Double Cross-linked Hydrogels Research Articles

Bionic double-crosslinked hydrogel of poly (γ-glutamic acid)/poly (N-(2-hydroxyethyl) acrylamide) with ultrafast gelling process and ultrahigh burst pressure for emergency rescue

Injectable adhesive hydrogels combining rapid gelling with robust adhesion to wet tissues are highly required for fast hemostasis in surgical and major trauma scenarios. Inspired by the cross-linking mechanism of mussel adhesion proteins, we developed a bionic double-crosslinked (BDC) hydrogel of poly (γ-glutamic acid) (PGA)/poly (N-(2-hydroxyethyl) acrylamide) (PHEA) fabricated through a combination of photo-initiated radical polymerization and hydrogen bonding cross-linking. The BDC hydrogel exhibited an ultrafast gelling process within 1 s. Its maximum adhesion strength to wet porcine skin reached 254.5 kPa (9 times higher than that of cyanoacrylate (CA) glue) and could withstand an ultrahigh burst pressure of 626.4 mmHg (24 times higher than that of CA glue). Notably, the BDC hydrogel could stop bleeding within 10 s from a rat liver incision 10 mm long and 5 mm deep. The wound treated with the BDC hydrogel healed faster than the control groups, underlining the potential for emergency rescue and wound care scenarios.

Strong and tough conductive hydrogels via an amphiphilic macromolecular crosslinker for flexible strain sensor

The strength and toughness of hydrogel are usually achieved through the synergy of chemical cross-linking and physical cross-linking from multi-component contributions. However, there are few reports on hydrogels that rely on a single component to obtain two cross-linked structures. Herein, we successfully synthesized an amphiphilic macromolecular crosslinker (polyoxyethylene 20 oleyl ether acrylate (O20AC)), and introduced it into a system composed of acrylamide (AAm), sodium chloride (NaCl) and water to prepare the P(AAm-O20AC)/NaCl hydrogel with high strength, outstanding toughness, and excellent good conductivity. Notably, the O20AC possess both crosslinker properties, which not only provide hydrogels with a stable chemical cross-linking network, but also its long hydrophobic chain act as physical crosslinking points to give the hydrogel a new pathway of energy dissipation.Depending on the O20AC crosslinker, the P(AAm-O20AC)/NaCl hydrogels exhibit good strength (tensile stress 714.46 kPa), toughness (elongation at break 3005 %), and fatigue resistance (overlap of hysteresis curves in repeated loading–unloading cycles). Besides, the existence of sodium ions and chloride ions also provides the hydrogel with highly sensitive deformation-dependent conductivity (GF is 5.8 in the 400 %-500 % strain range). Collectively, the strategy of preparing chemical and physical double-crosslinked hydrogels by amphiphilic O20AC will provide a bran-new insights for the development of hydrogel sensing materials.

High-strength double-network silk fibroin based hydrogel loaded with Icariin and BMSCs to inhibit osteoclasts and promote osteogenic differentiation to enhance bone repair

Large bone defects cause significant clinical challenges due to the lack of optimal grafts for effective regeneration. The tissue engineering way that requires the combination of biomaterials scaffold, stem cells and proper bioactive factors is a prospective method for large bone repair. Here, we synthesized a three-arm host-guest supramolecule (HGSM) to covalently crosslinking with the naturally derived polymer methacrylated silk fibroin (SFMA). The combination of HGSM and SFMA can form a high strength double-crosslinked hydrogel HGSFMA, that serve as the hydrogel scaffold for bone marrow mesenchymal stem cells (BMSCs) growing. Icariin (ICA) loaded in the HGSFMA hydrogel can promote the osteogenesis efficiency of BMSCs and inhibit the osteoclasts differentiation. Our findings demonstrated that the HGSFMA/ICA hydrogel effectively promoted the in vitro adhesion, proliferation, and osteogenic differentiation of BMSCs. Rat femoral defects model show that this hydrogel can completely repair femoral damage within 4 weeks and significantly promote the secretion of osteogenesis-related proteins. In summary, we have prepared an effective biomimetic bone carrier, offering a novel strategy for bone regeneration and the treatment of large-scale bone defects.

Double cross-linked graphene oxide hydrogel for promoting healing of diabetic ulcers.

This study explores the synthesis and characterization of a novel double cross-linked hydrogel composed of polyvinyl alcohol (PVA), sodium alginate (SA), graphene oxide (GO), and glutathione (GSH), henceforth referred to as PVA/SA/GO/GSH. This innovative hydrogel system incorporates two distinct types of cross-linking networks and is meticulously engineered to exhibit sensitivity to high glucose and/or reactive oxygen species (ROS) environments. A sequential approach was adopted in the hydrogel formation. The initial phase involved the absorption of GSH onto GO, which was subsequently functionalized with boric acid and polyethylene glycol derivatives via a bio-orthogonal click reaction. This stage constituted the formation of the first chemically cross-linked network. Subsequently, freeze-thaw cycles were utilized to induce a secondary cross-linking process involving PVA and SA, thereby forming the second physically cross-linked network. The resultant PVA/SA/GO/GSH hydrogel retained the advantageous hydrogel properties such as superior water retention capacity and elasticity, and additionally exhibited the ability to responsively release GSH under changes in glucose concentration and/or ROS levels. This feature finds particular relevance in the therapeutic management of diabetic ulcers. Preliminary in vitro evaluation affirmed the hydrogel's biocompatibility and its potential to promote cell migration, inhibit apoptosis, and exhibit antibacterial properties. Further in vivo studies demonstrated that the PVA/SA/GO/GSH hydrogel could facilitate the healing of diabetic ulcer sites by mitigating oxidative stress and regulating glucose levels. Thus, the developed PVA/SA/GO/GSH hydrogel emerges as a promising candidate for diabetic ulcer treatment, owing to its specific bio-responsive traits and therapeutic efficacy.

Regenerated silk fibroin coating stable liquid metal nanoparticles enhance photothermal antimicrobial activity of hydrogel for wound infection repair

The integration of liquid metal (LM) and regenerated silk fibroin (RSF) hydrogel holds great potential for achieving effective antibacterial wound treatment through the LM photothermal effect. However, the challenge of LM's uncontrollable shape-deformability hinders its stable application. To address this, we propose a straightforward and environmentally-friendly ice-bath ultrasonic treatment method to fabricate stable RSF-coated eutectic gallium indium (EGaIn) nanoparticles (RSF@EGaIn NPs). Additionally, a double-crosslinked hydrogel (RSF-P-EGaIn) is prepared by incorporating poly N-isopropyl acrylamide (PNIPAAm) and RSF@EGaIn NPs, leading to improved mechanical properties and temperature sensitivity. Our findings reveal that RSF@EGaIn NPs exhibit excellent stability, and the use of near-infrared (NIR) irradiation enhances the antibacterial behavior of RSF-P-EGaIn hydrogel in vivo. In fact, in vivo testing demonstrates that wounds treated with RSF-P-EGaIn hydrogel under NIR irradiation completely healed within 14 days post-trauma infection, with the formation of new skin and hair. Histological examination further indicates that RSF-P-EGaIn hydrogel promoted epithelialization and well-organized collagen deposition in the dermis. These promising results lay a solid foundation for the future development of drug release systems based on photothermal-responsive hydrogels utilizing RSF-P-EGaIn.

Study of Injectable Hydrogel Based on ALN/nHA Promoting Osteogenesis and Inhibiting Osteoclasts in Osteoporotic Bone Defects Repair.

Osteoporotic bone defects cannot withstand surgery with more significant trauma due to bone fragility, while systemic drug therapy has formidable adverse effects. Consequently, the present study introduces an innovatively devised injectable double-crosslinked hydrogel, as a potential therapeutic avenue for addressing varied shapes of osteoporotic bone defects via a minimally invasive approach. The injectable hydrogel is formed by the formation of Schiff base bonds between oxidized sodium alginate (OSA) and carboxymethyl chitosan, and the polymerization of gelatin methacrylate by UV light crosslinking. Additionally, alendronate sodium (ALN) is loaded into the hydrogel through Schiff base formation with OSA, and nanohydroxyapatite (nHA) is incorporated into the hydrogel via blending. The hydrogel demonstrates excellent injectability, and the nHA improves the mechanical properties of hydrogel and can promote bone formation. In addition, the hydrogel can sustain the release of ALN, which has the effect of inhibiting osteoclasts. Cell studies indicate that the hydrogel can promote the differentiation of osteoblasts and inhibit the activity of osteoclast, so as to obtain better osteogenic effect. Therefore, the injectable hydrogel can be used to repair osteoporotic bone defects through a minimally invasive, simple treatment modality.

Double Cross-Linked Hydrogel Dressings Based on Triblock Copolymers Bearing Antifreezing, Antidrying, and Inherent Antibacterial Properties.

Bacterial infections typically invade the living tissue of wounds, thereby aggravating the inflammatory response, delaying wound healing, or causing further complications. In this paper, the antibacterial hydrogel (PNVBA) with antifreezing and antidrying properties was prepared by a two-step method using N-isopropylacrylamide (NIPAM), 1-butyl-3-vinylimidazolium bromide (VBIMBr), and 3-acrylamidophenylboronic acid (AAPBA). PNVBA hydrogels exhibited a high adsorption capacity of 280 mg·g-1 for bovine serum albumin (BSA) and can adhere to the surface of different materials through ion-dipole or hydrogen-bonding interactions. Meanwhile, the PNVBA hydrogels exhibited high viscoelasticity and good adhesion after freezing at -20 °C or heating at 70 °C for 24 h with a sterilizing rate of up to 98% against multidrug-resistant (MDR) Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). Moreover, a survival rate of up to 90% after incubation with L929 cells over 24 h was observed. Therefore, this inherent antibacterial hydrogel can be used as an excellent alternative material for wound dressings.

A double-crosslinked nanocellulose-reinforced dexamethasone-loaded collagen hydrogel for corneal application and sustained anti-inflammatory activity

In cases of blinding disease or trauma, hydrogels have been proposed as scaffolds for corneal regeneration and vehicles for ocular drug delivery. Restoration of corneal transparency, augmenting a thin cornea and postoperative drug delivery are particularly challenging in resource-limited regions where drug availability and patient compliance may be suboptimal. Here, we report a bioengineered hydrogel based on porcine skin collagen as an alternative to human donor corneal tissue for applications where long-term stability of the hydrogel is required. The hydrogel is reinforced with cellulose nanofibers extracted from the Ciona intestinalis sea invertebrate followed by double chemical and photochemical crosslinking. The hydrogel is additionally loaded with dexamethasone to provide sustained anti-inflammatory activity. The reinforced double-crosslinked hydrogel after drug loading maintained high optical transparency with significantly improved mechanical characteristics compared to non-reinforced hydrogels, while supporting a gradual sustained drug release for 60 days in vitro. Dexamethasone, after exposure to crosslinking and sterilization procedures used in hydrogel production, inhibited tube formation and cell migration of TNFα-stimulated vascular endothelial cells. The drug-loaded hydrogels suppressed key pro-inflammatory cytokines CCL2 and CXCL5 in TNFα-stimulated human corneal epithelial cells. Eight weeks after intra-stromal implantation in the cornea of 12 New-Zealand white rabbits subjected to an inflammatory suture stimulus, the dexamethasone-releasing hydrogels suppressed TNFα, MMP-9, and leukocyte and fibroblast cell invasion, resulting in reduced corneal haze, sustained corneal thickness and stromal morphology, and reduced overall vessel invasion. This collagen-nanocellulose double-crosslinked hydrogel can be implanted to treat corneal stromal disease while suppressing inflammation and maintaining transparency after corneal transplantation. Statement of significanceTo treat blinding diseases, hydrogel scaffolds have been proposed to facilitate corneal restoration and ocular drug delivery. Here, we improve on a clinically tested collagen-based scaffold to improve mechanical robustness and enzymatic resistance by incorporating sustainably sourced nanocellulose and dual chemical-photochemical crosslinking to reinforce the scaffold, while simultaneously achieving sustained release of an incorporated anti-inflammatory drug, dexamethasone. Evaluated in the context of a corneal disease model with inflammation, the drug-releasing nanocellulose-reinforced collagen scaffold maintained the cornea's transparency and resisted degradation while suppressing inflammation postoperatively. This biomaterial could therefore potentially be applied in a wider range of sight-threatening diseases, overcoming suboptimal administration of postoperative medications to maintain hydrogel integrity and good vision.

A double cross-linked hydrogel based on water-soluble chitosan and oxidized hyaluronic acid as an antibacterial dressing

Quaternary ammonium chitosan (QCS) is a cationic polymer with high antimicrobial properties, but its cations can cause damage to normal cells. Thus, the biocompatibility of QCS in hydrogel dressings should be concerned. In this study, QCS was used as an additive in the preparation of the carboxymethyl chitosan (CMC) and oxidized hyaluronic acid (OHA) hydrogel, and the effect of its content in the hydrogel on antibacterial and biocompatibility was systematically investigated. First, QCS was mixed at a different ratio with CMC to form a QCS/CMC solution. Then, the QCS/CMC solution was added into the OHA solution to obtain the OHA-CMC/QCS hydrogel, which is a double cross-linked network formed by the Schiff base and electrostatic interaction. With the increase of the QCS content in the hydrogel, its mechanical and antibacterial properties were enhanced. The antibacterial rate of OHA-CMC/QCS5 hydrogel with 5% QCS content against Staphylococcus aureus reached 99.80%, and it also showed biocompatibility under the experimental conditions. This work provides a theoretical basis for the use of QCS to prepare the hydrogels that are both antibacterial and biocompatible. The prepared OHA-CMC/QCS5 hydrogel is an ideal candidate for antimicrobial dressings.

Stripping Superficial polystyrene sulfonate on PEDOT:PSS via dodecyl benzenesulfonic acid for high-performance double-crosslinked hydrogel in flexible supercapacitor

For Poly(3,4-ethylenedioxythiophene): polystyrene sulfonate (PEDOT:PSS), peeling off the PSS on its surface is a crucial step in improving its morphology and conductivity. Herein, a PVA-PP double-crosslinked hydrogel is developed using a chemical crosslinking method in situ based on PVA matrix. By utilizing dodecyl benzenesulfonic acid (DBSA), the PSS on the surface of PEDOT:PSS is partially peeled off and a distributed porous structure of PVA-PP-DBSA hydrogels is formed. The mechanical properties are greatly improved, with the tensile properties increasing from 90% to 580%. Additionally, the potential window is expanded from 0.8 V to 1.5 V. Furthermore, due to the formation of the pore structure and improved conductivity, a specific capacitance of up to 412 F g−1 (energy density of 131.4 Wh kg−1 and a power density of 1200 W kg−1) is achieved, demonstrating its excellent performance as a flexible and wearable power supply in the future.

Fabrication of triple-crosslinked gelatin/alginate hydrogels for controlled release applications

Hydrogels have been demonstrated as smart drug carriers to recognize the tumor microenvironment for cancer treatment, where the dynamic crosslinks in the hydrogel network contribute to the stimuli-responsive features but also result in poor stability and weak mechanical property of the hydrogels. Here, phenylboronic acid-grafted polyethyleneimine (PBA-PEI)-modified gelatin (PPG) was synthesized to crosslink alginate dialdehyde (ADA) through imine bonds and boronate ester bonds, and then calcium ions (Ca2+) were added to introduce the third calcium-carboxylate crosslinking in the network to form the triple-crosslinked PPG/ADA-Ca2+ hydrogels. Given the three types of dynamic bonds in the network, PPG/ADA-Ca2+ hydrogels possessed a self-healing manner, stimuli-responsiveness, and better mechanical properties compared to single- or double-crosslinked hydrogels. The controlled release capability of PPG/ADA-Ca2+ hydrogels was also demonstrated, showing the encapsulated molecules can be rapidly released from the hydrogel network in the presence of hydrogen peroxide while the release rate can be slowed down at acidic pH. Furthermore, PPG/ADA-Ca2+ hydrogels presented selected cytotoxicity and drug delivery to cancer cells due to the regulated degradation by the cellular microenvironment. Taken together, PPG/ADA-Ca2+ hydrogels have been demonstrated as promising biomaterials with multiple desirable properties and dynamic features to perform controlled molecule release for biomedical applications.

Facile synthesis of double-cross-linked alginate-based hydrogel: Characterization and use in a context of circular economy for cationic dye removal.

Hydrogels based on natural polysaccharides have received special attention in the last decade due to their interesting features, such as availability, biocompatibility, biodegradability and safety. Such characteristics may make them sustainable and eco-friendly materials for water and wastewater treatment, meeting the concept of circular economy. In this study, a novel double-cross-linked alginate-based hydrogel has been successfully synthesized using epichlorhydrin and sodium trimetaphosphate (STMP) as cross-linker agents and then used for the removal of methylene blue (MB) dye under different operating conditions. The obtained hydrogel was deeply characterized by using various analytical techniques, namely Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy and differential scanning calorimetry. Experimental results showed that the synthesized double cross-linked hydrogel with relatively high STMP concentration (0.26 M) has promising structural and textural properties. This material exhibited excellent removal ability towards MB with a maximum adsorption capacity of about 992 mg/g for an initial pH of 10. The kinetic and isotherm modeling study revealed that the pseudo-second-order and Freundlich models fitted well the measured adsorption experimental data. The MB adsorption process onto the synthesized hydrogel is exothermic, feasible and spontaneous. It mainly includes electrostatic interaction and hydrogen bonds. These findings suggest that double-cross-linked alginate-based hydrogel can be considered as an attractive and potential adsorbent for an effective cationic dye removal from aqueous environments. The use of such a green adsorbent for the treatment of organic-pollutants-rich industrial wastewaters promotes sustainability and circular economy concepts.

Novel Double Cross-Linked Acrylic Acid/Bagasse Cellulose Porous Hydrogel for Controlled Release of Citral and Bacteriostatic Effects.

In this study, double cross-linked acrylic acid/bagasse cellulose (AA/BC) porous hydrogels were first prepared using cold plasma (CP) technology instead of chemical initiators. The structure and properties of porous hydrogels, as well as the controlled release and bacteriostatic application as functional carriers, were investigated. Results showed that a novel double cross-linked hydrogel had been successfully synthesized by utilizing •OH and H+ produced during plasma discharge. The acrylic acid (AA) monomers were successfully grafted onto the main chains of bagasse cellulose (BC), forming a porous three-dimensional network structure. The AA/BC porous hydrogels showed excellent swelling levels and intelligent responses. The release of citral in hydrogel inclusion compounds embedded with citral was controlled by adjusting the pH, and the slow release period was about 2 days. The inclusion compounds presented strong bacteriostatic effects against Escherichia coli and Staphylococcus aureus, extending the shelf life of fruits for about 4 days. Therefore, it can be concluded that CP technology is considered to be an efficient and environmental-friendly initiation technology for preparing hydrogels. The potential application of hydrogel inclusion compounds in the food field is expanded.

One-Pot Synthesis of Double-Network PEG/Collagen Hydrogel for Enhanced Adipogenic Differentiation and Retrieval of Adipose-Derived Stem Cells.

Hydrogels are widely used in stem cell therapy due to their extensive tunability and resemblance to the extracellular matrix (ECM), which has a three-dimensional (3D) structure. These features enable various applications that enhance stem cell maintenance and function. However, fast and simple hydrogel fabrication methods are desirable for stem cells for efficient encapsulation and to reduce adverse effects on the cells. In this study, we present a one-pot double-crosslinked hydrogel consisting of polyethylene glycol (PEG) and collagen, which can be prepared without the multi-step sequential synthesis of each network, by using bio-orthogonal chemistry. To enhance the adipogenic differentiation efficiency of adipose-derived stem cells (ADSCs), we added degradable components within the hydrogel to regulate matrix stiffness through cell-mediated degradation. Bio-orthogonal reactions used for hydrogel gelation allow rapid gel formation for efficient cell encapsulation without toxic by-products. Furthermore, the hybrid network of synthetic (PEG) and natural (collagen) components demonstrated adequate mechanical strength and higher cell adhesiveness. Therefore, ADSCs grown within this hybrid hydrogel proliferated and functioned better than those grown in the single-crosslinked hydrogel. The degradable elements further improved adipogenesis in ADSCs with dynamic changes in modulus during culture and enabled the retrieval of differentiated cells for potential future applications.

High strength, anti-freezing and conductive silkworm excrement cellulose-based ionic hydrogel with physical-chemical double cross-linked for pressure sensing

Recently, ionic conductive hydrogels have attracted extensive attention in the field of flexible pressure sensors due to their mechanical flexibility and high conductivity. However, the trade-off between the high electrical and mechanical properties of ionic conductive hydrogels and the loss of mechanical and electrical properties of traditional high water content hydrogels at low temperature are still the main hurdles in this area. Herein, a rigid Ca-rich silkworm excrement cellulose (SECCa) extracted from silkworm breeding waste was prepared. SEC-Ca was combined with the flexible hydroxypropyl methylcellulose (HPMC) molecules through hydrogen bonding and double ionic bonds of Zn2+ and Ca2+ to obtain the physical network SEC@HPMC-(Zn2+/Ca2+). Then, the covalently cross-linked network of polyacrylamide (PAAM) and the physical network were cross-linked by hydrogen bonding to obtain the physical-chemical double cross-linked hydrogel (SEC@HPMC-(Zn2+/Ca2+)/PAAM). The hydrogel showed excellent compression properties (95 %, 4.08 MPa), high ionic conductivity (4.63 S/m at 25 °C) and excellent frost resistance (possessing ionic conductivity of 1.20 S/m at −70 °C). Notably, the hydrogel can monitor pressure changes in a wide temperature range (−60–25 °C) with high sensitivity, stability and durability. This newly fabricated hydrogel-based pressure sensors can be deemed of great prospects for large-scale application of pressure detection at ultra-low temperatures.

A Dual-Crosslinked Hydrogel Based on Gelatin Methacryloyl and Sulfhydrylated Chitosan for Promoting Wound Healing.

The skin is the largest organ of the human body. Skin injuries, especially full-thickness injuries, are a major treatment challenge in clinical practice. Therefore, wound dressing materials with therapeutic effects have great practical significance in healthcare. This study used photocrosslinkable gelatin methacryloyl (GelMA) and sulfhydrylated chitosan (CS-SH) to design a double-crosslinked hydrogel for wound dressing. When crosslinked together, the resulting hydrogels showed a highly porous inner structure, and enhanced mechanical properties and moisture retention capacity. The compression modulus of the GelMA/CS-SH hydrogel (GCH) reached up to about 40 kPa and was much higher than that of pure GelMA hydrogel, and the compression modulus was increased with the amount of CS-SH. In vitro study showed no cytotoxicity of obtained hydrogels. Interestingly, a higher concentration of CS-SH slightly promoted the proliferation of cells. Moreover, the double-crosslinked hydrogel exhibited antibacterial properties because of the presence of chitosan. In vivo study based on rats showed that full-thickness skin defects healed on the 15th day. Histological results indicate that the hydrogel accelerated the repair of hair follicles and encouraged the orderly growth of collagen fibers in the wound. Furthermore, better blood vessel formation and a higher expression of VEGFR were observed in the hydrogel group when compared with the untreated control group. Based on our findings, GCH could be a promising candidate for full-thickness wound dressing.

Tofacitinib combined with melanocyte protector α-MSH to treat vitiligo through dextran based hydrogel microneedles

Vitiligo can cause serious damage to the appearance of patients and affect physical and mental health, but there is currently no simple and effective treatment. According to the theory of autoimmune disorder, the separable hydrogel microneedles delivering alpha-melanocyte-stimulating hormone (α-MSH) and tofacitinib were designed to treat vitiligo. This hydrogel microneedles were formed by dextran methacrylate (DexMA) and cyclodextrin-adamantane based host-guest supramolecules (HGSM) through CC double bond polymerization and host-guest assembly. The microneedle tips formed by the double cross-linked hydrogel can pierce the stratum corneum and deliver melanocyte protector α-MSH and JAK inhibitor tofacitinib directly to the epidermis and dermis. Under the treatment of α-MSH/tofacitinib microneedles, massive deposition of melanin in epidermis and hair follicles significantly accelerated skin and hair pigmentation.

In situ forming double-crosslinked hydrogels with highly dispersed short fibers for the treatment of irregular wounds.

In situ forming injectable hydrogels hold great potential for the treatment of irregular wounds. However, their practical applications were hindered by long gelation time, poor mechanical performance, and a lack of a natural extracellular matrix structure. Herein, amino-modified electrospun poly(lactic-co-glycolic acid) (APLGA) short fibers with uniform distribution were introduced into gelatin methacrylate/oxidized dextran (GM/ODex) hydrogels. In comparison with the fiber aggregation structure in the PLGA fiber-incorporated hydrogels, the hydrogels with APLGA fibers possessed a uniform porous structure. The highly dispersed APLGA short fibers accelerated the sol-gel phase transition of the hydrogel due to the formation of dynamic Schiff-base bonds between the fibers and hydrogels. Furthermore, in combination with UV-assisted crosslinking, a rapid gelation time of 90 s was achieved for the double-crosslinked hydrogels. The addition of APLGA short fibers as fillers and the formation of the double-crosslinking network enhanced the mechanical performance of the hydrogels. Furthermore, the fiber-hydrogel composites exhibited favorable injectability, excellent biocompatibility, and improved cell infiltration. In vivo assessment indicated that the GM/ODex-APLGA hydrogels successfully filled the full-thickness defects and improved wound healing. This work demonstrates a promising solution for the treatment of irregular wounds.

Temperature/pH-Sensitive Double Cross-Linked Hydrogels as Platform for Controlled Delivery of Metoclopramide.

Novel double cross-linked (DC) hydrogels with pH-/temperature-sensitive properties were designed and developed. Therefore, linear pH-sensitive poly(methyl vinyl ether-alt-maleic acid) (P(VME/MA)) macromolecules were absorbed within a thermosensitive poly(N-isopropylacrylamide-co-hydroxyethylacrylamide)-hydrogel (PNH) and, subsequently, cross-linked together through a solvent-free thermal method. As a novelty, double cross-linked hydrogels were obtained from previously purified polymers in the absence of any solvent or cross-linking agent, which are generally harmful for the body. The new DC structures were characterized by FT-IR spectroscopy, SEM, swelling kinetic measurements, and mechanical tests. The resulting scaffolds exhibited interconnected pores and a flexible pattern, compared to the brittle structure of conventional PNH. The swelling kinetics of DC hydrogels were deeply affected by temperature (25 and 37 °C) and pH (7.4 and 1.2). Furthermore, the hydrogels absorbed a great amount of water in a basic environment and displayed improved mechanical properties. Metoclopramide (Met) was loaded within DC hydrogels as a model drug to investigate the ability of the support to control the drug release rate. The results obtained recommended them as convenient platforms for the oral administration of drugs, with the release of the largest part of the active principle occurring in the colon.

Low-Swelling Adhesive Hydrogel with Rapid Hemostasis and Potent Anti-Inflammatory Capability for Full-Thickness Oral Mucosal Defect Repair.

Full-thickness oral mucosal defects are accompanied by significant blood loss and frequent infections. Instead of conventional therapies that separate hemostasis and anti-inflammation in steps, emerging hydrogels can integrate multiple functions for the successive process after defect including hemostasis/inflammatory phase, proliferative phase, and remodeling phase. However, these functions can be easily compromised by rapid swelling and degradation of hydrogels in wet oral environment. Herein, a low-swelling adhesive hydrogel with rapid hemostasis and potent anti-inflammatory capability was developed using a dual cross-linking strategy as well as a safe and facile fabrication method. It was double cross-linked hydrogel consisting of gelatin methacrylate (GelMA), nanoclay, and tannic acid (TA) (referred to as GNT). GNT hydrogel exhibited low-swelling (one-eighth of that of GelMA), excellent stretchability (211.86%), and good adhesive properties (5 times the adhesive strength of GelMA). Physicochemical characterization illuminated the close interactions among the three components. A systematic investigation of the therapeutic effects of GNT hydrogels was performed. In vitro and in vivo experimental results demonstrated the potent hemostatic property and excellent antibacterial and anti-inflammatory effects of GNT hydrogels. The RNA sequencing analysis results for rat full-thickness oral mucosal samples showed that GNT reduced inflammation levels by down-regulating the expression of multiple inflammation-related pathways, including TNF and IL-17 pathways. It also enhanced the expression levels of tissue regeneration-related genes and thus accelerated defective mucosal repair. More importantly, the therapeutic effects of GNT were superior to those of a commercial oral tissue repair membrane when applied for full-thickness oral mucosal defect repair in rabbits. In summary, the prepared low-swelling adhesive GNT hydrogel with rapid hemostasis and potent anti-inflammatory is a promising therapy for full-thickness mucosal defect in the moist and dynamic oral environment.