Injectable Self-healing Hydrogel Research Articles

The preparation and characterization of self-healing hydrogels based on polypeptides with a dual response to light and hydrogen peroxide

An injectable self-healing polypeptide-based hydrogel that is responsive to hydrogen peroxide and light is prepared. The controlled release of hydrophobic drug molecules at specific sites, such as tumor tissues, was accordingly achieved.

A Choline Phosphoryl-Conjugated Chitosan/Oxidized Dextran Injectable Self-Healing Hydrogel for Improved Hemostatic Efficacy.

The development of injectable hydrogels with good biocompatibility, self-healing, and superior hemostatic properties is highly desirable in emergency and clinical applications. Herein, we report an in situ injectable and self-healing hemostatic hydrogel based on choline phosphoryl functionalized chitosan (CS-g-CP) and oxidized dextran (ODex). The CP groups were hypothesized to accelerate hemostasis by facilitating erythrocyte adhesion and aggregation. Our results reveal that the CS-g-CP/ODex hydrogels exhibit enhanced blood clotting and erythrocyte adhesion/aggregation capacities compared to those of the CS/ODex hydrogels. The CS-g-CP50/ODex75 hydrogel presents rapid gelation time, good mechanical strength and tissue adhesiveness, satisfactory bursting pressure, and favorable biocompatibility. The hemostatic ability of the CS-g-CP50/ODex75 hydrogel was significantly improved compared to that of the CS/ODex hydrogel and commercial fibrin sealant in the rat tail amputation and liver/spleen injury models. Our study highlights the positive and synergistic effects of CP groups on hemostasis and strongly supports the CS-g-CP50/ODex75 hydrogel as a promising adhesive for hemorrhage control.

Injectable self-healing polysaccharide hydrogel loading CuS and pH-responsive DOX@ZIF-8 nanoparticles for synergistic photothermal-photodynamic-chemo therapy of cancer

The injectable self-healing polysaccharide hydrogel was prepared by the formation of Schiff base bonds between aldehyde-modified methylcellulose (MCCHO) and carboxymethyl chitosan (CMC). The copper sulfide nanoparticles (CuS NPs) and pH-sensitive doxorubicin-loaded zeolitic imidazolate frameworks nanoparticles ([email protected] NPs) were prepared and could be well-dispersed into the hydrogel system. The presence of CuS NPs can achieve photothermal therapy (PTT) for tumors under the irradiation of the near-infrared (NIR) laser. Moreover, CuS NPs can generate photodynamic effects under NIR irradiation, converting oxygen into toxic reactive oxygen species (ROS) and presenting efficient photodynamic therapy (PDT). The [email protected] NPs can be decomposed under an intracellular acidic environment and realize the controlled release of DOX. The injectable self-healing hydrogel loading CuS and [email protected] NPs can achieve synergistic photothermal-photodynamic-chemo therapy for tumors and will inspire the researchers to construct a platform from hydrogel combined with multifunctional nanomaterials to realize the effective multimodal therapy for tumor.

Enhancing cartilage repair with optimized supramolecular hydrogel-based scaffold and pulsed electromagnetic field.

Functional tissue engineering strategies provide innovative approach for the repair and regeneration of damaged cartilage. Hydrogel is widely used because it could provide rapid defect filling and proper structure support, and is biocompatible for cell aggregation and matrix deposition. Efforts have been made to seek suitable scaffolds for cartilage tissue engineering. Here Alg-DA/Ac-β-CD/gelatin hydrogel was designed with the features of physical and chemical multiple crosslinking and self-healing properties. Gelation time, swelling ratio, biodegradability and biocompatibility of the hydrogels were systematically characterized, and the injectable self-healing adhesive hydrogel were demonstrated to exhibit ideal properties for cartilage repair. Furthermore, the new hydrogel design introduces a pre-gel state before photo-crosslinking, where increased viscosity and decreased fluidity allow the gel to remain in a semi-solid condition. This granted multiple administration routes to the hydrogels, which brings hydrogels the ability to adapt to complex clinical situations. Pulsed electromagnetic fields (PEMF) have been recognized as a promising solution to various health problems owing to their noninvasive properties and therapeutic potentials. PEMF treatment offers a better clinical outcome with fewer, if any, side effects, and wildly used in musculoskeletal tissue repair. Thereby we propose PEMF as an effective biophysical stimulation to be 4th key element in cartilage tissue engineering. In this study, the as-prepared Alg-DA/Ac-β-CD/gelatin hydrogels were utilized in the rat osteochondral defect model, and the potential application of PEMF in cartilage tissue engineering were investigated. PEMF treatment were proven to enhance the quality of engineered chondrogenic constructs in vitro, and facilitate chondrogenesis and cartilage repair in vivo. All of the results suggested that with the injectable self-healing adhesive hydrogel and PEMF treatment, this newly proposed tissue engineering strategy revealed superior clinical potential for cartilage defect treatment.

Injectable self-healing chitosan-based POSS-PEG hybrid hydrogel as wound dressing to promote diabetic wound healing

Promoting the healing of diabetic wounds remains a major challenge in scientific research today. A star-like eight-arm cross-linker octafunctionalized POSS of benzaldehyde-terminated polyethylene glycol (POSS-PEG-CHO) was synthesized, and crosslinked with hydroxypropyltrimethyl ammonium chloride chitosan (HACC) via Schiff base reaction to obtain Chitosan-based POSS-PEG hybrid hydrogels. The designed composite hydrogels exhibited strong mechanical strength, injectability, excellent self-healing efficiency, good cytocompatibility and antibacterial properties. Furthermore, the composite hydrogels could accelerate cells migration and proliferation, as expected by remarkably promoting wound healing in diabetic mice. The wounds treated with the composite hydrogels displayed faster regeneration of epithelial tissue, fewer inflammatory cells, more collagen deposition and higher expression level of VEGF. Therefore, Chitosan-based POSS-PEG hybrid hydrogel has great application potential as a dressing for promoting the healing of diabetic wounds.

Injectable chitosan hydrogels tailored with antibacterial and antioxidant dual functions for regenerative wound healing

Herein, an injectable self-healing hydrogel with inherent antibacterial activity was fabricated based on the dynamic covalent bond formation between boronic acid and catechol groups in quaternized chitosan as building blocks in conjunct with the in-situ encapsulation of epigallocatechin-3-gallate (EGCG, a green tea derivative). Benefiting from the catechol groups and therapeutic effect of EGCG, the resulting natural-based injectable hydrogels showed excellent antibacterial and antioxidant dual functions in preventing bacterial infection and scavenging radicals. The hydrogels loaded with EGCG also exhibited good biocompatibility along with contact-active antibacterial activity via a “capture and kill” strategy. The dynamic covalent bonding enables shear-thinning delivery of the gels via syringe, followed by rapid self-healing. Additionally, the in vivo wound healing evaluation in a full-thickness skin defect model revealed the appreciable and regenerative wound healing performance of the hydrogels, demonstrating their great potential as novel wound dressings for wound management.

Dexamethasone loaded injectable, self-healing hydrogel microspheres based on UPy-functionalized Gelatin/ZnHAp physical network promotes bone regeneration

Biopolymer-based injectable hydrogels provide great potential as bone tissue engineering (BTE) scaffolds on account of biocompatibility, and pore interconnectivity that enables delivery of cells and/or signaling molecules for bone repair. Recently, Gelatin hydrogels based on H-bonds were considered in response to concerns around the chemical crosslinking agents. In this study, a self-healing gelatin hydrogel with remarkable compressive and self-healing properties was prepared via formation of quadruple hydrogen bonds between ureidopyrimidinon functional groups, which were substituted on NH2 groups of gelatin(GelUPy). Degree of substitution controls properties of the resulting hydrogel from a shape- memory hydrogel (100% substitution), to a hydrogel (about 80%), to this self-healing hydrogel (about 40%). We report a strategy that adopts an emulsion synthesis approach to delivery of dexamethasone and Ca/Zn ions from injectable self-healing GelUPy hydrogel (GelUPy-ZnHApUPy-DEX), to induce osteogenic differentiation of adipose-derived stem cells, in vitro, and enhance bone regeneration in a cranial bone defect in a rat model. We show that key properties of the composite hydrogels, including mechanical properties, and release behavior of DEX are a match to the requirements of BTE. Overall, our results demonstrate that this self-healing gelatin approach is a promising strategy to enhance bone regeneration through a minimally invasive procedure.

Bioinspired Injectable Self-Healing Hydrogel Sealant with Fault-Tolerant and Repeated Thermo-Responsive Adhesion for Sutureless Post-Wound-Closure and Wound Healing

HighlightsMussel and brown algae inspired dual-bionic bioadhesive cross-linked by dynamic bonds exhibits good self-healing capacity and sufficient adhesive strength. And the adhesive hydrogel shows temperature-dependent reversible adhesive behavior, and could achieve fault-tolerate adhesive application and repeated tissue adhesion.The coordination interaction between ferric ions and protocatechualdehyde equips the hydrogel with photothermal antibacterial effect.The injectable adhesive with antioxidation and good hemostatic effect shows promising application in tissue sealant and wound closure.

Injectable and fast gelling hyaluronate hydrogels with rapid self-healing ability for spinal cord injury repair

Self-healing natural hydrogels still suffer from some issues such as unfit stiffness, poor healing efficiency, and lack of biocompatibility and hydrolytic stability, although they have been used to treat spinal cord injury (SCI). Herein, we develop the injectable, self-healing hyaluronate hydrogels based on multiple dynamic covalent bonds. The hydrogels exhibit fast gelation and excellent self-healing capability as well as injectability, favoring in situ formation for the hydrogels in target sites and maintaining their structural stability. Furthermore, the hydrogels are compatible with neural stem cells and various tissues and possess proper stiffness similar to nervous tissue. Interestingly, the hydrogel can induce neural differentiation of neural stem cells. In vivo experiment further illustrates that the hydrogels promote angiogenesis and remyelination as well as neuron regeneration, leading to the significant locomotor recovery of the SCI model rats. This injectable self-healing hyaluronic acid-based hydrogel is a potential candidate for nerve repair.

Injectable self-healing hydrogel fabricated from antibacterial carbon dots and ɛ-polylysine for promoting bacteria-infected wound healing

Developing highly efficient pharmaceuticals to eradicate pathogens and facilitate wound healing is of great concern. Despite some cationic carbon dots (CDs) have been used for sterilization, hardly any anionic CDs with antimicrobial activity have appeared. In the present work, we engineered a string of anionic CDs (especially CD31) as valid broad-spectrum bactericides to kill bacteria. Furthermore, CD31 conjugated with ɛ-polylysine (Plys) to construct injectable, and self-healing hydrogel (CD-Plys) that possess the advantages of remarkable broad spectrum antibacterial activity, excellent wound healing ability and satisfied biocompatibility. CD-Plys could dramatically accelerate wound healing with epithelization and enhanced angiogenesis. Taken together, this work provides a two-pronged strategy to explore CDs-based antimicrobial agents for disease therapy and tissue engineering.

Injectable Self-Healing Adhesive Chitosan Hydrogel with Antioxidative, Antibacterial, and Hemostatic Activities for Rapid Hemostasis and Skin Wound Healing.

Engineered wound dressing materials with excellent injectability, self-healing ability, tissue-adhesiveness, especially the ones possessing potential therapeutic effects have great practical significance in healthcare. Herein, an injectable quaternary ammonium chitosan (QCS)/tannic acid (TA) hydrogel based on QCS and TA was designed and fabricated by facile mixing of the two ingredients under physiological conditions. In this system, hydrogels were mainly cross-linked by dynamic ionic bonds and hydrogen bonds between QCS and TA, which endows the hydrogel with excellent injectable, self-healing, and adhesive properties. Benefitting from the inherent antioxidative, antibacterial, and hemostatic abilities of TA and QCS, this hydrogel showed superior reactive oxygen species scavenging activity, broad-spectrum antibacterial ability, as well as rapid hemostatic capability. Moreover, the QCS/TA2.5 hydrogel (containing 2.5% TA) exhibited excellent biocompatibility. The in vivo experiments also showed that QCS/TA2.5 hydrogel dressing not only rapidly stopped the bleeding of arterial and deep incompressible wounds in mouse tail amputation, femoral artery hemorrhage, and liver incision models but also significantly accelerated wound healing in a full-thickness skin wound model. For the great potentials listed above, this multifunctional QCS/TA2.5 hydrogel offers a promising network as a dressing material for both rapid hemostasis and skin wound repair.

An injectable, self-healing carboxymethylated chitosan hydrogel with mild photothermal stimulation for wound healing

Hydrogels can mimic extracellular matrix and provide a suitable microenvironment for accelerating wound healing. Nevertheless, the complicated wound condition, the disturbance of external forces, and the manufacturing process of the dressing were still difficult problems. An injectable self-healing hydrogel with mild photothermal therapy (MPTT) was developed for wound healing via dynamic Schiff bonds. After covalently incorporating GO-BPEI (branched polyethyleneimine grafting graphene oxide), an observable mechanical strength improvement and photothermal conversion property of GO-BPEI/carboxymethylated chitosan (CMCS) /aldehyde terminated polyethylene glycol (PEG-CHO) (GCP) hydrogel has been witnessed. MPTT induced by near-infrared (NIR) irradiation could accelerate NIH-3 T3 cells proliferation in vitro. Moreover, in vivo wound defect healing and histological analysis suggested that GCP hydrogels incorporated with MPTT significantly accelerated wound healing by improving collagen fibers deposition, enhancing re-epithelialization, and promoting granulation tissue neogenesis. The GCP hydrogels provide a unique route for wound dressing and present new inspirations for complicated wound management.

Development of an injectable self-healing hydrogel based on N-succinyl chitosan/ oxidized pectin for biomedical applications

Development of an injectable self-healing hydrogel based on N-succinyl chitosan/ oxidized pectin for biomedical applications

Synergistic osteogenic and angiogenic effects of KP and QK peptides incorporated with an injectable and self-healing hydrogel for efficient bone regeneration.

Irregular defects generated by trauma or surgery in orthopaedics practice were usually difficult to be fitted by the preformed traditional bone graft substitute. Therefore, the injectable hydrogels have attracted an increasing interest for bone repair because of their fittability and mini-invasivity. However, the uncontrollable spreading or mechanical failures during its manipulation remain a problem to be solved. Moreover, in order to achieve vascularized bone regeneration, alternatives of osteogenic and angiogenic growth factors should be adopted to avoid the problem of immunogenicity and high cost.In this study, a novel injectable self-healing hydrogel system (GMO hydrogel) loaded with KP and QK peptides had been developed for enhancing vascularized regeneration of small irregular bone defect. The dynamic imine bonds between gelatin methacryloyl and oxidized dextran provided the GMO hydrogel with self-healing and shear-thinning abilities, which led to an excellent injectability and fittability. By photopolymerization of the enclosed GelMA, GMO hydrogel was further strengthened and thus more suitable for bone regeneration. Besides, the osteogenic peptide KP and angiogenic peptide QK were tethered to GMO hydrogel by Schiff base reaction, leading to desired releasing profiles. In vitro, this composite hydrogel could significantly improve the osteogenic differentiation of BMSCs and angiogenesis ability of HUVECs. In vivo, KP and QK in the GMO hydrogel demonstrated a significant synergistic effect in promoting new bone formation in rat calvaria. Overall, the KP and QK loaded GMO hydrogel was injectable and self-healing, which can be served as an efficient approach for vascularized bone regeneration via a minimally invasive approach.

Functionalization of an Injectable Self-Healing pH-Responsive Hydrogel by Incorporating a Curcumin/Polymerized β-Cyclodextrin Inclusion Complex for Selective Toxicity to Osteosarcoma

Functionalization of an Injectable Self-Healing pH-Responsive Hydrogel by Incorporating a Curcumin/Polymerized β-Cyclodextrin Inclusion Complex for Selective Toxicity to Osteosarcoma

Comprehensive evaluation of self-healing polyampholyte gel particles for the severe leakoff control of drilling fluids

Lost circulation has been a serious problem to be solved in many drilling practices during oil, gas and geothermal well drillings. Many materials have been developed and evaluated for the purpose. However, their performance to plug severe leakoff is very limited. Herein, an injectable self-healing hydrogel based on polyampholyte with sulfonated and quaternary ammonium functionalities (P(MPTC-co-NaSS)) was developed and comprehensively evaluated to prevent the severe loss of fluids to formation. By incorporating cation-π (π is for aromatic residues) interaction, the hydrogel shown self-healing property and robustness in severe environment (temperature, salt) by comparison with other hydrogels merely consisting of cation-anion and H-bonding interactions. Aromatic residues enhanced thermal stability above 310 °C. The plugging measurement shown that an addition of 2 wt% dried gel particles can plug high-permeability formation and endure a high pressure of 6 MPa, produce much lower circulation loss and result in a dramatically increased loss volume reduction rate (63.5%) compared with a commercial polymer gel product and an inert material (9.4%) after a self-healing process. Markedly, P(MPTC-co-NaSS) can be used in a wide range of formation temperature (as high as 150 °C) and salt concentrations (NaCl, CaCl2, as high as 15 wt %). In addition to suitable particle size and mechanically robustness, it was also attributed to the soft, swelling, deformable, toughness and self-healable features of P(MPTC-co-NaSS) gel particles as well as the strong adhesion to negatively charged formations in water, even under high thermal and saline condition. These characteristics also contributed to a long-term plugging performance, beneficial to avoid repeated lost circulation in drilling operation. Besides, this self-healing polyampholyte gel particles dispersed well in saline fluid and maintained stable rheological properties after hot rolling, which was favorable to drilling fluid circulation. This study shown the application potential of self-healing materials as plugging material candidate in petroleum drilling industry.

MSCs-laden injectable self-healing hydrogel for systemic sclerosis treatment.

As a novel cellular therapy, the anti-inflammatory and immunomodulatory virtues of mesenchymal stem cells (MSCs) make them promising candidates for systemic sclerosis (SSc) treatment. However, the clinical efficacy of this stratagem is limited because of the short persistence time, poor survival, and engraftment of MSCs after injection in vivo. Herein, we develop a novel MSCs-laden injectable self-healing hydrogel for SSc treatment. The hydrogel is prepared using N, O-carboxymethyl chitosan (CS-CM) and 4-armed benzaldehyde-terminated polyethylene glycol (PEG-BA) as the main components, imparting with self-healing capacity via the reversible Schiff-base connection between the amino and benzaldehyde groups. We demonstrate that the hydrogel laden with MSCs not only promoted the proliferation of MSCs and increased the cellular half-life in vivo, but also improve their immune-modulating functions. The tube formation assay indicates that the MSCs could significantly promote angiopoiesis. Moreover, the MSCs-laden hydrogel could inhibit fibrosis by modulating the synthesis of collagen and ameliorate disease progression in SSc disease model mice after subcutaneous injection of bleomycin. All these results highlight this novel MSCs-laden hydrogel and its distinctive functions in treatment of chronic SSc, indicating the additional potential to be used widely in the clinic.

Injectable self-healing cellulose hydrogel based on host-guest interactions and acylhydrazone bonds for sustained cancer therapy

Tumor local chemotherapy employing injectable hydrogel reservoirs is a promising platform to achieve precise drug administration. However, balanced injectability, pH-responsiveness and long-term hydrolysis resistance of self-healing hydrogels remain appealing challenges. Herein, a modular preassembly strategy combining host-guest interactions with dynamic acylhydrazone bonds, was exploited to fabricate injectable cellulose-based hydrogels (CAAs) dressed with self-healing properties, pH-responsiveness and hydrolytic degradation resistance. Attributed to the host-guest interaction between β-cyclodextrin (CD) and 1-adamantane (AD), the hydrogels exhibited injectability, self-healing properties (healing efficiency of 97.5%) and rapid recovery (< 10 min) without external stimuli in physiological environment. Moreover, the hydrogels equipped with dynamic acylhydrazone linkages underwent slow hydrolytic degradation (> 30 days) and pH-responsive behavior, endowing the hydrogels with precise spatiotemporal drug release administration. The in vivo application of CAA as a carrier was studied using doxorubicin (DOX) model drug, and the results shows that using CAA as DOX carrier not only greatly enhances the anti-tumor efficacy of DOX, but also reduced the side effects of DOX. Statement of significanceWith the preassemble approach combining host-guest interactions with dynamic acylhydrazone bonds, this work demonstrated a multi-functional self-healing hydrogel as drug carrier developed by using natural polysaccharides, which offers a new avenue for the high-value utilization of biomass. The strategy demonstrated in the present work may also supply a pathway for the preparation and regulation of hydrogels as intelligent biomedicine materials.

An injectable self-healing CS/PDA–AgNPs hybrid hydrogel for mild and highly-efficient photothermal sterilization

An injectable self-healing hybrid hydrogel was constructed for combating bacterial infection under mild photothermal conditions.

A NIR-II light-modulated injectable self-healing hydrogel for synergistic photothermal/chemodynamic/chemo-therapy of melanoma and wound healing promotion.

The development of an injectable multifunctional hydrogel with tumor therapy, antibacterial treatment and wound healing properties is essential for simultaneously eradicating melanoma and promoting wound healing of tumor-initiated skin defects. Herein, iron ion-doped polyaniline (PANI(Fe)) tethered with guar gum (GG) chains is employed for the first time as a building unit for constructing a superior hydrogel (GG@PANI(Fe)-borax) crosslinked by borate/didiol bonds. Due to the dynamic and reversible properties of boronate ester bonds, the GG@PANI(Fe)-borax hydrogels had convenient injectability, rapid self-healing ability, and reversible gel-sol transformations under thermal- or pH-stimuli. More importantly, they took advantage of the second near-infrared (NIR-II) responsive photothermal conversion capability, accompanied by the photothermal-enhanced high cytotoxic ˙OH generation in the H2O2-enriched tumor microenvironment induced by iron-doped PANI. The as-prepared hydrogels exhibited excellent photothermal effects and controllable NIR-triggered drug release, leading to distinctly synergistic photothermal/chemodynamic/chemo-therapy effects of melanoma both in vitro (98.2%) and in vivo (98.8%). In addition, the obtained hydrogels also exhibited good anti-bacterial activity (>97.1%) against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria because they were based on PANI(Fe) and borax, which exhibit antibacterial activity. Furthermore, these GG@PANI(Fe)-incorporated scaffolds could improve fibroblast cell proliferation and angiogenesis for accelerating wound repair in tumor-bearing and infected wound mice. Taken together, GG@PANI(Fe)-borax hydrogels may be used simultaneously for eradication of skin-tumor cells, inhibiting infection and accelerating wound healing. This work offers an effective and facile strategy to fabricate an "all-in-one" multifunctional hydrogel platform for synergetic multimodal integrated therapy of tumors.