Inorganic-Nanomaterial-Composited Hydrogel Dressings for Wound Healing

: Wound management heavily relies on the vital contribution of wound dressings, emphasizing the significance of finding an ideal dressing that can fulfill the intricate requirements of the wound healing process with multiple functions. A promising strategy is combining several materials and therapies to create multifunctional wound dressings. Nanocomposite hydrogel dressings based on nanomaterials, combining the advantages of nanomaterials and hydrogels in wound treatment, can significantly improve their respective performance and compensate for their shortcomings. A variety of nanocomposite wound dressings with diverse structures and synergistic functions have been developed in recent years, achieving ideal results in wound management applications. In this review, the multiple functions, advantages, and limitations of hydrogels as wound dressings are first discussed. Additionally, the application of inorganic nanomaterials in wound healing is also elaborated on. Furthermore, we focused on summarizing and analyzing nanocomposite hydrogel dressings for wound healing, which contain various inorganic nanomaterials, including metals, metal oxides, metal sulfides, carbon-based nanomaterials, and silicon-based nanoparticles. Finally, prospects for nanocomposite hydrogel wound dressings are envisaged, providing insights for further research in wound management.


Introduction
The skin, serving as the first line of defense against external factors, safeguards the body from detrimental substances and microbial invasion, thereby upholding biological equilibrium and preserving the body's well-being [1].Skin is a delicate organ that can be easily damaged by external factors such as machinery, temperature, and chemicals.Acute wounds usually heal within 10-20 days through the body's orderly repair process.When the skin is injured, multiple biological pathways are activated immediately and respond synchronously, triggering a complex, orderly, dynamic, and strictly regulated healing process.Wound repair is one of the most intricate biological processes in human life, and it involves four stages, namely hemostasis, inflammation, proliferation, and remodeling [2,3].
After a skin injury, various physiological reactions are immediately triggered to stop the bleeding, then quickly transition to the inflammatory stage.The proliferation stage begins two to three days after the injury, during which crucial events such as granulation tissue formation, re-epithelialization, and vascular regeneration occur.The final stage of wound healing is the contraction and remodeling of granulation tissue, along with the generation of scars.This process starts 2-3 weeks after the injury and can last a year or even longer [4].Each stage cooperates and influences each other, with time overlapping partly.Each stage involves the complex and coordinated joint effects of different types of cells and multiple growth factors.
However, wound healing does not always proceed in an orderly manner.Diabetes, infection, inflammation, reactive oxygen species (ROS), and other factors can delay wound healing or cause chronic wounds [5].Chronic wounds caused by chronic underlying diseases like metabolic disorders and vascular dysfunction cannot heal in an orderly and timely manner [6].Chronic wounds have complex pathogenesis, long treatment cycles, and high treatment difficulty, and are prone to recurrence, with high disability and mortality rates.Skin chronic wounds can cause significant physical and psychological trauma to patients, and expensive wound care products and long-term treatments can financially burden individuals and society [7].
Research has shown that covering wounds can effectively promote healing, so the use of wound dressings has become an essential part of the wound management process.Traditional dry wound dressings such as gauze are still commonly used due to their convenience, cost-effectiveness, and ability to quickly create hemostasis and act as a physical barrier for wounds.Gauze dressings are crucial for the initial stages of wound healing, but they can adhere to dry wounds and cause damage during removal [8,9].The wound healing process is expedited by utilizing wet dressings in contrast to dry dressings, as the occurrence of renewed skin without inflammation and the formation of eschars can exclusively happen in a moist environment.Hydrogels are highly regarded among developed wet dressings due to their ability to act as a barrier to microorganisms, absorb excess exudates, maintain a moist environment, allow gaseous exchange, and promote rapid healing of wounds.Moreover, they display exceptional biocompatibility and can be removed effortlessly without causing any trauma to the patient [10][11][12].
As research on wound dressings advances, medical dressings are continuously being improved and updated.Wound dressings have evolved from simple covering dressings to dressings with various functions to promote wound healing, such as hemostasis [13,14], antibacterial [15], angiogenesis [16], and smart wound dressings [17].To develop wound dressings that meet the complex requirements of the wound healing process, it is necessary to combine multiple strategies to achieve multifunctional wound management.Various nanomaterials are being investigated for wound healing applications, dramatically broadening the range of tools available for infection control and wound care because of the unique physical, chemical, and biological characteristics of these materials [18].Therefore, nanocomposite wound dressings combining hydrogels and nanomaterials have recently gained significant attention [19,20].This review first discusses the multiple functions, advantages, and limitations of hydrogel as wound dressings.Then, the applications of inorganic nanoparticles for wound healing are elaborated on.Moreover, the nanocomposite hydrogel dressings containing inorganic nanomaterials, including metals, metal oxides, metal sulfides, and carbon-based and silica-based nanoparticles, are classified and discussed.Finally, the future trends for development are further prospected.

Application of Hydrogels for Wound Healing
Hydrogels are polymer networks via physical or chemical cross-linking, which are extensively used as advanced biomaterials in the healthcare industry, particularly in wound management, tissue regeneration, and drug delivery [21][22][23].The three-dimensional porous hydrophilic network of hydrogels enables them to mimic the microstructure of the extracellular matrix and makes them highly effective in keeping moisture at the wound site.Moreover, hydrogel dressings can stimulate the growth of fibroblasts and the migration of keratinocytes, which are essential for epithelialization and wound healing [24,25].As the clinical requirements for wound repair increase, there are growing functional requirements for wound dressings.Therefore, various hydrogel dressings with enhanced single or multiple biological functions have been sequentially developed.These functions encompass adhesive properties and hemostasis, antimicrobial activity, anti-inflammatory and antioxidation, drug-controlled release, self-healing, stimuli-response, and easily removable properties [26].
Hemostasis occurs at the initial stage of wound healing, which is crucial for wound management.The hemostatic function of hydrogel dressings mainly relies on the adhesion of adhesive hydrogels, which can seal the wound, resulting in hemostasis.Meanwhile, adhesive hydrogels attached to the wound site can prevent infection.Because of a specific bio-polysaccharide adhesion, chitosan-based hydrogels show outstanding tissue adhesion, blood cell coagulation, and hemostasis functions [27].When the positively charged quaternary ammonium group is attached to the chitosan's backbone, electrostatic interaction enhances the adhesion between the hydrogel and biological tissue and promotes blood clotting capacity (Figure 1A) [28].At a physiological pH, ε-polylysine (EPL) is a cationic polymer that is well known for its ability to adhere to biological surfaces.Lv et al. developed a multifunctional hydrogel prepared from catechol-modified oxidized hyaluronic acid, EPL, and Fe 3+ , which has been found to exhibit good adhesion to dynamic wounds and hemostatic properties [29].
Bacterial infections can significantly impede wound healing by causing tissue damage and inflammation and delaying recovery.Antimicrobial drugs have been the preferred antibacterial agent for treating bacterial infections, and many of these drugs have been encapsulated into hydrogels to prepare antimicrobial wound dressings.These drugs include antibiotics like amoxicillin [30], ciprofloxacin [31], and other antibacterial drugs such as chlorhexidine acetate [32].However, the excessive use of antibiotics has resulted in the emergence of bacterial strains that are resistant to multiple drugs.Inorganic nanoparticle antibacterial agents have distinct mechanisms of action against bacteria, which make them less susceptible to most antibiotic resistance mechanisms.Compared to antibiotics, inorganic nanoparticles are less likely to cause bacterial resistance.A more promising research strategy is to combine antibacterial agents with hydrogels to develop nanocomposite wound dressings for antibacterial applications [33]; this will be discussed in detail in subsequent sections.Moreover, some hydrogels have been developed in recent years, which possess inherent antibacterial properties and can be used as effective antibacterial agents with minimal or no side effects, unlike drug-loaded hydrogels.These hydrogels are commonly created using natural or synthetic antimicrobial polymers [34] and antimicrobial peptides [35].
Inflammation is the second stage of wound healing.Proper inflammation is necessary for wound repair, but excessive inflammation can result in high oxidative stress and cell destruction.Therefore, controlling inflammation is a crucial aspect of wound dressings.Hydrogels with antioxidant properties can help trap and eliminate ROS, realize anti-inflammatory activity, and promote wound healing.Hydrogels combining natural polyphenol antioxidants, such as curcumin and cannabidiol, have shown anti-inflammatory and antioxidant properties for promoting wound healing [36,37].Dopamine molecules, which contain catechol structures, are known to have excellent antioxidant activity.As a result, antioxidant hydrogels based on dopamine have been developed and their effectiveness in promoting wound healing through their antioxidant properties has been confirmed [38].
The porous structure of hydrogel makes it very suitable for loading various substances and achieving controlled release.In addition to delivering antibiotics, hydrogels can also be used to load and deliver cell growth factors (GFs) to promote wound healing.Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are frequently encapsulated in hydrogel dressings for wound healing due to their ability to promote angiogenesis and tissue regeneration (Figure 1B) [39].In addition, hydrogels also show the potential to act as carriers and controlled release systems for nitric oxide (NO) and are utilized as functional wound dressings [40].NO released from hydrogels can promote wound healing through vasodilation, which can increase microvessel blood flow, enabling the delivery of nutrients and cells to the injured site.
Self-healing hydrogels are capable of repairing their own functional and structural damage.This is essential to preserve the structural integrity of hydrogel dressings, prevent functional deterioration, and avoid wound infection to ensure effective wound healing.Physical self-healing hydrogels rely on a healing mechanism that involves the reconstruction of networks by forming dynamically non-covalent interactions [41,42], such as host-guest interactions, hydrogen bonds, etc., while chemical self-healing hydrogels reconstruct networks through dynamic covalent bonding, like the Schiff base (imines) [37].In recent years, dual-network and multi-cross-linked hydrogels designed through two or more non-covalent interactions and covalent bonding have demonstrated excellent self-healing properties (Figure 1C) [43].
Stimuli-responsive hydrogels that respond to external stimulation, including temperature, pH, and light, can undergo changes in size or shape.This stimuli-responsive property shows promising application prospects in wound dressings.Poly(N-isopropylacrylamide) (pNIPAM) and a PEG-based block copolymer (referred to as PF127) are commonly used for the preparation of thermo-responsive hydrogels due to their excellent temperatureresponsive properties [40,44].The pH-responsive hydrogel can respond to pH changes in the wound site, which is essential in controlled drug release for wound management.For example, tannic acid and metal ions were coordinated to create antibacterial and antiinflammatory hydrogels that release tannic acid under acidic conditions and are suitable for wound dressings (Figure 1D) [45].
Injectable hydrogels have the unique ability to temporarily become fluidized under shear stress and then recover their original mechanical properties [46].Compared to traditional preformed hydrogels, injectable hydrogels offer several advantages, such as causing less trauma and producing less blood loss, shorter operation time, and faster recovery [47].Minimally invasive procedures can be administered locally with narrow syringes instead of requiring invasive surgery.Their moldability makes them suitable for specific patient interventions, showing great potential for personalized medical treatment [10,22].
healing.Physical self-healing hydrogels rely on a healing mechanism that involves the reconstruction of networks by forming dynamically non-covalent interactions [41,42], such as host-guest interactions, hydrogen bonds, etc., while chemical self-healing hydrogels reconstruct networks through dynamic covalent bonding, like the Schiff base (imines) [37].In recent years, dual-network and multi-cross-linked hydrogels designed through two or more non-covalent interactions and covalent bonding have demonstrated excellent self-healing properties (Figure 1C) [43].
Stimuli-responsive hydrogels that respond to external stimulation, including temperature, pH, and light, can undergo changes in size or shape.This stimuli-responsive property shows promising application prospects in wound dressings.Poly(N-isopropylacrylamide) (pNIPAM) and a PEG-based block copolymer (referred to as PF127) are commonly used for the preparation of thermo-responsive hydrogels due to their excellent temperature-responsive properties [40,44].The pH-responsive hydrogel can respond to pH changes in the wound site, which is essential in controlled drug release for wound management.For example, tannic acid and metal ions were coordinated to create antibacterial and anti-inflammatory hydrogels that release tannic acid under acidic conditions and are suitable for wound dressings (Figure 1D) [45].
Injectable hydrogels have the unique ability to temporarily become fluidized under shear stress and then recover their original mechanical properties [46].Compared to traditional preformed hydrogels, injectable hydrogels offer several advantages, such as causing less trauma and producing less blood loss, shorter operation time, and faster recovery [47].Minimally invasive procedures can be administered locally with narrow syringes instead of requiring invasive surgery.Their moldability makes them suitable for specific patient interventions, showing great potential for personalized medical treatment [10,22].Reproduced with permission from [28], Copyright 2021, American Chemical Society.(B) Comparative study of heparin-poloxamer hydrogel-modified bFGF and aFGF for in vivo wound healing efficiency.Reproduced with permission from [39], Copyright 2016, American Chemical Society.(C) Fabrication of dual-network hydrogel with injectable, self-healing, and in vitro antibacterial and anti-inflammatory properties.Reproduced with permission from [43], Copyright 2023, American Chemical Society.(D) pH-Responsive tannic-acid-carboxylated agarose composite hydrogels with antibacterial and anti-inflammatory properties for wound healing.Reproduced with permission from [45], Copyright 2016, American Chemical Society.
Hydrogels are a popular choice for wound dressings because of their remarkable ability to attract and hold water, biocompatibility, and versatility.In the last decade, research on hydrogels as wound dressings has increased significantly.Hydrogels are no longer used only to cover wounds; their functions have expanded to include multiple purposes.However, not all individual hydrogels meet all the requirements for wound healing, such as enough antibacterial capacity and suitable mechanical properties.Hydrogels can be combined with other materials, such as therapeutic drugs and inorganic nanoparticles, to improve their properties.

Application of Inorganic Nanomaterials for Wound Healing
Inorganic nanomaterials, typically made from metals, metal oxides, carbon, silica, and other materials, have been widely used in various biomedical applications thanks to their distinct physicochemical properties [48,49].These properties include a small size, large surface area, uniform structure, biocompatibility, bioactivity, and functionalizing ability.Inorganic nanomaterials have garnered significant attention as they are an effective treatment for wound healing.They can deliver therapeutic agents in a controlled manner [50] or display intrinsic properties, such as antibacterial [51,52], anti-inflammatory [53], antioxidant [54], and angiogenesis-promoting abilities [55], to act as a therapeutic agent.Because of their small size and high surface-area-to-volume ratio, nanoparticles can be used to enhance the effectiveness of wound healing treatments.They can increase the chances of interaction and penetration at the wound site, promote cell growth and signaling, and stimulate blood vessel formation [18,56].
Among all the intrinsic therapeutic properties, the antibacterial activities of inorganic nanomaterials have been most widely researched and applied in wound healing.Inorganic antibacterial materials mainly include, but are not limited to, metal ions, metal oxides, metal sulfides, carbon-based and silica-based nanomaterials.The understanding of the antibacterial mechanisms of inorganic nanomaterials is limited, yet the presently acknowledged mechanisms encompass the release of metal ions, induction of oxidative stress, photothermal effect, and implementation of a synergistic antibacterial strategy.
Metal ions, such as Ag + , Au + , Cu 2+ , Zn 2+ , Co 2+ , etc., are commonly used in various antibacterial materials for wound healing.Among them, Ag has a rich historical background as an effective antimicrobial agent in the prevention of infections during the process of wound healing.It is capable of combating a wide range of bacteria, including both Gram-negative and Gram-positive strains, without eliciting antimicrobial resistance.At present, the use of Ag ions for antibacterial applications is still an area of active research [57,58].However, the use of Ag nanoparticles in antibacterial applications is limited by their reported toxicity to animal and human cells [59,60].Au nanoparticles have become of great interest in wound healing due to their high biocompatibility and low toxicity properties [61,62].In addition, due to their small size and high specific surface area, Cu nanoparticles, a non-noble metal, can closely interact with microbial films, releasing Cu 2+ to bind with DNA and showing a bactericidal effect [63].
Some inorganic nanoparticles can produce ROS under the assistance of light irradiation (known as photodynamic therapy, PDT) or endogenous H 2 O 2 (known as chemodynamic therapy, CDT).ROS is considered to be cytotoxic and can be used as an antibacterial agent for infection control during wound healing.PDT is a non-invasive treatment method that utilizes photosensitizers to react with surrounding oxygen species to generate ROS.Usually, photosensitizers mainly consist of inorganic semiconductor materials like TiO 2 and ZnO, which demonstrate remarkable antibacterial performance by leveraging the generation of ROS under visible or UV light exposure [64].Some inorganic nanoparticles, such as iron oxide nanoparticles [65], MnO 2 [66], CeO 2 [67], and MoS 2 (Figure 2A) [68], exhibit peroxidase-like properties and can act as antibacterial agents by reacting with H 2 O 2 to generate ROS.
In recent years, photothermal therapy (PTT) has emerged as an effective alternative therapeutic approach for treating pathogenic bacterial infections.Some inorganic nanoparticles can act as photothermal agents, generating significant heat that deactivates essential proteins and consequently kills bacteria.PTT therapy rapidly damages bacteria, preventing the development of drug-resistant strains.Noble metals (e.g., Au, Ag) [69-71], MoS 2 [72], CuS [73], and 2D materials [74] are commonly employed as low-cost and biocompatible photothermal antibacterial agents due to their excellent light absorption and ease of fabrication.
There has been increasing attention on synergistic antibacterial strategies in recent years.The strategy involves combining two or more antibacterial mechanisms, resulting in greater efficacy compared to single-mode treatment.For example, Yin et al. developed plasmonic-MoO 3−x -nanosheet-supported Ag nanocubes, which serve as highly efficient near-infrared (NIR) light-driven antibacterial agents [75].The synergy of the NIR lightdriven photothermal effect, Ag + release, and photocatalytic reaction allows these hybrid nanoparticles to exhibit excellent antibacterial effects against S. aureus and E. coli.The simultaneous action of multiple mechanisms against microorganisms requires multiple gene mutations for antibacterial resistance to develop.Hybrid nanoparticles with multiple mechanisms prevent microorganisms from developing resistance and are widely used for effective infection control during wound healing (Figure 2B) [76].like TiO2 and ZnO, which demonstrate remarkable antibacterial performance by leveraging the generation of ROS under visible or UV light exposure [64].Some inorganic nanoparticles, such as iron oxide nanoparticles [65], MnO2 [66], CeO2 [67], and MoS2 (Figure 2A) [68], exhibit peroxidase-like properties and can act as antibacterial agents by reacting with H2O2 to generate ROS.
In recent years, photothermal therapy (PTT) has emerged as an effective alternative therapeutic approach for treating pathogenic bacterial infections.Some inorganic nanoparticles can act as photothermal agents, generating significant heat that deactivates essential proteins and consequently kills bacteria.PTT therapy rapidly damages bacteria, preventing the development of drug-resistant strains.Noble metals (e.g., Au, Ag) [69][70][71], MoS2 [72], CuS [73], and 2D materials [74] are commonly employed as low-cost and biocompatible photothermal antibacterial agents due to their excellent light absorption and ease of fabrication.
There has been increasing attention on synergistic antibacterial strategies in recent years.The strategy involves combining two or more antibacterial mechanisms, resulting in greater efficacy compared to single-mode treatment.For example, Yin et al. developed plasmonic-MoO3−x-nanosheet-supported Ag nanocubes, which serve as highly efficient near-infrared (NIR) light-driven antibacterial agents [75].The synergy of the NIR lightdriven photothermal effect, Ag + release, and photocatalytic reaction allows these hybrid nanoparticles to exhibit excellent antibacterial effects against S. aureus and E. coli.The simultaneous action of multiple mechanisms against microorganisms requires multiple gene mutations for antibacterial resistance to develop.Hybrid nanoparticles with multiple mechanisms prevent microorganisms from developing resistance and are widely used for effective infection control during wound healing (Figure 2B) [76].When it comes to wound care, nanomaterials offer unparalleled advantages.Firstly, their high reaction activity and large specific surface area make them more efficient at catalyzing and drug loading.Secondly, nanomaterials possess controllable conductivity and penetration depth into the wound through the modification of nanomaterial size and shape.In addition, it is possible to utilize nanomaterials in other fields for wound healing, such as drug delivery and tumor treatment.Nanomaterials have great potential in wound When it comes to wound care, nanomaterials offer unparalleled advantages.Firstly, their high reaction activity and large specific surface area make them more efficient at catalyzing and drug loading.Secondly, nanomaterials possess controllable conductivity and penetration depth into the wound through the modification of nanomaterial size and shape.In addition, it is possible to utilize nanomaterials in other fields for wound healing, such as drug delivery and tumor treatment.Nanomaterials have great potential in wound healing, but their widespread adoption in commercial and clinical settings still faces challenges.Firstly, some nanoparticles are toxic, which can cause inflammation and oxidative stress in cells, and it is very difficult to collect information on the expected behavior and toxicity of nanoparticles in the human body.Secondly, the function of nanomaterials in wound treatment is single, mainly focused on anti-infection, which cannot meet the complexity requirements of the wound healing process.In addition, it is easy for them to overflow after an in situ injection of nanomaterials into the wound, and it is challenging to ensure sustained effectiveness [19].
Therefore, to achieve wound care based on nanomaterials in clinical practice, it is essential to develop safer and more effective nanoparticle materials.In addition, hydrogels and other carriers can be utilized to prevent the toxicity that may arise due to the burst release of nanomaterials.At the same time, nanomaterials can significantly expand their functions in wound treatment, including hemostasis, moisturizing, adhesion, and the isolation of the external environment.

Inorganic-Nanomaterial-Composited Hydrogel Dressings
Inorganic nanomaterials can be introduced into the hydrogel network through various covalent and non-covalent interactions (electrostatic interactions, hydrogen bonding, π-π stacking, van der Waals forces, and covalent bonding) [77,78].This amalgamation of these two different materials will significantly improve the respective properties and make up for the deficiency.On the one hand, through the incorporation of nanomaterials, mechanical properties, adhesive properties, and stimuli responsiveness of the hydrogel will be greatly improved, and the natural performance of the cross-linked polymer chains in its 3D macromolecular networks will not be affected [79][80][81][82][83]. On the other hand, hydrogels promote the long-term stable dispersion and controlled release of nanomaterials and improve their bioavailability [84,85].
The combination of nanomaterials and hydrogels is considered to generate structural diversity and develop various composite materials with synergistic properties of both components.A lot of inorganic nanomaterials, including metal nanoparticles, metal oxide nanoparticles, metal sulfide nanoparticles, carbon-based nanomaterials, and silica-based nanomaterials, have been integrated into hydrogel networks to form nanocomposite hydrogels.Extensive research has been conducted on nanocomposite hydrogels due to their extraordinary intrinsic characteristics and application prospects in the field of wound dressings.

Metal Nanoparticles
Some noble metal nanoparticles, such as Ag nanoparticles and Au nanoparticles, are attractive due to their unique properties.They have a large surface-to-volume ratio, allowing for increased surface area.They also possess optical and electronic properties and high stability, and can be easily synthesized.Moreover, noble metal nanoparticles are widely used in biological applications, such as antimicrobial agents, due to their excellent compatibility with biomaterials [49].After being incorporated into hydrogels, they can endow the hydrogels with additional antibacterial properties and be applied for bacteriainfected wound healing (Figure 3A) [86].
It has been reported that Ag is effective against a broad spectrum of microorganisms, including aerobic and anaerobic bacteria, Gram-positive and Gram-negative bacteria, as well as fungi and viruses [87].Liu et al. [88] prepared Ag nanoparticles modified with gallic acid (GA-Ag).These GA-Ag nanoparticles showed a remarkable ability to kill bacteria by releasing silver ions (Ag + ) and acting as a photothermal agent under NIR irritation.Then, GA-Ag nanoparticles were incorporated into the network structure of carrageenan to create a nanocomposite hydrogel, which exhibited excellent properties for wound healing, such as blood clotting, swelling, breathability, and anti-dehydration.Research findings show that Ag@graphene oxide nanocomposites exhibit better antibacterial properties than pure Ag nanoparticles [89].Fan et al. cross-linked Ag/graphene composites with acrylic acid and N, N ′ -methylene bisacrylamide to prepare hydrogels, which effectively killed bacteria and promoted wound healing [90].
Au nanoparticles are extensively studied for photothermal sterilization as they offer good stability and high photothermal conversion efficiency [91,92].Li et al. [93] developed a nanocomposite hydrogel wound dressing by incorporating polydopamine-coated gold nanorods into a poly(N-acryloyl glycinamide) network, then being coated with a bacteriaactivated macrophage membrane.The hydrogels produced can precisely identify and eliminate 98% of the source bacteria in vitro, within just 5 min of NIR irradiation, which can speed up the healing process of infected wounds.Moreover, the polymer network is strengthened via multiple hydrogen bonding and the non-covalent interactions between macromolecular chains and Au-based nanoparticles, which improves the mechanical performance of the hydrogel.Au nanoparticles were encapsulated by semiconductor-like metalorganic frameworks to achieve a visible light response and generate ROS efficiently [94].These nanoparticles were then integrated into a biomimetic, injectable double-network hydrogel.The nanocomposite hydrogel exhibited potent antibacterial properties against S. aureus and E. coli, and significantly accelerated the process of wound healing.
Cu nanoparticles have gained significant interest for their potential application in wound healing due to their relatively low production cost, high redox potential, and desired antibacterial activity against a broad range of microorganisms, including both Gram-positive and Gram-negative bacteria, viruses, and fungi.Li et al. [95] developed a hydrogel cross-linked with calcium ions for the controlled release of deferoxamine and Cu nanoparticles.This nanocomposite hydrogel showed antibacterial properties and thus reduced the prolonged inflammatory responses in diabetic wounds.The synergistic effect of deferoxamine and Cu nanoparticles on angiogenesis by increasing HIF-1α and VEGF levels accelerated the closure of diabetic wounds.Moreover, Cu nanoparticles also exhibit photothermal effects like Ag-and Au-based nanoparticles [96].Tao et al. prepared a composite hydrogel combining methacrylate-modified gelatin with N, N-bis(acryloyl)cystaminechelated Cu nanoparticles [97].When exposed to NIR irradiation, the composite hydrogel demonstrated significant antibacterial properties regarding both E. coli and S. aureus, which can be attributed to the synergistic effect of photothermal performance and the released Cu 2+ from Cu nanoparticles.
Kumar and collaborators prepared chitin nanogels containing Ni nanoparticles, which showed desired antibacterial activity and cytocompatibility [98].Moreover, Jin et al. investigated the thermosensitive F127 hydrogel loaded with Ni−Cu bimetallic nanospheres to accelerate the healing of acute wounds (Figure 3B) [99].The CAT-like and SOD-like enzymatic activities were observed in the Ni−Cu nanospheres, aiding in the scavenging of free radicals.The composite hydrogel showcased distinctive properties against inflammation, reducing inflammatory factor secretion and macrophage polarization.Furthermore, it stimulated angiogenesis, promoted collagen formation, and accelerated wound re-epithelialization.

Metal Oxide Nanoparticles
Due to their ability to release metal ions or exhibit enzyme-mimicking catalytic properties and photothermal effects, metal oxide nanoparticles, such as MnO2, CuO, ZnO, and CeO2, are widely applied for anti-infection and promoting wound healing.
MnO2 nanoparticles, mostly nanosheets, can mimic various enzymatic activities, such as catalytic, oxidative, peroxidase, and superoxide dismutase activities, and have emerged as multifunctional nanoplatforms for biomedical applications [100,101].Besides serving as MRI contrast agents, they can also function as nanoenzymes that decompose H2O2 and generate O2 and have been widely studied for alleviating hypoxia and improving oxygen-

Metal Oxide Nanoparticles
Due to their ability to release metal ions or exhibit enzyme-mimicking catalytic properties and photothermal effects, metal oxide nanoparticles, such as MnO 2 , CuO, ZnO, and CeO 2 , are widely applied for anti-infection and promoting wound healing.
MnO 2 nanoparticles, mostly nanosheets, can mimic various enzymatic activities, such as catalytic, oxidative, peroxidase, and superoxide dismutase activities, and have emerged as multifunctional nanoplatforms for biomedical applications [100,101].Besides serving as MRI contrast agents, they can also function as nanoenzymes that decompose H 2 O 2 and generate O 2 and have been widely studied for alleviating hypoxia and improving oxygen-based therapies [102][103][104].In addition, MnO 2 nanoparticles are effective in catalyzing H 2 O 2 into hydroxyl radicals via a Fenton-like catalytic reaction [105,106] and also show a high photothermal conversion capacity under NIR irradiation [107].Crucially, MnO 2 displays excellent biocompatibility since manganese is an essential and nontoxic component vital to physiological metabolism [108,109].Based on the above multifunctional characteristics, MnO 2 nanoparticles are the most promising candidate for wound repair applications.MnO 2 nanosheets have some limitations, such as the inability to sustain catalytic action, short action time, and difficulty in degradation.Additionally, using MnO 2 nanosheets alone may result in inaccurate dosage control, as the burst release of metal ions can cause undesirable side effects.Consequently, MnO 2 nanosheets have been incorporated into hydrogels with good biocompatibility to form multifunctional composite hydrogels [110,111].
Tu et al. [112] synthesized a new type of multifunctional nanomaterial by compositing hyperbranched poly-L-lysine with MnO 2 nanosheets, resulting in improved dispersion stability and antibacterial properties.This nanomaterial was then cross-linked with hydrophilic polymers to form a hydrogel.Moreover, the water-soluble drug of pravastatin sodium was mixed into the hydrogel before cross-linking.The results showed that the hydrogel dressing could scavenge various types of ROS, produce O 2 , stimulate NO synthesis, and effectively eliminate methicillin-resistant S. aureus, reducing inflammation and accelerating wound healing (Figure 4A).MnO 2 nanosheets are known for their high photothermal conversion efficiency among photothermally active materials.They have been used as antibacterial agents under NIR irradiation, resulting in rapid and highly effective antibacterial efficacy [113] and promoting wound healing [114].A hybrid hydrogel made of gelatin, iron, and MnO 2 nanosheets, prepared through multiple interactions, has been used to treat bacteria-infected wounds.This hydrogel combines photothermal therapy (PTT), chemodynamic therapy (CDT), and gas therapy (O 2 evolution) for better efficacy [115].
CuO nanoparticles exhibit excellent photocatalytic and antimicrobial activity, demonstrating their significance in ecological and antimicrobial applications [116,117].Copper ions have been proven to induce vascular endothelial growth factor expression and stimulate angiogenesis [118,119]; therefore, CuO nanoparticles have been widely investigated for bacterial elimination and improving wound healing [120,121].Abdollahi and colleagues [122] developed a nanocomposite hydrogel containing sodium carboxymethyl starch (CMS) and CuO nanoparticles via solution-casting, utilizing citric acid as a crosslinking agent.The nanocomposite hydrogel exhibited good antibacterial and antioxidant activities and accelerated wound healing.The incorporation of CuO nanoparticles into the CMS hydrogel improved its thermal stability and swelling properties and also enhanced the antioxidant activity and antibacterial properties.Wang et al. [123] developed a sprayable hydrogel that contains virus-like hollow mesoporous CuO nanospheres modified with glucose oxidase.The hydrogel helps restore diabetic foot ulcers by promoting angiogenesis, alleviating hypoxia, and exhibiting antibacterial properties (Figure 4B).In the presence of high glucose levels in bacterial biofilms, glucose can be converted by CuO nanospheres into H 2 O 2 , which can produce toxic •OH to be used as an antibacterial agent.During the inflammatory stage of wound healing, after bacteria have been eradicated, CuO nanospheres can be utilized as catalase mimics and catalyze the production of large amounts of O 2 by intracellular H 2 O 2 , thereby alleviating hypoxia.At the same time, the Cu 2+ ions released from these nanospheres can promote the proliferation and migration of keratinocytes and induce the formation of tubules by endothelial cells, therefore promoting diabetic foot ulcer healing.
ZnO nanoparticles are well known for their remarkable photocatalytic and antimicrobial properties [124], and Zn 2+ released from ZnO can stimulate the production of fibroblasts and immune cells that are essential during skin regeneration.Therefore, ZnO nanoparticles have been extensively utilized to treat both topical and systemic diseases, particularly for wound healing purposes [125,126].It has been observed that the antimicrobial activity of ZnO nanoparticles increases as their particle size decreases [127].However, larger ZnO nanoparticles have been found to promote the growth of fibroblast cells [128].There are concerns about the toxicity of ZnO nanoparticles both in vivo and in vitro [129,130].Studies have shown that incorporating nanoparticles into polymeric hydrogel matrices reduces toxicity and improves effectiveness through controlled and sustained release [131].
Mao et al. [132] developed a composite hydrogel that contains Ag/Ag@AgCl/ZnO hybrid nanostructures and carboxymethyl cellulose.The composite hydrogel has a broadspectrum antibacterial activity against both Gram-negative and Gram-positive bacteria when exposed to visible light, which results in rapid sterilization.Moreover, the hydrogel possesses a pH-responsive swelling-shrinking property, which allows for controlled and sustained release of Ag + and Zn 2+ , resulting in synergistic antibacterial activities and expedited wound healing.Zhang et al. [133] developed ZnO-incorporated chitin-based hydrogels with a one-pot, environment-friendly, and efficient strategy.The chitin/ZnO composite hydrogels exhibit excellent antibacterial activity and acceptable biocompatibility, and accelerate healing of infectious full-thickness wounds.Hu and collaborators [134] prepared a fusiform zinc oxide nanorod (brZnO), which is more likely to penetrate bacterial cell walls than spherical particles.They combined brZnO with carboxymethyl chitosan to create an injectable, multifunctional hydrogel.The brZnO is both a cross-linking agent and a nano-filler, which helped to shorten the gel time, improve the cross-linking degree, and enhance the mechanical strength of the hydrogel.The resulting hydrogel has good antibacterial properties against E. coli and S. aureus.Furthermore, the slow and sustainable release of Zn 2+ significantly promotes wound healing and reduces inflammatory responses (Figure 4C).
Low levels of ROS are beneficial in wound healing as they aid in preventing the entry of bacteria and other pathogens and are involved in intracellular signaling.However, excessive ROS can cause oxidative stress, which can delay the wound healing process by preventing the transition from the inflammatory stage to the proliferative stage at the wound site [135,136].Cerium oxide (CeO 2 ) nanoparticles have been known to be able to generate ROS under light irradiation due to their semiconductor properties [137,138], effectively killing bacteria, which can prevent wound infection and promote wound healing during the inflammation stage.On the other hand, CeO 2 nanoparticles have also demonstrated excellent ROS scavenging ability, such as for the hydroxyl radical [139] and superoxide anion [140].Therefore, CeO 2 nanoparticles promote wound healing during the proliferation stage by enhancing fibroblast, keratinocyte, and vascular endothelial cell (VEC) proliferation and migration [141].Due to their excellent biological properties, including anti-inflammatory, antioxidant, antibacterial, and angiogenic functions, CeO 2 nanoparticles can benefit wound healing in multiple stages [142,143].
CeO 2 nanoparticles can be incorporated into various polymer-based scaffolds [144] to prevent their aggregation and provide sustained release systems, reducing potential toxicity.A catechol-modified sprayable hydrogel was designed and characterized by Cheng et al. [145].It was loaded with an antimicrobial peptide and CeO 2 nanoparticles, which were uniformly dispersed in the hydrogel scaffold.The antimicrobial peptide helped to eliminate bacteria, while the CeO 2 nanoparticles were utilized to reduce the production of reactive oxygen species by exploiting the inflammatory response.Gong and colleagues developed an antioxidant nanocomposite hydrogel by incorporating amino-group-modified CeO 2 nanorods into a hydrogel that contained PF127 [146].Combining the ROS-scavenging ability of CeO 2 nanorods with the advantages of hydrogels, the nanocomposite hydrogel exhibits multifunctional properties such as thermal sensitivity, injectability, self-healing, and excellent ROS scavenging ability.Similarly, Zheng and colleagues combined 2D antibacterial conductive Ti3C2Tx MXenes and antioxidant CeO 2 to prepare nanocomposites, which were then incorporated in a dynamic Schiff-based chemical cross-linked hydrogel of polyethyleneimine grafted PF127 and oxidized sodium alginate [147].This hydrogel scaffold can be used for multimodal therapy in the treatment of skin infected with multidrug-resistant (MDR) bacteria.It possesses multifunctional properties, including fast hemostatic capacity; antibacterial, anti-inflammatory, and conductive bioactivities; and antioxidative abilities.Additionally, it is tissue-adhesive and shows injectable and selfhealing behavior (Figure 4D).

Metal Sulfide Nanoparticles
Some metal sulfide nanoparticles exhibit excellent photodynamic and photothermal properties when exposed to NIR light.Consequently, they have emerged as a promising nanoplatform with vast potential for biomedical applications.In recent years, CuS [148,149], MoS2 [150,151], Ag2S [152,153], WS2 [154,155], etc., have been widely used as photodynamic and photothermal therapeutic agents for promoting bacteria-infected wound healing.
CuS nanoparticles have been shown to be promising candidates for in vivo photothermal therapy, which is due to their strong ability to absorb NIR radiation and their photostability, low cost, and biodegradability [156,157].Under NIR radiation, CuS nanoparticles can serve as photosensitizers for photothermal therapy and also trigger the generation of ROS for photodynamic therapy [158].This property may enhance its antibacterial efficacy when CuS is exposed to NIR irradiation.In addition, CuS-based nanomaterials have been proven to accelerate the process of wound healing by stimulating cell proliferation and promoting angiogenesis [159][160][161][162].However, the biocompatibility of Cu

Metal Sulfide Nanoparticles
Some metal sulfide nanoparticles exhibit excellent photodynamic and photothermal properties when exposed to NIR light.Consequently, they have emerged as a promising nanoplatform with vast potential for biomedical applications.In recent years, CuS [148,149], MoS 2 [150,151], Ag 2 S [152,153], WS 2 [154,155], etc., have been widely used as photodynamic and photothermal therapeutic agents for promoting bacteria-infected wound healing.
CuS nanoparticles have been shown to be promising candidates for in vivo photothermal therapy, which is due to their strong ability to absorb NIR radiation and their photostability, low cost, and biodegradability [156,157].Under NIR radiation, CuS nanoparticles can serve as photosensitizers for photothermal therapy and also trigger the generation of ROS for photodynamic therapy [158].This property may enhance its antibacterial efficacy when CuS is exposed to NIR irradiation.In addition, CuS-based nanomaterials have been proven to accelerate the process of wound healing by stimulating cell proliferation and promoting angiogenesis [159][160][161][162].However, the biocompatibility of Cu ions is of great concern, especially at high concentrations.Therefore, the controlled release of Cu ions instead of a burst release is crucial in biomedical applications.Combining CuS nanoparticles with hydrogels can be a viable solution.Li et al. [163] modified CuS nanoparticles using mesoporous silica to enable tight and uniform grafting onto a hydrogel, which comprised N-isopropyl acrylamide and acrylamide.The NIR light irradiation can alter the intrinsic volume of this hybrid hydrogel and, therefore, control the rate of Cu ion release into the physiological environment.The results indicated high antibacterial efficacy of the hydrogel against S. aureus and E. coli (99.80% and 99.94%, respectively) under NIR light irradiation within 10 min.The CuS nanoparticle hybrid hydrogels exhibit excellent noninvasive rapid bacteria-killing and wound-healing acceleration due to the synergistic photothermal and photodynamic effects and the effect of the released Cu ions during NIR irradiation.
Lin et al. [164] incorporated CuS nanoparticles into biodegradable hyaluronic acid hydrogels through metal-ligand interactions, using Fe 3+ -EDTA complexes as cross-linking agents.Bacteria can attach to the hydrogel surface, produce hyaluronidase, and break down hyaluronic acid, releasing Fe 3+ .The Fe 3+ is then converted to Fe 2+ within the microenvironment of bacteria, which leads to the formation of hydroxyl radicals, ultimately resulting in localized CDT-based sterilization.Moreover, the photothermal properties of CuS nanoparticles can achieve low-temperature photothermal sterilization, improving antibacterial efficiency and minimizing damage to normal tissues.The synergistic function of localized CDT and low-temperature PTT effectively promotes the S. aureus-infected wound healing process in vivo (Figure 5A).
MoS 2 nanoparticles are also one of the two-dimensional materials that exhibit broad spectral responses from UV to NIR, enabling the generation of hyperthermia and ROS [165,166].In addition, Mo is an essential trace element for certain types of cellular enzymes, and S is an abundant element in biological systems.Because of these factors, MoS 2 is biocompatible and an excellent choice for biological applications [167].It has been demonstrated that MoS 2 showed excellent photothermal conversion ability and low cytotoxicity [168,169], making it a promising photothermal antibacterial agent for bacteria-infected wound healing therapy [170].Zhang and collaborators [171] developed a composite hydrogel that contains CuS@MoS 2 microspheres.The CuS@MoS 2 -incorporated hydrogel demonstrated remarkable antibacterial activity against both S. aureus and E. coli within 10 min due to the synergistic effect of PDT and PTT under the co-irradiation of 660 nm of visible light and 808 nm of NIR (Figure 5B).The hydrogel enhanced endothelial cell proliferation and differentiation and the secretion of HIF-1α and VEGF, promoting vascularization and accelerating wound healing.
Li and coworkers [172] developed a type of nanosheet (MoS 2 @TA/FeNSS) made from MoS 2 that was chelated with tannic acid (TA) and decorated with Fe.Then, MoS 2 @TA/ FeNSS was embedded into a hydrogel that is adhesive and self-healing and can adapt to different shapes.The resulting composite hydrogel exhibits excellent antibacterial activity through glutathione loss, PTT, and peroxidase-like activity of MoS 2 when exposed to acidic conditions.On the other hand, when in a neutral environment, the hydrogel was capable of providing oxygen using the CAT-like enzymes of TA/Fe, it had antioxidant properties by scavenging ROS and RNS, and it also showed anti-inflammatory activity by TA.

Carbon-Based Nanomaterials
Graphene oxide (GO) and carbon nanotubes (CNTs) are carbon-based nanomaterials that exhibit promising potential in the field of biomedical applications because of their excellent mechanical properties, high conductivity, and unique optical properties [173][174][175].It was found that a wound-induced electric current may stimulate tissue growth, so an external electric current can be applied at the wound site to mimic endogenous electrical stimulation, thereby accelerating wound closure.Carbon-based conductive materials have the potential to enhance the activity of electrically responsive cells and monitor the process of wound healing, offering an opportunity for the improvement in traditional wound dressings [176].Carbon-based nanomaterials pose an obstacle to biomedical use because of their poor biodegradability and potential long-term toxicity, which can be mitigated by incorporating them into hydrogel systems.
CNTs possess remarkable properties such as excellent electrical conductivity, compact dimensions, and an expansive surface area.These unique characteristics facilitate their interaction with biomolecules, cells, and tissues, ultimately resulting in a substantial improvement in the bioactivity of wound dressings.He and coworkers [177] reported several hydrogels prepared from N-carboxyethyl chitosan, benzaldehyde-terminated PF127, and CNTs.These nanocomposite hydrogels exhibit conductive, adhesive, and self-healing properties and can be applied as wound dressings.Introducing CNTs to the hydrogels resulted in a shorter gelation time and improved mechanical properties due to strong ππ stacking interactions among individual CNTs.Due to their strong interaction with skin tissues, hydrogels showed remarkable adhesion behaviors, resulting in good hemostatic capability.These hydrogels containing CNTs showed excellent photothermal effects, suggesting potential for treating bacteria-infected wounds via PTT.Furthermore, their conductive properties suggest great potential for transferring bioelectrical signals and accelerating wound healing (Figure 6A).In another report, antibacterial, adhesive, antioxidant, conductive, and injectable composite hydrogels were prepared via coupling of catechol groups between polydopamine-coated carbon nanotubes (CNT-PDA) and gelatin-grafted dopamine (GT-DA) [178].The incorporation of the antimicrobial agent doxycycline into the hydrogel exhibited sustained patterns of drug release and favorable antibacterial characteristics.CNT-PDA conferred improved photothermal and broad-spectrum antimicrobial activities to these hydrogels.Dopamine contributed to their tissue adhesion, hemostatic effects, and superior antioxidative properties.

Carbon-Based Nanomaterials
Graphene oxide (GO) and carbon nanotubes (CNTs) are carbon-based nanomaterials that exhibit promising potential in the field of biomedical applications because of their excellent mechanical properties, high conductivity, and unique optical properties [173][174][175].It was found that a wound-induced electric current may stimulate tissue growth, so an external electric current can be applied at the wound site to mimic endogenous electrical stimulation, thereby accelerating wound closure.Carbon-based conductive materials have the potential to enhance the activity of electrically responsive cells and monitor the process of wound healing, offering an opportunity for the improvement in traditional wound dressings [176].Carbon-based nanomaterials pose an obstacle to biomedical use because of their poor biodegradability and potential long-term toxicity, which can be mitigated by incorporating them into hydrogel systems.
CNTs possess remarkable properties such as excellent electrical conductivity, compact dimensions, and an expansive surface area.These unique characteristics facilitate their interaction with biomolecules, cells, and tissues, ultimately resulting in a substantial improvement in the bioactivity of wound dressings.He and coworkers [177] reported several hydrogels prepared from N-carboxyethyl chitosan, benzaldehyde-terminated PF127, and CNTs.These nanocomposite hydrogels exhibit conductive, adhesive, and self-healing properties and can be applied as wound dressings.Introducing CNTs to the hydrogels resulted in a shorter gelation time and improved mechanical properties due to strong π-π stacking interactions among individual CNTs.Due to their strong interaction with skin tissues, hydrogels showed remarkable adhesion behaviors, resulting in good hemostatic capability.These hydrogels containing CNTs showed excellent photothermal effects, suggesting potential for treating bacteria-infected wounds via PTT.Furthermore, their conductive properties suggest great potential for transferring bioelectrical signals and accelerating wound healing (Figure 6A).In another report, antibacterial, adhesive, antioxidant, conductive, and injectable composite hydrogels were prepared via coupling of catechol groups between polydopamine-coated carbon nanotubes (CNT-PDA) and gelatin-grafted dopamine (GT-DA) [178].The incorporation of the antimicrobial agent doxycycline into the hydrogel exhibited sustained patterns of drug release and favorable antibacterial characteristics.CNT-PDA conferred improved photothermal and broad-spectrum antimicrobial activities to these hydrogels.Dopamine contributed to their tissue adhesion, hemostatic effects, and superior antioxidative properties.GO exhibits low cytotoxicity, high dispersion in aqueous solutions, and high biocompatibility [179].Its promising applications against MDR bacteria are attributed to its strong ability to disrupt microbial membranes [180,181].Additionally, GO has been found to have a photothermal effect that can be used for antibacterial therapies [182,183].Therefore, GO possesses the ability to serve as an effective antibacterial agent for the treatment of wounds infected by bacteria.Huang et al. [184] applied β-cyclodextrin (βCD)functionalized GO as NIR-responsive nanocarriers to deliver the NO donor (BNN6) for bacteria-infected wound healing.The nanocarriers were incorporated into a hydrogel made of methacrylate-modified gelatin (GelMA) and hyaluronic acid graft dopamine (HA-DA).The combination of gas and photothermal therapy effectively improved antibacterial effects and overcame heat-resistant bacterial species while also exhibiting anti-inflammatory action and promoting angiogenesis under NIR irradiation (Figure 6B).GO exhibits low cytotoxicity, high dispersion in aqueous solutions, and high biocompatibility [179].Its promising applications against MDR bacteria are attributed to its strong ability to disrupt microbial membranes [180,181].Additionally, GO has been found to have a photothermal effect that can be used for antibacterial therapies [182,183].Therefore, GO possesses the ability to serve as an effective antibacterial agent for the treatment of wounds infected by bacteria.Huang et al. [184] applied β-cyclodextrin (βCD)-functionalized GO as NIR-responsive nanocarriers to deliver the NO donor (BNN6) for bacteriainfected wound healing.The nanocarriers were incorporated into a hydrogel made of methacrylate-modified gelatin (GelMA) and hyaluronic acid graft dopamine (HA-DA).The combination of gas and photothermal therapy effectively improved antibacterial effects and overcame heat-resistant bacterial species while also exhibiting anti-inflammatory action and promoting angiogenesis under NIR irradiation (Figure 6B).

Silica-Based Nanomaterials
Silica-based nanoparticles possess many exceptional benefits, such as extensive specific surface area and pore volume, heightened loading capacity, convenient surface modification opportunities, favorable biocompatibility, and the ability to enhance drug bioavailability.These attributes make them highly promising in fields like imaging, energy storage, and especially biomedicine [185,186].Mesoporous silica nanoparticles (MS-NPs) are often used as nanocarriers for drug delivery systems due to their honeycomb-like porous structures [187].MS-NPs have the ability to modify their drug loading capacity depending on the desired dosage, making fewer doses possible.This is achieved through controlling the particle shape and size, as well as the manipulation of mesoporous dimensions and pore shapes [188,189].Furthermore, research has indicated that MS-NPs have the potential to function as convenient and highly adaptable adhesives to meet the requirements of wound closure.Additionally, they can prompt appropriate inflammation while preventing prolonged inflammation and expediting the wound healing procedure [190].
As previously mentioned, the hydrogels' poor mechanical properties present a significant constraint in biomedical use.To overcome this limitation, incorporating silicabased nanoparticles into the polymeric networks of hydrogels has been found to enhance their mechanical strength [191,192].This improvement in mechanical strength makes

Silica-Based Nanomaterials
Silica-based nanoparticles possess many exceptional benefits, such as extensive specific surface area and pore volume, heightened loading capacity, convenient surface modification opportunities, favorable biocompatibility, and the ability to enhance drug bioavailability.These attributes make them highly promising in fields like imaging, energy storage, and especially biomedicine [185,186].Mesoporous silica nanoparticles (MS-NPs) are often used as nanocarriers for drug delivery systems due to their honeycomb-like porous structures [187].MS-NPs have the ability to modify their drug loading capacity depending on the desired dosage, making fewer doses possible.This is achieved through controlling the particle shape and size, as well as the manipulation of mesoporous dimensions and pore shapes [188,189].Furthermore, research has indicated that MS-NPs have the potential to function as convenient and highly adaptable adhesives to meet the requirements of wound closure.Additionally, they can prompt appropriate inflammation while preventing prolonged inflammation and expediting the wound healing procedure [190].
As previously mentioned, the hydrogels' poor mechanical properties present a significant constraint in biomedical use.To overcome this limitation, incorporating silica-based nanoparticles into the polymeric networks of hydrogels has been found to enhance their mechanical strength [191,192].This improvement in mechanical strength makes nanocomposite hydrogels a promising option for various biomedical applications.Nikdel et al. explored novel biodegradable material treated with polyvinyl alcohol hydrogel, which included ZnO nanoparticles and MS-NPs.The material exhibited excellent antibacterial properties against E. coli and S. aureus and could be applied as medical dressings for infected skin wounds [193].It has been noticed that the produced nanocomposite has a significant ability to absorb water via swelling.Moreover, the addition of ZnO nanoparticles and MS-NPs to the hydrogel structure has raised the swelling ratio of the specimens to about eight times.
The use of pure hydrogel is also limited due to its poor ability to sustain drug release.Nanocomposite hydrogel systems can be developed to stabilize drug molecules and slow down the release rate.Nanocomposite hydrogels greatly benefit from the incorporation of silica nanoparticles as they enhance mechanical properties, enable sustained drug release, and exhibit versatile functionality.Xue et al. [194] developed a composite hydrogel by using scaffold methacrylate gelatin (GelMA), methacrylate hyaluronic acid (HAMA), and MS-NPs.This hydrogel was created for the sustained release of an Artemisia argyi extract (AE), which can help in treating chronic wounds.The prepared GelMA/1%HAMA hydrogel has stable rheological properties, appropriate mechanical strength, biodegradability, and swelling characteristics.Moreover, the considerable specific surface area and pore volume of MS-NPs can be utilized to attain sustained and controlled release of AE in hydrogels.As a result of their antibacterial and anti-inflammatory properties, the hydrogels promote M2 macrophage polarization, enhance collagen deposition and angiogenesis, and effectively promote wound healing.
It was reported that amorphous silica nanoparticles could penetrate platelet plasma membranes and induce platelet aggregation [195], indicating potential applications for hemostasis.Silica nanoparticles are often incorporated into hydrogel systems to prevent their diffusion into normal blood vessels.Liu et al. [196] developed a polydopamine-coated silica nanoparticle (PDA/SiNP) exhibiting commendable degradability and antibacterial efficacy, displaying the potential use for controlling hemorrhage.The extrinsic pathway of the coagulation cascade might be triggered by the porous PDA/SiNP, leading to platelet adhesion, enhancing erythrocyte aggregation, accelerating blood clotting, and realizing hemorrhage control (Figure 7A).In a similar study, Sundaram and coworkers developed injectable chitosan-bioglass nanocomposite hydrogels, which exhibited faster blood clotting compared to chitosan hydrogel alone (Figure 7B) [197].Bioglass is an inorganic bioactive material consisting of SiO 2 , Na 2 O, CaO, and P 2 O 5 .It has been embedded into a hydrogel system to develop bioactive hydrogel wound dressing, which can regulate the inflammatory response of the host.Additionally, it can enhance the movement and growth of endothelial cells and fibroblasts, which in turn helps to stimulate the formation of new blood vessels and the development of granulation tissue, ultimately resulting in faster wound healing [198,199].
In summary, silica-based nanoparticles can improve the mechanical properties of hydrogel wound dressings, as well as sustained and controllable drug release.They possess antibacterial and hemostatic properties and also promote angiogenesis and granulation tissue formation, thus promoting wound healing.
In conclusion, the combination of inorganic nanomaterials and hydrogels would produce composite materials with a variety of characteristics and multi-functions, which can meet the complex needs of various stages of wound healing and are considered to be promising wound dressings.Table 1 summarizes some of the inorganic-nanomaterialcomposited hydrogel dressings outlined in this paper, along with their multi-functions and diverse characteristics for wound healing.In conclusion, the combination of inorganic nanomaterials and hydrogels would produce composite materials with a variety of characteristics and multi-functions, which can meet the complex needs of various stages of wound healing and are considered to be promising wound dressings.Table 1 summarizes some of the inorganic-nanomaterialcomposited hydrogel dressings outlined in this paper, along with their multi-functions and diverse characteristics for wound healing.
However, wound healing is a very complex process that goes through multiple stages, and the wound environment and demand for wound dressings in each stage are different, even contradictory.For example, ROS can kill bacteria in bacteria-infected wounds during the inflammatory stage, but it needs to be elevated during the proliferation stage.Therefore, although the inorganic-nanomaterial-composite hydrogel dressings possess a variety of characteristics and multi-functions, it is not easy to regulate and control them accurately to meet the intricate needs of each stage.This will be the main limitation for the clinical application of inorganic-nanomaterial-composite hydrogel dressings.

Categories Inorganic Nanomaterials
Functions and Characteristics of Nanocomposite Hydrogels Refs.

Metal sulfide nanoparticles
CuS NIR-responsive photothermal and photodynamic properties, antibacterial activity, controlled release, skin tissue regeneration, biodegradable [163,164] MoS 2 photothermal and photodynamic synergistic effects, vascularization, antibacterial activity, anti-inflammation, peroxidase-like activity, catalase-like activity [171,172] Ag 2 S NIR-responsive, multimodal antibacterial, highly biocompatible [153] WS 2 injectable, self-adapting, rapidly molding, good tissue adherence, excellent biocompatibility, NIR-responsive, antioxidant, antibacterial activity [155] Carbon-based nanomaterials carbon nanotubes conductive, adhesive, self-healing, hemostasis, antioxidant, injectable, photothermal antibacterial activity [176][177][178] graphene oxide photodynamic and photothermal effect, anti-inflammatory, antibacterial activity, promoting angiogenesis [181,182,184] Silica-based nanomaterials mesoporous silica nanoparticles stable rheological property, appropriate mechanical strength, biodegradability, excellent swelling characteristics, sustained and controlled drug release, antibacterial activity [193,194] amorphous silica nanoparticles degradability, antibacterial activity, platelet aggregation, rapid hemostasis [195,196] bioglass injectability, adhesiveness, bioactivity, bleeding control, promoting revascularization [197][198][199] However, wound healing is a very complex process that goes through multiple stages, and the wound environment and demand for wound dressings in each stage are different, even contradictory.For example, ROS can kill bacteria in bacteria-infected wounds during the inflammatory stage, but it needs to be elevated during the proliferation stage.Therefore, although the inorganic-nanomaterial-composite hydrogel dressings possess a variety of characteristics and multi-functions, it is not easy to regulate and control them accurately to meet the intricate needs of each stage.This will be the main limitation for the clinical application of inorganic-nanomaterial-composite hydrogel dressings.

Summary and Prospect
Chronic wounds can be a considerable challenge for patients, doctors, and their families.Wound dressings can cover the wound, improve the surrounding environment, and promote healing.The integration of novel technologies is progressively merging with the advancement of wound dressings, providing better solutions for effective wound management.Various nanocomposite hydrogel dressings have been developed based on different principles and strategies.These dressings leverage the benefits of nanotechnology and hydrogel dressings, offering innovative wound care solutions.However, it remains necessary to investigate the secure and efficient transition of these dressings from experimental investigations to their practical implementation in clinical settings.
Most hydrogel dressings have poor mechanical properties and may break when subjected to external force, leading to bacterial invasion and hindering the healing process.As such, many researchers use physical or chemical methods to create nanomaterial-based hydrogel dressings, which enhance the mechanical properties of hydrogels, allowing them to cover wounds better and therefore minimizing the risk of infection.However, the interaction between hydrogels and nanomaterials is complex.The further understanding and in-depth exploration of their interaction mechanism will be more conducive to the controllable adjustment of nanocomposite hydrogel dressings to meet the needs of different wound environments.
In clinical practice, wounds can vary significantly in terms of their shape, depth, cause of injury, and infection status, and the patient's physical condition.These differences can make it challenging for wound dressings to meet the specific needs of each wound, ultimately resulting in unsatisfactory therapeutic outcomes.To effectively treat wounds, it is crucial to thoroughly understand the individual patient's situation and the specific environment of the wound itself.Based on this information, personalized wound dressings are developed and tailored to each wound's particular needs.Personalized wound dressings may have adjustable or controllable properties, including shape, composition, mechanical properties, and optional functions.Nanocomposite hydrogel dressings offer a diverse selection for personalized wound care, given their varied composition, structure, and multi-functions.
Wound healing is an intricate biochemical procedure that encompasses several stages.Each stage necessitates different functionalities from wound dressings, including but not limited to hemostasis, anti-infection, and the promotion of repair.The development of a wound dressing that fulfills the requirements of the entire wound healing process poses a significant challenge.Consequently, it becomes imperative to take into account the entirety of the wound healing process during the design of wound dressings.Corresponding functions should be designed according to the needs of different stages, and wound dressings should be replaced in a certain order during use.However, it is difficult to distinguish the boundaries between different stages of wound healing accurately, and frequent replacement of wound dressings also increases the burden on wound care and patients.Stimuli-responsive nanocomposite hydrogel dressing can make corresponding responses according to the changes in the temperature, pH, ROS level, and glucose during wound healing, actively changing the wound environment to meet the needs of different stages of wound healing.
In conclusion, nanocomposite hydrogel dressings combine the advantages of nanomaterials and hydrogels, making up for their respective shortcomings and providing research ideas for designing multifunctional, personalized, and smart wound dressings.Despite the many challenges that need to be conquered before their implementation in clinics, these innovations provide increased potential for enhancing wound management in terms of effectiveness, convenience, and precision.

Figure 1 .
Figure 1.Application of hydrogels for wound healing.(A) Schematic illustration for the preparation of dual-dynamic-bond cross-linked adhesive hydrogel and its applications in infected wound healing.Reproduced with permission from [28], Copyright 2021, American Chemical Society.(B) Comparative study of heparin-poloxamer hydrogel-modified bFGF and aFGF for in vivo wound healing

Figure 1 .
Figure 1.Application of hydrogels for wound healing.(A) Schematic illustration for the preparation of dual-dynamic-bond cross-linked adhesive hydrogel and its applications in infected wound healing.Reproduced with permission from[28], Copyright 2021, American Chemical Society.(B) Comparative study of heparin-poloxamer hydrogel-modified bFGF and aFGF for in vivo wound healing efficiency.Reproduced with permission from[39], Copyright 2016, American Chemical Society.(C) Fabrication of dual-network hydrogel with injectable, self-healing, and in vitro antibacterial and anti-inflammatory properties.Reproduced with permission from[43], Copyright 2023, American Chemical Society.(D) pH-Responsive tannic-acid-carboxylated agarose composite hydrogels with antibacterial and anti-inflammatory properties for wound healing.Reproduced with permission from[45], Copyright 2016, American Chemical Society.

Figure 2 .
Figure 2. Application of inorganic nanomaterials for wound healing.(A) Synthesis of light-modulated nanozyme based on MoS2 and its application for Gram-selective antimicrobial activity.Reproduced with permission from [68], Copyright 2018, American Chemical Society.(B) Schematic illustration of the preparation of carbon-iron-oxide nanohybrid with rough surfaces and its antibacterial mechanism for synergistic antibacterial therapy.Reproduced with permission from [76], Copyright 2021, American Chemical Society.

Figure 2 .
Figure 2. Application of inorganic nanomaterials for wound healing.(A) Synthesis of light-modulated nanozyme based on MoS 2 and its application for Gram-selective antimicrobial activity.Reproduced with permission from [68], Copyright 2018, American Chemical Society.(B) Schematic illustration of the preparation of carbon-iron-oxide nanohybrid with rough surfaces and its antibacterial mechanism for synergistic antibacterial therapy.Reproduced with permission from [76], Copyright 2021, American Chemical Society.

27 Figure 3 .
Figure 3. Nanocomposite hydrogels containing metal nanoparticles for wound healing.(A) Preparation of a hydrogel composite containing non-releasing silver nanoparticle colloids with potent hemostatic and photodynamic bactericidal properties, and its application for promoting wound healing.Reproduced with permission from [86], Copyright 2023, American Chemical Society.(B) Schematic diagram of the preparation of the thermosensitive composite hydrogel loaded with Ni−Cu bimetallic nanospheres and application for accelerating acute wound healing.Reproduced with permission from [99], Copyright 2022, American Chemical Society.

Figure 3 .
Figure 3. Nanocomposite hydrogels containing metal nanoparticles for wound healing.(A) Preparation of a hydrogel composite containing non-releasing silver nanoparticle colloids with potent hemostatic and photodynamic bactericidal properties, and its application for promoting wound healing.Reproduced with permission from [86], Copyright 2023, American Chemical Society.(B) Schematic diagram of the preparation of the thermosensitive composite hydrogel loaded with Ni−Cu bimetallic nanospheres and application for accelerating acute wound healing.Reproduced with permission from [99], Copyright 2022, American Chemical Society.

Figure 4 .
Figure 4. Nanocomposite hydrogels containing metal oxide nanoparticles for wound healing.(A) Fabrication of ROS-scavenging, O 2 -generating, and NO-producing antibacterial hydrogel containing MnO 2 nanosheets and application for killing bacteria, relieving inflammation, and promoting wound healing.Reproduced with permission from [112], Copyright 2022, Elsevier.(B) A sprayable hydrogel containing glucose-oxidase-modified virus-like hollow mesoporous CuO nanospheres used for synergistic diabetic foot ulcer healing through the synergistic effect of antibacterial and angiogenesis promotion, and hypoxia alleviation.Reproduced with permission from [123], Copyright 2021, Elsevier.(C) An injectable ZnO nanocomposite hydrogel wound dressing with antibacterial activity, self-healing, and adhesion properties.Reproduced with permission from [134], Copyright 2022, Elsevier.(D) An MXene@CeO 2 nanocomposite hydrogel used for bacterial-infection-induced wound healing.Reproduced with permission from [147], Copyright 2021, Elsevier.

Figure 5 .
Figure 5. Nanocomposite hydrogels containing metal sulfide nanomaterials for wound healing.(A) A multifunctional hydrogel containing CuS nanoparticles applied for bacterial inactivation and treatment of wound infections based on localized CDT and low-temperature PTT.Reproduced with permission from [164], Copyright 2021, John Wiley and Sons.(B) A bifunctional hydrogel incorporated with CuS@MoS2 microspheres for disinfection, and schematic illustration of ROS generation mechanism.Reproduced with permission from [171], Copyright 2020, Elsevier.

Figure 5 .
Figure 5. Nanocomposite hydrogels containing metal sulfide nanomaterials for wound healing.(A) A multifunctional hydrogel containing CuS nanoparticles applied for bacterial inactivation and treatment of wound infections based on localized CDT and low-temperature PTT.Reproduced with permission from [164], Copyright 2021, John Wiley and Sons.(B) A bifunctional hydrogel incorporated with CuS@MoS 2 microspheres for disinfection, and schematic illustration of ROS generation mechanism.Reproduced with permission from [171], Copyright 2020, Elsevier.

Figure 6 .
Figure 6.Nanocomposite hydrogels containing carbon-based nanomaterials for wound healing.(A) Schematic representation of a conductive adhesive self-healing nanocomposite hydrogel containing CNTs for infected wound healing.Reproduced with permission from [177], Copyright 2020, Elsevier.(B) Schematic illustration of GO-incorporated hydrogels with nitric oxide release and photothermal activity for infected wound healing.Reproduced with permission from [184], Copyright 2020, American Chemical Society.

Figure 6 .
Figure 6.Nanocomposite hydrogels containing carbon-based nanomaterials for wound healing.(A) Schematic representation of a conductive adhesive self-healing nanocomposite hydrogel containing CNTs for infected wound healing.Reproduced with permission from [177], Copyright 2020, Elsevier.(B) Schematic illustration of GO-incorporated hydrogels with nitric oxide release and tothermal activity for infected wound healing.Reproduced with permission from [184], Copyright 2020, American Chemical Society.

Table 1 .
The summarized functions and characteristics of the inorganic-nanomaterial-composited hydrogel dressings.