosan-based covalent hydrogels was investigated employing the widely used thiol-ene reaction. This versatile “click” chemistry can be activated either photochemically or thermochemically. Initially, well-purified chitosan (CS, DA ∼4 %, Mw ∼580 kg mol−1) was separately functionalized with vinyl (CS-ene) or thiol (CS-SH) groups in aqueous media. Subsequently, two strategies were compared where thiol-ene reaction occurs respectively between: (S1) modified chitosans CS-ene and CS-SH, in a polymer – polymer strategy, and (S2) CS-ene and di(ethylene glycol) dithiol (dEG-(SH)2), in a polymer – molecule strategy.Both crosslinking strategies were evaluated through rheological measurements, starting with entangled chitosan solutions. The difference in diffusion of functional groups, whether attached to polymer chains or to free molecules, leads to faster gelation kinetics with S2. Consequently, stronger gels were obtained with S2, where the modulus was connected with the degree of functionalization, while S1 produced weaker gels closer to the percolation point, where crosslinked density was associated with the entanglement number derived from the initial concentration. Nevertheless, networks formed by both strategies were homogenous with minimal dissipative contributions to their rheological properties, indicating that structural defects are negligible.

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.

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.

One Stone Three Birds: Silver Sulfadiazine Modulates the Stability and Dynamics of Hydrogels for Infected Wound Healing.

Dynamic covalent bond hydrogels have demonstrated significant application potential in biomedical fields for their dynamic reversibility. However, the contradiction between the stability and dynamics of the hydrogel restricts its application. Here, utilizing silver sulfadiazine (AgSD) as a catalyst, hyaluronic acid-based hydrogels are constructed through imine bond crosslinking and incorporated disulfide bonds within the same crosslinking chain. It is found that AgSD can accelerate the formation of imine crosslinking bonds to improve the stability of hydrogels, thereby shortening the gelation time by ≈36.9 times, enhancing compression strength and adhesion strength by ≈2.4 times and 1.7 times, respectively, while inhibiting swelling and degradation rates to ≈2.1 times and 3.7 times. Besides, AgSD can coordinate with disulfide bonds to enhance the dynamics of hydrogel, enhancing the hydrogel self-healing efficiency by ≈2.3 times while reducing the relaxation time by ≈25.1 times. Significantly, AgSD imparts remarkable antibacterial properties to the hydrogel, thereby effectively facilitating the healing of bacterial infected wounds. Consequently, introducing AgSD enables hydrogels to possess concurrent stability, dynamics, and antibacterial properties. This strategy of regulating hydrogels by introducing AgSD provides a valuable reference for the application of dynamic covalent bonds.

Microinterfaces in biopolymer-based bicontinuous hydrogels guide rapid 3D cell migration

Cell migration is critical for tissue development and regeneration but requires extracellular environments that are conducive to motion. Cells may actively generate migratory routes in vivo by degrading or remodeling their environments or instead utilize existing extracellular matrix microstructures or microtracks as innate pathways for migration. While hydrogels in general are valuable tools for probing the extracellular regulators of 3-dimensional migration, few recapitulate these natural migration paths. Here, we develop a biopolymer-based bicontinuous hydrogel system that comprises a covalent hydrogel of enzymatically crosslinked gelatin and a physical hydrogel of guest and host moieties bonded to hyaluronic acid. Bicontinuous hydrogels form through controlled solution immiscibility, and their continuous subdomains and high micro-interfacial surface area enable rapid 3D migration, particularly when compared to homogeneous hydrogels. Migratory behavior is mesenchymal in nature and regulated by biochemical and biophysical signals from the hydrogel, which is shown across various cell types and physiologically relevant contexts (e.g., cell spheroids, ex vivo tissues, in vivo tissues). Our findings introduce a design that leverages important local interfaces to guide rapid cell migration.

Dynamically bonded cellulose nanocrystal hydrogels: Structure, rheology and fire prevention performance

Flame retardant composite hydrogels offer many advantages over conventional flame retardants, such as high water-retention capacity, enhanced fire resistance, and mechanical tunability. Herein, we developed flame-retardant dynamic covalent hydrogels using wood-derived cellulose nanocrystals (CNCs) crosslinked with boronate ester bonds, addressing environmental and health issues associated with the presence of non-biodegradable synthetic polymer and/or inorganic nanoparticle components in the existing systems. Our rheological investigation shows a liquid-to-soft-solid transition of CNC dispersions with tunable network elasticity ranging between ≈ 0.2 kPa to 3.5 kPa and an immediate self-healing ability. Coating pine wood with these hydrogels delayed ignition by about 30 s compared to native wood, and achieved a remarkable limiting oxygen index of 64.5 %. Also, the increased borax content of the gels was found to decrease and delay the first peak of the heat release rate up to 40 s, causing an increase in the fire retardancy index by 277 %. We correlate the microstructure and rheological behavior with the fire prevention mechanisms for the rational design of sustainable fire-retardant materials, and the results showcased a circular use of plant-based dynamic gels to prevent wood fires, even after drying- a feature lacking in conventional hydrogels.

A Nanocomposite Dynamic Covalent Cross-Linked Hydrogel Loaded with Fusidic Acid for Treating Antibiotic-Resistant Infected Wounds.

Methicillin-resistant Staphylococcus aureus (MRSA) is associated with high levels of morbidity and is considered a difficult-to-treat infection, often requiring nonstandard treatment regimens and antibiotics. Since over 40% of the emerging antibiotic compounds have insufficient solubility that limits their bioavailability and thus efficacy through oral or intravenous administration, it is crucial that alternative drug delivery products be developed for wound care applications. Existing effective treatments for soft tissue MRSA infections, such as fusidic acid (FA), which is typically administered orally, could also benefit from alternative routes of administration to improve local efficacy and bioavailability while reducing the required therapeutic dose. Herein, we report an antimicrobial poly(oligoethylene glycol methacrylate) (POEGMA)-based composite hydrogel loaded with fusidic acid-encapsulating self-assembled polylactic acid-b-poly(oligo(ethylene glycol) methyl ether methacrylate) (PLA-POEGMA) nanoparticles for the treatment of MRSA-infected skin wounds. The inclusion of the self-assembled nanoparticles (380 nm diameter when loaded with fusidic acid) does not alter the favorable mechanical properties and stability of the hydrogel in the context of its use as a wound dressing, while fusidic acid (FA) can be released from the hydrogel over ∼10 h via a diffusion-controlled mechanism. The antimicrobial studies demonstrate a clear zone of inhibition in vitro and a 1-2 order of magnitude inhibition of bacterial growth in vivo in an MRSA-infected full-thickness excisional murine wound model even at very low antibiotic doses. Our approach thus can both circumvent challenges in the local delivery of hydrophobic antimicrobial compounds and directly deliver antimicrobials into the wound to effectively combat methicillin-resistant infections using a fraction of the drug dose required using other clinically relevant strategies.

Dynamic Exchange in 3D Cell Culture Hydrogels Based on Crosslinking of Cyclic Thiosulfinates

AbstractDynamic polymer materials are highly valued substrates for 3D cell culture due to their viscoelasticity, a time‐dependent mechanical property that can be tuned to resemble the energy dissipation of native tissues. Herein, we report the coupling of a cyclic thiosulfinate, mono‐S‐oxo‐4‐methyl asparagusic acid, to a 4‐arm PEG‐OH to prepare a disulfide‐based dynamic covalent hydrogel with the addition of 4‐arm PEG‐thiol. Ring opening of the cyclic thiosulfinate by nucleophilic substitution results in the rapid formation of a network showing a viscoelastic fluid‐like behaviour and relaxation rates modulated by thiol content through thiol‐disulfide exchange, whereas its viscoelastic behaviour upon application as a small molecule linear crosslinker is solid‐like. Further introduction of 4‐arm PEG‐vinylsulfone in the network yields a hydrogel with weeks‐long cell culture stability, permitting 3D culture of cell types that lack robust proliferation, such as human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs). These cells display native behaviours such as cell elongation and spontaneous beating as a function of the hydrogel's mechanical properties. We demonstrate that the mode of dynamic cyclic thiosulfinate crosslinker presentation within the network can result in different stress relaxation profiles, opening the door to model tissues with disparate mechanics in 3D cell culture.

Dynamic Exchange in 3D Cell Culture Hydrogels Based on Crosslinking of Cyclic Thiosulfinates.

Dynamic polymer materials are highly valued substrates for 3D cell culture due to their viscoelasticity, a time-dependent mechanical property that can be tuned to resemble the energy dissipation of native tissues. Herein, we report the coupling of a cyclic thiosulfinate, mono-S-oxo-4-methyl asparagusic acid, to a 4-arm PEG-OH to prepare a disulfide-based dynamic covalent hydrogel with the addition of 4-arm PEG-thiol. Ring opening of the cyclic thiosulfinate by nucleophilic substitution results in the rapid formation of a network showing a viscoelastic fluid-like behaviour and relaxation rates modulated by thiol content through thiol-disulfide exchange, whereas its viscoelastic behaviour upon application as a small molecule linear crosslinker is solid-like. Further introduction of 4-arm PEG-vinylsulfone in the network yields a hydrogel with weeks-long cell culture stability, permitting 3D culture of cell types that lack robust proliferation, such as human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). These cells display native behaviours such as cell elongation and spontaneous beating as a function of the hydrogel's mechanical properties. We demonstrate that the mode of dynamic cyclic thiosulfinate crosslinker presentation within the network can result in different stress relaxation profiles, opening the door to model tissues with disparate mechanics in 3D cell culture.