Hydrogels, being hydrophilic polymer networks capable of absorbing and retaining aqueous fluids, hold significant promise in biomedical applications owing to their high water content, permeability, and structural similarity to the extracellular matrix. Recent chemical advancements have bolstered their versatility, facilitating the integration of the molecules guiding cellular activities and enabling their controlled activation under time constraints. However, conventional synthetic hydrogels suffer from inherent weaknesses such as heterogeneity and network imperfections, which adversely affect their mechanical properties, diffusion rates, and biological activity. In response to these challenges, hybrid hydrogels have emerged, aiming to enhance their strength, drug release efficiency, and therapeutic effectiveness. These hybrid hydrogels, featuring improved formulations, are tailored for controlled drug release and tissue regeneration across both soft and hard tissues. The scientific community has increasingly recognized the versatile characteristics of hybrid hydrogels, particularly in the biomedical sector. This comprehensive review delves into recent advancements in hybrid hydrogel systems, covering the diverse types, modification strategies, and the integration of nano/microstructures. The discussion includes innovative fabrication techniques such as click reactions, 3D printing, and photopatterning alongside the elucidation of the release mechanisms of bioactive molecules. By addressing challenges, the review underscores diverse biomedical applications and envisages a promising future for hybrid hydrogels across various domains in the biomedical field.

Intense and persistent oxidative stress, excessive inflammation, and impaired angiogenesis severely hinder diabetic wound healing. Bioactive hydrogel dressings with immunoregulatory and proangiogenic properties have great promise in treating diabetic wounds. However, the therapeutic effects of dressings always depend on drugs with side effects, expensive cytokines, and cell therapies. Herein, a novel dynamic borate-bonds crosslinked hybrid multifunctional hydrogel dressings with photothermal properties are developed to regulate the microenvironment of diabetic wound sites and accelerate the whole process of its healing without additional medication. The hydrogel is composed of phenylboronic acid-modified chitosan and hyaluronic acid (HA) crosslinked by tannic acid (TA) through borate bonds and Prussian blue nanoparticles (PBNPs) with photothermal response characteristics are embedded in the polymer networks. The results indicate hydrogels show inherent broad-spectrum antioxidative activities through the integrated interaction of borate bonds, TA, and PBNPs. Meanwhile, combined with the regulation of macrophage phenotype by HA, the inflammatory microenvironment of diabetic wounds is transformed. Moreover, the angiogenesis is then enhanced by the mild photothermal effect of PBNPs, followed by promoted epithelialization and collagen deposition. In summary, this hybrid hydrogel system accelerates all stages of wound repair through antioxidative stress, immunomodulation, and proangiogenesis, showing great potential applications in diabetic wound management.

Soft matter bioelectronics represents an emerging and interdisciplinary research frontier aiming to harness the synergy between biology and electronics for advanced diagnostic and healthcare applications. In this context, a whole family of soft gels have been recently developed with self-healing ability and tunable biological mimetic features to act as a tissue-like space bridging the interface between the electronic device and dynamic biological fluids and body tissues. This review article provides a comprehensive overview of electroactive polymer gels, formed by noncovalent intermolecular interactions and dynamic covalent bonds, as injectable electroactive gels, covering their synthesis, characterization, and applications. First, hydrogels crafted from conducting polymers (poly(3,4-ethylene-dioxythiophene) (PEDOT), polyaniline (PANi), and polypyrrole (PPy))-based networks which are connected through physical interactions (e.g., hydrogen bonding, π-π stacking, hydrophobic interactions) or dynamic covalent bonds (e.g., imine bonds, Schiff-base, borate ester bonds) are addressed. Injectable hydrogels involving hybrid networks of polymers with conductive nanomaterials (i.e., graphene oxide, carbon nanotubes, metallic nanoparticles, etc.) are also discussed. Besides, it also delves into recent advancements in injectable ionic liquid-integrated gels (iongels) and deep eutectic solvent-integrated gels (eutectogels), which present promising avenues for future research. Finally, the current applications and future prospects of injectable electroactive polymer gels in cutting-edge bioelectronic applications ranging from tissue engineering to biosensing are outlined.

Effectively controlling bacterial infection, reducing the inflammation and promoting vascular regeneration are all essential strategies for wound repair. Nanozyme technology has potential applications in the treatment of infections because its non-antibiotic dependent, topical and noninvasive nature. In wound management, copper-based nanozymes have emerged as viable alternatives to antibiotics. In this study, an ultrasmall cupric enzyme with high enzymatic activity is synthesized and added to a nontoxic, self-healing, injectable cationic guar gum (CG) hydrogel network. The nanozyme exhibits remarkable antioxidant properties under neutral conditions, effectively scavenging reactive nitrogen and oxygen species (RNOS). Under acidic conditions, Cu NDs have peroxide (POD) enzyme-like activity, which allows them to eliminate hydrogen peroxides and produce free radicals locally. Antibacterial experiments show that they can kill bacteria and remove biofilms. It reveals that low concentrations of Cu ND/CG decrease the expression of the inflammatory factors in cells and tissues, effectively controlling inflammatory responses. Cu ND/CG hydrogels also inhibit HIF-1α and promote VEGF expression in the wound with the ability to promote vascular regeneration. In vivo safety assessments reveal a favorable biosafety profile. Cu ND/CG hydrogels offer a promising solution for treating acute and infected wounds, highlighting the potential of innovative nanomaterials in wound healing.

In this study, we synthesized and characterized pH-responsive Chitosan-AgCl-doped ZnO hybrid hydrogels and evaluated their potential for loading aquaculture bioactive compounds, and assessed their antimicrobial properties against a threatening pathogen associated with disease across a broad spectrum of warm water fish and invertebrates. Hydrogel characterization consisted of assessing morphology via SEM, composition via EDS, hydrogels\' network components interactions via FT-IR and pH response through swelling behavior determinations. The swelling characterization of the synthesized hydrogels demonstrated a pH-responsive behavior, showing that low pH values caused the hydrogel polymeric network to expand and capture more of the aqueous solution. These characteristics make the synthesized hydrogels suitable for the encapsulation and controlled release of drugs and bioactive compounds in aquaculture. Chitosan_ZnO hybrid hydrogels showed great antimicrobial activity against Vibrio harveyi, even better than that of loaded PB hydrogels. Here, we provide evidence for the potential capacity of Chitosan_ZnO hybrid hydrogels for the preventive and curative treatment of diseases that impact aquaculture animal health and prevent drug resistance by bacteria.

The healing of infected bone defects (IBD) is a complex physiological process involving a series of spatially and temporally overlapping events, including pathogen clearance, immunological modulation, vascularization, and osteogenesis. Based on the theory that bone healing is regulated by both biochemical and biophysical signals, in this study, a copper doped bioglass (CuBGs)/methacryloyl-modified gelatin nanoparticle (MA-GNPs)/methacrylated silk fibroin (SilMA) hybrid hydrogel is developed to promote IBD healing. This hybrid hydrogel demonstrates a dual-photocrosslinked interpenetrating network mechanism, wherein the photocrosslinked SilMA as the main network ensures structural integrity, and the photocrosslinked MA-GNPs colloidal network increases strength and dissipates loading forces. In an IBD model, the hydrogel exhibits excellent biophysical characteristics, such as adhesion, adaptation to irregular defect shapes, and in situ physical reinforcement. At the same time, by sequentially releasing bioactive ions such as Cu2+ , Ca2+ , and Si2+ ions from CuBGs on demand, the hydrogel spatiotemporally coordinates antibacterial, immunomodulatory and bone remodeling events, efficiently removing infection and accelerating bone repair without the use of antibiotics or exogenous recombinant proteins. Therefore, the hybrid hydrogel can be used as a simple and effective method for the treatment of IBD.

Hydrogels, also known as three-dimensional, flexible, and polymer networks, are composed of natural and/or synthetic polymers with exceptional properties such as hydrophilicity, biocompatibility, biofunctionality, and elasticity. Researchers in biomedicine, biosensing, pharmaceuticals, energy and environment, agriculture, and cosmetics are interested in hydrogels. Hydrogels have limited adaptability for complicated biological information transfer in biomedical applications due to their lack of electrical conductivity and low mechanical strength, despite significant advances in the development and use of hydrogels. The nano-filler-hydrogel hybrid system based on supramolecular interaction between host and guest has emerged as one of the potential solutions to the aforementioned issues. Black phosphorus, as one of the representatives of novel two-dimensional materials, has gained a great deal of interest in recent years owing to its exceptional physical and chemical properties, among other nanoscale fillers. However, a few numbers of publications have elaborated on the scientific development of black phosphorus hybrid hydrogels extensively. In this review, this review thus summarized the benefits of black phosphorus hybrid hydrogels and highlighted the most recent biological uses of black phosphorus hybrid hydrogels. Finally, the difficulties and future possibilities of the development of black phosphorus hybrid hydrogels are reviewed in an effort to serve as a guide for the application and manufacture of black phosphorus -based hydrogels. Recent applications of black phosphorus hybrid hydrogels in biomedicine.

Bioprinting is an emerging technology involved in the fabrication of three-dimensional tissue constructs for the repair and regeneration of various tissues and organs. Collagen, a natural protein found abundantly in the extracellular matrix of several tissues, can be extracted from collagen-rich tissues of animals such as sheep, cows, rats, pigs, horses, birds, and marine animals. However, due to the poor printability of collagen bioinks, biocompatible collagen scaffolds that mimic the extracellular matrix (ECM) are difficult to fabricate using bioprinting techniques. Gelatin methacrylate (GelMA), a semi-synthetic polymer with tunable physical and chemical properties, has been found to be a promising biomaterial in various bioprinting applications. The printability of collagen can be improved by combining it with semi-synthetic polymers such as GelMA to develop hybrid hydrogels. Such hybrid hydrogels printed have also been identified to have enhanced mechanical properties. Hybrid GelMA meshes have not previously been prepared with collagen from ovine sources. This study provides a novel comparison between the properties of hybrid meshes with ovine skin and bovine hide collagen. GelMA (8% w/v) was integrated with three different concentrations (0.5%, 1%, and 2%) of bovine and ovine collagen forming hybrid hydrogels inks that were printed into meshes with enhanced properties. The maximum percentage of collagen suitable for integration with GelMA, forming hybrid hydrogels with a stable degradation rate was 1%. The water-soluble nature of ovine collagen promoted faster degradation of the hybrid meshes, although the structural crosslinking was identified to be higher than bovine hybrid meshes. The 1% bovine collagen hybrid meshes stood out in terms of their stable degradation rates.

Tissue-mimicking gels provide a cost-effective medium to optimize histotripsy treatment parameters with immediate feedback. Agarose and polyacrylamide gels are often used to evaluate treatment outcomes as they mimic the acoustic properties and stiffness of a variety of soft tissues, but they do not exhibit high toughness, a characteristic of fibrous connective tissue. To mimic pathologic fibrous tissue found in benign prostate hyperplasia (BPH) and other diseases that are potentially treatable with histotripsy, an optically transparent hydrogel with high toughness was developed that is a hybrid of polyacrylamide and alginate. The stiffness was established using shear wave elastography (SWE) and indentometry techniques and was found to be representative of human BPH ex vivo prostate tissue. Different phantom compositions and excised ex vivo BPH tissue samples were treated with a 700-kHz histotripsy transducer at different pulse repetition frequencies. Post-treatment, the hybrid gels and the tissue samples exhibited differential reduction in stiffness as measured by SWE. On B-mode ultrasound, partially treated areas were present as hyperechoic zones and fully liquified areas as hypoechoic zones. Phase contrast microscopy of the gel samples revealed liquefaction in regions consistent with the target lesion dimensions and correlated to findings identified in tissue samples via histology. The dose required to achieve liquefaction in the hybrid gel was similar to what has been observed in ex vivo tissue and greater than that of agarose of comparable or higher Young\'s modulus by a factor >10. These results indicate that the developed hydrogels closely mimic elasticities found in BPH prostate ex vivo tissue and have a similar response to histotripsy treatment, thus making them a useful cost-effective alternative for developing and evaluating different treatment protocols.

M1 macrophage accumulation and excessive inflammation are commonly encountered issues in diabetic wounds and can fail in the healing process. Hence, hydrogel dressings with immunoregulatory capacity have great promise in the clinical practice of diabetic wound healing. However, current immunoregulatory hydrogels are always needed for complex interventions and high-cost treatments, such as cytokines and cell therapies. In this study, a novel glycyrrhizic acid (GA)-based hybrid hydrogel dressing with intrinsic immunoregulatory properties is developed to promote rapid diabetic wound healing. This hybrid hydrogel consists of interpenetrating polymer networks composed of inorganic Zn2+ -induced self-assembled GA and photo-crosslinked methyl acrylated silk fibroin (SF), realizing both excellent injectability and mechanical strength. Notably, the SF/GA/Zn hybrid hydrogel can regulate macrophage responses in the inflammatory microenvironment, circumventing the use of any additives. The immunomodulatory properties of the hydrogel can be harnessed for safe and efficient therapeutics that accelerate the three phases of wound repair and serve as a promising dressing for the management of diabetic wounds.