Cross-linked Double Network Hydrogels Research Articles

Injectable Dual Fenton/Enzymatically Cross-Linked Double-Network Hydrogels Based on Acrylic/Phenolic Polymers with Highly Reinforced and Tunable Mechanical Properties.

Injectable hydrogels have been extensively used as promising therapeutic scaffolds for a wide range of biomedical applications, such as tissue regeneration and drug delivery. However, their low fracture toughness and brittleness often limit their scope of application. Double-network (DN) hydrogel, which is composed of independently cross-linked rigid and ductile polymer networks, has been proposed as an alternative technique to compensate for the weak mechanical properties of hydrogels. Nevertheless, some challenges still remain, such as the complicated and time-consuming process for DN formation, and the difficulty in controlling the mechanical properties of DN hydrogels. In this study, we introduce a simple, rapid, and controllable method to prepare in situ cross-linkable injectable DN hydrogels composed of acrylamide (AAm) and 4-arm-PPO-PEO-tyramine (TTA) via dual Fenton- and enzyme-mediated reactions. By varying the concentration of Fenton's reagent, the DN hydrogels were rapidly formed with controllable gelation rate. Importantly, the DN hydrogels showed a 13-fold increase in compressive strength and a 14-fold increase in tensile strength, compared to the single network hydrogels. The mechanical properties, elasticity, and plasticity of DN hydrogels could also be modulated by simply varying the preparation conditions, including the cross-linking density and reagent concentrations. At low cross-linker concentration (<0.05 wt %), the plastic DN hydrogel stretched to over 6,500%, whereas high cross-linker concentration (≥0.05 wt %) induced fully elastic hydrogels, without hysteresis. Besides, DN hydrogels were endowed with rapid self-recovery and highly enhanced adhesion, which can be further applied to wearable devices. Moreover, human dermal fibroblasts treated with DN hydrogels retained viability, demonstrating the biocompatibility of the cross-linking system. Therefore, we expect that the dual Fenton-/enzyme-mediated cross-linkable DN hydrogels offer great potential as advanced biomaterials applied for hard tissue regeneration and replacement.

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.

Double Network Physical Crosslinked Hydrogel for Healing Skin Wounds: New Formulation Based on Polysaccharides and Zn2.

Developing convenient, efficient, and natural wound dressings remain the foremost strategy for treating skin wounds. Thus, we innovatively combined the semi-dissolved acidified sol-gel conversion method with the internal gelation method to fabricate SA (sodium alginate)/CS (chitosan)/Zn2+ physically cross-linked double network hydrogel and named it SA/CS/Zn2+ PDH. The characterization results demonstrated that increased Zn2+ content led to hydrogels with improved physical and chemical properties, such as rheology, water retention, and swelling capacity. Moreover, the hydrogels exhibited favorable antibacterial properties and biocompatibility. Notably, the establishment of an in vitro pro-healing wound model further confirmed that the hydrogel had a superior ability to repair wounds and promote skin regeneration. In future, as a natural biomaterial with antimicrobial properties, it has the potential to promote wound healing.

Tannic acid-based dual-network homogeneous hydrogel with antimicrobial and pro-healing properties for infected wound healing

The clinical treatment of infected skin injuries caused by exogenous bacteria faces great challenges. Conventional therapeutic approaches are difficult to achieve synergistic effects of infection control and induction of skin regeneration. In this study, a novel tannic acid-based physically cross-linked double network hydrogel (PDH gel) was prepared on demand by covalent cross-linking of tannic acid (TA) with polyvinyl alcohol (PVA) and chelating ligand of TA with Fe3+. The homogeneity of the hydrogel was achieved by the action of glycol dispersant. With the anti-inflammatory and antioxidant properties of Fe3+ and TA, this hydrogel exhibited excellent antibacterial properties by achieving 99.69% and 99.36% bacterial inhibition against E.coli and S. aureus, respectively. Moreover, the PDH gel exhibits good biocompatibility, stretchability (up to 200%) and skin-friendliness. After 14 days of PDH-1 gel implantation in a rat model infected by S. aureus, the wound healing rate was as high as 95.21%. PDH gel-1 showed more granulation tissue, more pronounced blood vessels, higher collagen fiber density and good collagen deposition, and its recovery effect was better than that of PSH gel and PDH gel-2 in vivo. Hence, this study provides a novel avenue for the design of future clinical infected wound healing dressings.

A physically cross-linked double network polysaccharides/Ca2+ hydrogel scaffold for skeletal muscle tissue engineering

The current therapy for muscle injury is facing challenges in tissue self-regeneration and function restoration, which declines steeply with age. Tissue engineering is a promising strategy for treating skeletal muscular disorders. Natural polysaccharides have great potential to support cell growth and attachment as tissue-engineered scaffolds. A three-dimensional (3D) porous hydrogel scaffold has been prepared based on the double network of natural polysaccharide sodium alginate (SA), chitosan (CS) and Ca2+ ions through the freeze-drying process. The physical, mechanical, and biological properties of the CS/SA/Ca2+ hydrogel scaffold can be controlled by adjusting the SA/CS ratio. The physically cross-linked double network hydrogel showed good biosafety, high stability and satisfactory degradation rate. When the CS/SA molar ratio was 1:1.2 (H-1.2 group), the pore size and compression modulus of the double network hydrogel were 104.06 ± 2.64 µm and 40.00 ± 2.52 kPa, respectively. The results of in vitro evaluation showed that the 3D structure of the CS/SA/Ca2+ double network hydrogel could well support adhesion and proliferation of C2C12 murine myoblasts and porcine skeletal muscle stem cells. The best cell growth effect was achieved in the H-1.2 group. The physically cross-linked CS/SA/Ca2+ double network hydrogel can be a promising printable material as the cell scaffold in applications of skeletal muscle tissue engineering.

Simultaneously stimulated osteogenesis and anti-bacteria of physically cross-linked double-network hydrogel loaded with MgO-Ag2O nanocomposites

Hydrogels, with a three-dimensional network of water-soluble polymer and water, could simulate the critical properties of extracellular matrix, which has been widely used in bone tissue engineering. However, most of conventional hydrogels for bone regeneration are fragile and have poor osteogenic activity, which restricts their applications. In this work, a novel nanoparticle-hydrogel composite consisting of physically cross-linked double-network loaded with MgO-Ag2O nanocomposites was developed by the sol-gel method. The Mg2+ released from MgO-Ag2O nanocomposites was used as an ionic cross-linking site of sodium alginate (SA), while the hydrophobic micelles in the polyacrylamide (PAAM) network is acted as another crosslinking point. The results indicated that the novel nanoparticle-hydrogel composites had good self-recovery ability and excellent mechanical properties compared with the conventional sodium alginate (SA)/polyacrylamide (PAAM) hydrogels. Additionally, it showed a slow release of Mg and Ag ions due to the dual function of the embedding effect of hydrogels and the increasing pH of the solution induced by the hydrolysis of sodium alginate. In terms of in vitro tests, the nanoparticle-hydrogel composites showed significantly stimulatory effects on the proliferation and differentiation of SaOS-2 cells. In addition, the antibacterial effects of the nanoparticle-hydrogel composites were gradually enhanced with the increase of MgO-Ag2O content.

Physically cross-linked gellan gum/hydrophobically associated polyacrylamide double network hydrogel for cartilage repair

Biopolymer hydrogels have attracted much attention as scaffolds for tissue engineering owing to the unique physical features analogous to native extracellular matrices. However, the poor mechanical property and fast degradation greatly limit their application in cartilage repair. Herein, a robust physically cross-linked gellan gum/hydrophobically associated polyacrylamide double network hydrogel is developed. Benefitting from the synergistic energy dissipation mechanism, the resultant hydrogel exhibits outstanding mechanical properties, which is comparable with native cartilage. Moreover, the physically cross-linked double network hydrogel displays excellent anti-fatigue, wear resistant, self-healing, and stability in the physiological environment. Owing to the feature of natural biopolymer and the absence of toxic chemical cross-linking agents, the double network hydrogel demonstrates excellent biocompatibility and can promote the adhesion and proliferation of chondrocytes. Based on the comparable mechanical performance and excellent biocompatibility, the hydrogel is explored as cartilage substitute for the repair of damaged cartilage. The in vivo evaluation in a cartilage defect rabbit model indicates that the hydrogel can serve as a growth-factor-free scaffold to promote the repair of cartilage defect. This study shows the potential of a robust biopolymer hydrogel for cartilage regeneration.

Strong, tough, anti-freezing, non-drying and sensitive ionic sensor based on fully physical cross-linked double network hydrogel

Ionic conductive double network (DN) sensors have attracted increasing attention in wearable electronic devices. However, their low mechanical and sensing properties as well as poor moisture retention and freezing resistance restrict severely their applications. Herein, we synthesized a fully physical cross-linked poly (N-hydroxymethyl acrylamide)/agar/ethylene glycol (PHA/Agar/EG) ionic conductive DN hydrogel exhibiting high strength and toughness, fast self-recovery, good fatigue resistance and good self-healing. Agar could form a physical network via reversible sol-gel transition, and interact with physical cross-linked poly (N-hydroxymethyl acrylamide) and sodium chloride (NaCl) via hydrogen bonds and salting-out effect, respectively. Meanwhile, ethylene glycol and NaCl improved the mechanical properties, long-lasting moisture retention and anti-freezing ability. The PHA/Agar/EG gel-based flexible sensor possessed excellent long-lasting and fatigue resistant sensing properties, and could monitor various human activities stably and sensitively. Therefore, this work would provide a simple and promising strategy to fabricate flexible sensors with integrated high performances for smart wearable devices.

Force-mediated molecule release from double network hydrogels.

The incorporation of mechanosensitive linkages into polymers has led to materials with dynamic force responsivity. Here we report oxanorbornadiene cross-linked double network hydrogels that release molecules through a force-mediated retro Diels-Alder reaction. The molecular design and tough double network of polyacrylamide and alginate promote significantly higher activation at substantially less force than pure polymer systems. Activation at physiologically relevant forces provides scope for instilling dynamic mechanochemical behavior in soft biological materials.

Highly Sensitive Pressure and Strain Sensors Based on Stretchable and Recoverable Ion-Conductive Physically Cross-Linked Double-Network Hydrogels.

Ion-conductive hydrogel sensors have attracted great research interests for applications in wearable devices, electronic skins, and implantable sensors, but most such sensors are fragile, with low conductivity and sensitivity. This study reports on novel ion-conductive double network hydrogels with a cross-linked helical structure, hydrophobic association, and metal-ion coordination. The helical κ-carrageenan first network and the second network cross-linked by Pluronic F127 diacrylate micelles and tridentate Fe3+-COO- coordination work synergistically to show the tensile strength of 2.7 MPa, fracture strain of 1400%, and tensile toughness of 9.82 MJ m-3 and fatigue resistance against cyclic loadings with high strains. The hydrogels show an ion conductivity of 1.15 S m-1, a strain sensitivity of up to 2.8, and a pressure sensitivity of 0.33 kPa-1. Sensor arrays fabricated from the conductive hydrogels provide an in-plane detection of pressures less than 200 Pa. Such hydrogel sensors have potential applications to electron skins and implantable sensors.

Fully physically cross-linked double network hydrogels with strong mechanical properties, good recovery and self-healing properties.

Combining a hydrophobic interaction crosslinked curdlan as the first network and hydrophobic interaction crosslinked polyacrylamide as the second network, we have fabricated a curdlan/HPAAm double network (DN) hydrogel using a one-pot method. The resulting DN hydrogel exhibited good mechanical properties, i.e. an elastic modulus of 103 kPa, a tensile fracture strength of 0.81 MPa, a tensile stretch of 25.3 and a compressive stress of 62.5 MPa when the compressive strain increased up to 99%. The DN gel could withstand ten compression tests under 90% compressive strain without observable damage. The DN gel demonstrated 84% stiffness recovery and 97% toughness recovery after the deformed samples were relaxed and stored at 95 °C for 4 h. The stiffness and fracture stress of the DN gel were enhanced after sterilization treatment at 120 °C. Furthermore, the gels exhibited 52% self-healing of fracture stretch after the samples were cut and brought into contact at 95 °C for 4 h. The self-recovery and self-healing properties of the DN gel both originated from the first curdlan network via the reformation of hydrophobic interactions and the second HPAAm network via reformation of the broken hydrophobic associations.

Physically Cross-Linked Double-Network Hydrogel for High-Performance Oil–Water Separation Mesh

Hydrogel-based porous materials have attracted significant attention in the field of oil–water separation due to their oil–water selectivity and low oil adhesion. However, most of the hydrogel-base...

Dual Ionically Cross-linked Double-Network Hydrogels with High Strength, Toughness, Swelling Resistance, and Improved 3D Printing Processability.

We report a dual ionic cross-linking approach for the preparation of double-network hydrogels with robustness, high strength, and toughness, sodium alginate/poly(acrylamide- co-acrylic acid)/Fe3+ (SA/P(AAm- co-AAc)/Fe3+), in a facile "one-step" dual ionic cross-linking method. We take advantage of the abundant carboxyl groups on alginate molecules and the copolymer chains and their high coordination capacity with multivalent metal ions to obtain hydrogels with high strength and toughness. The optimal SA/P(AAm- co-AAc)/Fe3+ (SA 2 wt % and AAc 5 mol %) hydrogels showed a remarkable mechanical performance with 3.24 MPa tensile strength and 1228% strain, both of which remained stable with 76% water content and were highly swellingresistant in an aqueous environment. The hydrogels possessed high fatigue resistance, self-recovery, pH-triggered healingcapability, shape memory, and reversible gel-sol transition facilitated by pH regulation. Moreover, they show three-dimensional (3D) printing processability by properly adjusting the solution viscosity. The approach may provide a convenient way of obtaining hydrogels having high strength and toughness with a number of desirable properties for a broad range of biomedical applications.

Robust and flexible strain sensors based on dual physically cross-linked double network hydrogels for monitoring human-motion

Soft, stretchable, and elastic hydrogels have recently attracted immense interest due to their potential applications in wearable strain sensors. However, most of hydrogel-based sensors exhibit poor mechanical properties. Here, a robust, flexible and strain-sensitive conductive wearable sensor is prepared based on dual physically cross-linked double network hydrogels consisting of core-shell hybrid nanoparticles cross-linked polyacrylamide as first network and Ca2+ cross-linked alginate as second network. Dynamic physical cross-linking as sacrifice bonds can effectively dissipate energy and reconstruct the network structure, endowing hydrogels with high strength, toughness, stretchability and excellent self-recovery properties. Moreover, the hydrogels exhibit outstanding strain sensitive behavior with repeatable, stable, and precise changes in resistance signals. Based on the excellent strain sensitivity, the hydrogel can be assembled as a wearable strain sensor to monitor joint motions such as finger, wrist, elbow, neck, and knee joints, and even the slight motions including breathing and speaking. Thus, the tough, anti-fatigue, self-recovery and conductive hydrogels have promising potential as soft, high-performance and flexible wearable strain sensor for soft robots, biomimetic prostheses, human activity monitoring and health-monitoring systems.

(Invited) Double Network Hydrogel of Poly(2-hydroxyethyl methacrylate) and Alginate Embedded Hydroxyapatite

A facile one-pot method was developed to the preparation of a bone regenerating material which was fabricated by photo-polymerizing 2-hydroxyethyl methacrylate under the addition of cross-linker and initiator in the aqueous mixed dispersion of hydroxyapatite (HAp) and alginic acid. The hydration ratios (hydrated water per dried composite) of the as-prepared HAp-embedded cross-linked double network hydrogels were varied depending on the ratios of alginic acid to water, poly(2-hydroxyethyl methacrylate) to cross-linker, and HAp to alginic acid. Thus, the hydration ratio reached to maximum of 275%.

Dual ionic cross-linked double network hydrogel with self-healing, conductive, and force sensitive properties

Conventional chemically cross-linked double network hydrogels (DN hydrogels) are considered as one of the toughest soft materials. However, they lack self-healing properties due to their non-reversible covalent bonds. In this work, we propose a new design strategy to synthesize a dual ionic cross-linked polyethylene glycol (PEG)/poly(acrylamide-co-acrylic acid) (PAMAA) DN hydrogels, consisting of an ionic cross-linked linear chain extension of PEG and a PAMAA-Fe3+ as the first and second physical networks, respectively. Due to the reversible non-covalent bonds in both networks (Fe3+ coordination interactions and hydrogen bonds), the DN hydrogels can achieve high mechanical properties (σf of ∼0.36 MPa and strain of ∼1350%) and complete self-healing ability within 12 h. Moreover, due to the free ions diffusion in the water medium of the DN hydrogels, the as-prepared hydrogels also exhibited electrical conductivity and stretch sensitivity. Our results offer a new design strategy to improve the strength and self-healing ability of DN hydrogels by introducing a dual ionic cross-linking within the network, which we hope will provide an alternative focus for the design of tough and self-healing hydrogels with desirable properties.

A physically cross-linked self-healable double-network polymer hydrogel as a framework for nanomaterial

Physically cross-linked double-network hydrogels with different first networks act as a framework for graphene.

Bioinspired fully physically cross-linked double network hydrogels with a robust, tough and self-healing structure

The conventional covalently cross-linked double network (DN) hydrogels with high stiffness often show low toughness and self-healing property due to the irreversible bond breakages in their networks. Therefore, scarcity of hydrogels that possess simultaneous features of stiffness, toughness, and autonomous self-healing properties at the same time remains a great challenge and seriously limits their biomedical applications. While, many natural materials acquire these features from their dynamic sacrificial bonds. Inspired by biomaterials, herein we propose a novel strategy to design stiff, tough and self-healing DN gels by substitution of both covalently cross-linked networks with strong, dynamic hydrogen bond cross-linked networks. The prepared fully physically cross-linked DN gels composed of strong agar biopolymer gel as the first network and tough polyvinyl alcohol (PVA) biopolymer gel as the second network. The DN gels demonstrated multiple-energy dissipating mechanisms with a high modulus up to 2200kPa, toughness up to 2111kJm−3, and ability to self-heal quickly and autonomously with regaining 67% of original strength only after 10min. The developed DN gels will open a new avenue to hydrogel research and holds high potential for diverse biomedical applications, such as scaffold, cartilage, tendon and muscle.

Dual Physically Cross-Linked Double Network Hydrogels with High Mechanical Strength, Fatigue Resistance, Notch-Insensitivity, and Self-Healing Properties.

Double-network (DN) hydrogels with high strength and toughness have been developed as promising materials. Herein, we explored a dual physically cross-linked polyacrylamide/xanthan gum (PAM/XG) DN hydrogel. The nonchemically cross-linked PAM/XG DN hydrogels exhibited fracture stresses as high as 3.64 MPa (13 times higher than the pure PAM single network hydrogel) and compressive stresses at 99% strain of more than 50 MPa. The hydrogels could restore their original shapes after continuously loading-unloading tensile and compressive cyclic tests. In addition, the PAM/XG DN hydrogels demonstrated excellent fatigue resistance, notch-insensitivity, high stability in different harsh environments, and remarkable self-healing properties, which might result from their distinctive physical-cross-linking structures. The attenuated total reflectance infrared spectroscopy (ATR-IR) and dynamic thermogravimetric analysis (TGA) results indicated that there were no chemical bonds (only hydrogen bonds) between the XG and PAM networks. The PAM/XG DN hydrogel synthesis offers a new avenue for the design and construction of DN systems, broadening current research and applications of hydrogels with excellent mechanical properties.