# Application of Nanomaterial in Hydrogels Related to Wound Healing

Authors: Yangyang Liu; Shurui Song; Shuangyong Liu; Xiaoyan Zhu; Peige Wang
Journal: Journal of Nanomaterials
 (2022)

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## Abstract

Traditional dressings used for wound repair, such as gauze, have shortcomings; for example, they cannot provide a suitable microenvironment for wound recovery. Therefore, it is necessary to find a better dressing to overcome shortcomings. Hydrogel provides a suitable wet environment, has good biocompatibility, and has a strong swelling rate to absorb exudate. Nanomaterial in hydrogels has been used to improve their performance and overcome the shortcomings of current hydrogel dressings. Hydrogel dressing can also be loaded with nanodrug particles to exert a better therapeutic effect than conventional drugs and to make the dressing more practical. This article reviews the application of nanotechnology in hydrogels related to wound healing and discusses the application prospects of nanohydrogels. After searching for hydrogel articles related to wound healing, we found that nanomaterial can not only enhance the mechanical strength, antibacterial properties, and adhesion of hydrogels but also achieve sustained drug release. From the perspective of clinical application, these characteristics are significant for wound healing. The combination of nanomaterial and hydrogel is an ideal dressing with broad application prospects for wound healing in the future.


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## Body

## 1. Introduction

A skin wound, one of the most common clinical diseases, is defined as damage to the structure or integrity of skin tissue due to various causes [1–4]. In recent years, with the changes in the spectrum of human diseases, the number of patients and the cost of skin wounds have increased significantly. According to statistics, the total annual direct cost of wound treatment in the United States exceeds $25 billion [5]. Repairing wounds quickly and with high quality is challenging. Following the introduction of the theory of moist healing by Dr. George Winter of the University of London in the United Kingdom [6], the US Food and Drug Administration (FDA) pointed out in the industry guidelines in 2000 for wound medical supplies (external drugs and dressings) that maintaining a moist environment on the wound surface is the standard treatment method.Studies have shown that moist wounds, those with a moist microenvironment, are less susceptible to infection than dry wounds, inhibit wounds more effectively, and promote healing. A moist wound dressing can create and maintain a moist environment around the wound and promote the regeneration and repair of the dermis and epidermal tissue during the wound healing process. The ideal wound dressing should have the following characteristics: good biocompatibility, antibacterial activity, water absorption, water retention, noncytotoxicity, and good biodegradability [7].New wet wound dressings have the characteristics of moisture permeability and oxygen permeability and are mainly used as a physical barrier to protect the wound surface from microorganisms. As a new type of wet wound dressing that has emerged in recent years, hydrogel dressings have a three-dimensional network structure that can absorb or retain large amounts of water or biological fluids. Compared with traditional dressings, hydrogel dressings can provide a moist healing environment and speed up the wound healing time [8]. They have the advantages of good biocompatibility, strong water absorption, less bacterial growth, and less discomfort to patients [9, 10]. Moreover, the internal porous structure of hydrogel mimics the natural extracellular matrix (ECM), which is an ideal scaffold for tissue engineering [11]. However, hydrogels also have disadvantages, such as low mechanical strength, high brittleness, and poor antibacterial ability, so their application is limited [12–14].Nanomaterials have unique size effects and interface effects and have shown great application prospects in chip preparation, construction chemicals, and biomedicine [15–18]. Through template molding, self-assembly, microfluidics, and 3D printing technologies, building ultrastructures or dispersing nanoparticles in hydrogels to form composite materials can significantly improve the mechanical properties and stability of hydrogels while endowing hydrogel dressing with more functions. At the same time, nanohydrogel can achieve sustained drug release by wrapping or loading drugs, thereby promoting wound healing (Figure 1). At present, few studies have summarized the prospects and challenges to nanohydrogel applications in wound healing [19, 20]. In this article, we summarize the latest developments of nanohydrogel dressings and their application prospects in wound healing, and we further analyze the current opportunities and challenges in wound healing.Figure 1
The role of nanomaterial in wound hydrogels. (a) Reproduced with permission from ref. [21]. Copyright ©2019 WILEY-VCH. (b) Reproduced with permission from ref. [22]. Copyright © 2020 WILEY-VCH. (c) Reproduced with permission from ref. [23]. Copyright © 2021 Elsevier. (d) Reproduced with permission from ref. [24]. Copyright © 2021 Taylor & Francis.


## 2. The Role of Nanomaterial in Wound Hydrogel

### 2.1. Improving Mechanical Performance

Hydrogel is a three-dimensional hydrophilic network, insoluble in water or aqueous solutions, and capable of absorbing water or other biological fluids [25, 26]. It can promote the healing process, rehydrate necrotic tissue and increase the healing of debridement, and cool the wound surface, and it is suitable for cleaning dry, loose, or necrotic wounds [21, 27]. Furthermore, it does not react with organisms, is nonirritating and nonadhesive, and has permeable metabolites [28]. As an important wet wound dressing, hydrogels meet the requirements for ideal wound dressings [29]. Natural polymers are superior to synthetic polymers owing to their excellent biodegradability and biocompatibility [30]. However, the high water contents of natural polymer hydrogels often result in poor mechanical properties, low mechanical strength, and high brittleness, which greatly limit the speed of wound repair [31, 32].There are often multiple interactions in the hydrogel network to maintain systematic stability. Nanomaterials in hydrogel have greatly improved the mechanical strength of hydrogels through strong physical crosslinking, such as the formation of hydrogen bonds, electrostatic interactions, covalent bonds, hydrophobic interactions, and other physical crosslinks [33, 34] (Table 1). Although hydrogen bonding groups (-OH, -NH, and -C-O) are ubiquitous in a variety of natural and synthetic polymers, the water molecules in hydrogel usually screen the hydrogen bonding interactions in it [35]. Most polymers can only form hydrogels with weaker mechanical strength through hydrogen bonding, such as gelatin, agarose, and carrageenan [36]. PVA, chitosan, and cellulose can form crystalline domains ranging in size from nanometers to micrometers through hydrogen bonding under certain conditions. This strong physical crosslinking can endow hydrogel with excellent mechanical strength and maintain the stability of the system through a variety of interactions.Table 1
The role of nanotechnology in wound hydrogel.
EffectiveMechanismImproving mechanical propertiesIn situ polymerization [59], electrospinning technology [60], casting and coordination interaction [61–64]Drug releaseThree-tier structure [65] and embedding [66]Cross-linked and direct interaction [26, 49, 58, 67–70]Antibacterial effect [39]Interfering with DNA replication and RNA productionDestroy cell membranesInterference with cellular respirationChange enzyme conformation and inactivate enzyme activityIncreased adhesionCovalent coupling [71] and noncovalent complex [60, 72]Electrostatic interaction usually occurs between the fixed charged polymer and the corresponding ion, such as the physical crosslinking of alginate with divalent cations and the crosslinking of chitosan with multivalent anions [37, 38]. Other biopolymers that can form ionically crosslinked hydrogels include chiral polysaccharides, pectins, cellulose, and sodium polygalacturonate. A series of tough and self-healing hydrogels are produced through the formation of polyionic complexes and the gradual polymerization of oppositely charged monomers. Moreover, electrostatic interactions do not work in isolation. These bonds are caused by other noncovalent interactions, such as van der Waals interactions and hydrogen bonding, to further stabilize the hydrogel network.Covalent bonds are important structures constituting the hydrogel network, and covalent crosslinking is also a common way for nanotechnology to enhance the strength of hydrogels. Chemical crosslinking occurs between the polymer matrix and the crosslinking agent to form a covalent bond, thereby forming a fairly stable, strong, and heat-resistant hydrogel [39]. For example, cobalt oxide magnetic nanoparticles can be used as a covalent crosslinking agent to form acrylamide-based, magnetically responsive hydrogels.


### 2.2. Antibacterial Effect

The danger of antibiotic resistance is the human and economic losses it causes. Owing to the improper use of antibiotics, bacteria with resistance to traditional therapies have developed. Approximately 700,000 people die each year in the world from infections caused by antibiotic-resistant bacteria [40]. For example, in 2017, methicillin-resistant Staphylococcus aureus (MRSA) caused nearly 120,000 blood-borne infections and 20,000 related deaths in the US [41]. Excessive and inappropriate use of antibacterial drugs has led to the emergence of stronger strains, which are less vulnerable to treatment [42]. In addition, traditional antibacterial drugs also have many problems, such as low water solubility, reduced stability, minimal oral bioavailability, complexity of drug targeting, and reduced patient compliance due to frequent medication and different toxicities [43]. Nanomaterial plays an important role in improving the effectiveness of existing treatment methods by improving the physical and chemical properties and stability of antibiotics, increasing the opportunities for internalization of biofilms, extending the release time of antibiotics, and improving the effectiveness of drugs [44]. Nanosystems mainly include inorganic nanosystems, such as metal-based nanoparticles (e.g., silver (Ag NP), copper (Cu NP), metal oxide nanoparticles titanium oxide (TiO2 NP), zinc oxide (ZnO), cerium oxide (CeO2), and yttrium oxide (Y2O3)) and other substances with antibacterial activity, and they are used for wound healing [22, 24, 45]. The mechanism of action is generally as follows: (1) inhibiting bacterial replication by interfering with bacterial DNA replication and RNA production, (2) destroying cell membranes, (3) interfering with cell respiration, and (4) changing enzyme conformation and inactivating enzyme activity [46] (Table 1).There are two types of mechanisms of antimicrobial action of AgNPs: inhibitory action and bactericidal action [47]. The mechanism involves the formation of reactive oxygen species (ROS) resulting from the inhibition of a respiratory enzyme by the Ag + ions, which kills the cell. The bacterial cell contains sulfur and phosphorous, which are the soft bases that interact with the AgNP as soft acid, leading to apoptosis [48].Biocompatibility, high surface reactivity, antibacterial, antioxidation, antiplasmon resonance, and other necessary properties make AuNPs an integral part of the field of therapeutics and diagnosis [49]. AuNPs could inhibit the lipid from peroxidation and prevent the formation of ROS to restore antioxidant discrepancies.ZnO NPs have been used in nanocomposites for wound healing applications as well as for skin infections. The mechanism involved is (a) the inhibitory action and (b) the bactericidal action [48] (Figure 2).Figure 2
The role of nanomaterial in wound hydrogels. Panel is reproduced with permission from ref. [42]. Copyright © 2020MDPI.The protection against oxidative stress damage for wound treatment by CeO2 NPs and Y2O3 NPs can be explained by the three possible mechanisms that follow [50]: (a) these nanoparticles act as direct antioxidants and restrict the generation of ROS, which inhibits the programmed cell death pathway; (b) these nanoparticles directly cause a low level of ROS production, which rapidly induces the ROS defense system before the glutamate-induced cell death program is complete; and (c) the latter is a form of preconditioning that may be caused by the exposure of cells to particulate material known to induce low levels of ROS.


### 2.3. Achieve Sustained Drug Release

A controlled-release drug delivery system minimizes the side effects of drugs by delivering active substances to the site of action, and this type of system has attracted widespread attention [51]. The goal of a controlled-release drug delivery system is to achieve the temporal and spatial distribution of drugs. Nanomaterials are biocompatible, biodegradable, and nontoxic [23]. They combine the characteristics of hydrogels (high water content and flexible mechanical properties) in drug delivery (Figure 3). Fortunately, advances in nanomaterial have promoted the development of smarter nanocarriers, such that various drugs can be packaged, and the wound can be treated in a better way, thereby improving patient compliance. In addition, the nanohydrogel surface can be combined with different types of ligands to improve site-specific delivery, thereby reducing toxicity [52]. Various forms of nanocontrolled release systems are realized by encapsulating or loading drugs (Table 1), including nanospheres, nanogels, solid lipid nanoparticles (NPs), polymer nanoparticles, nanoemulsions, nanofiber mats, graphene-based nanocomposites material, and other forms [53]. In recent years, the incidence of various infectious diseases has increased significantly, which has placed a huge burden on the global economy and public health. Although antibiotics have played a critical role in wound treatment, the abuse of antibiotics has led to the emergence of drug-resistant pathogens, such as Pseudomonas aeruginosa, methicillin-resistant Staphylococcus, and vancomycin-resistant enterococcus [54, 55]. In the process of wound healing, nanomaterials can directly deliver antibacterial drugs to the wound site to make them continue to work [56], reduce the production of multidrug resistant bacteria, and promote wound healing. In addition, they eliminate the main problem of conventional dosage forms—frequent administration—which is beneficial for the treatment of chronic wounds.Figure 3
The role of nanotechnology in wound hydrogels. Panel is reproduced with permission from ref. [47]. Copyright © 2019 Wei Wang et al.


### 2.4. Increased Adhesion

For drug delivery, bioadhesion refers to the attachment of a drug carrier system to a designated biological location. The biological surface can be epithelial tissue or a mucous coating on the surface of the tissue. If it adheres to the mucus coating, this phenomenon is called adhesion [57]. Mucosal adhesions should not be confused with biological adhesions or bioadhesions. In bioadhesion, the polymer attaches to the biofilm. If the substrate is a mucous membrane, the polymer adheres to the mucous membrane. Combining nanotechnology with hydrogels can improve the adhesion of hydrogels and the efficiency of drug delivery by covalent coupling and noncovalent complexes, for example. Furthermore, hydrogels can be used directly on the wound site and can fill the wound area to promote wound healing and the growth of hair follicles and capillaries (Table 1).


### 2.5. Nanoenzyme

A nanoenzyme is a kind of mimetic enzyme that has the characteristics of nanomaterials and the catalytic performance of natural enzymes. Compared with natural enzymes, nanoenzymes have the advantages of high stability, strong catalytic activity, and low cost, so they are widely used in disease diagnosis, treatment, and biosensing. The oxidoreductase activity of nanoenzymes includes peroxidase, catalase, and superoxide dismutase, for example. The catalytic activity of nanoenzymes is determined by the electron transfer process on the surface. At present, the design of nanoenzymes focuses on improving the catalytic activity of nanoenzymes. Although the activity of nanoenzymes has been greatly improved, it is a challenging task to use nanoenzymes to construct multifunctional biological materials so as to meet the needs of different environments [58].


## 2.1. Improving Mechanical Performance

Hydrogel is a three-dimensional hydrophilic network, insoluble in water or aqueous solutions, and capable of absorbing water or other biological fluids [25, 26]. It can promote the healing process, rehydrate necrotic tissue and increase the healing of debridement, and cool the wound surface, and it is suitable for cleaning dry, loose, or necrotic wounds [21, 27]. Furthermore, it does not react with organisms, is nonirritating and nonadhesive, and has permeable metabolites [28]. As an important wet wound dressing, hydrogels meet the requirements for ideal wound dressings [29]. Natural polymers are superior to synthetic polymers owing to their excellent biodegradability and biocompatibility [30]. However, the high water contents of natural polymer hydrogels often result in poor mechanical properties, low mechanical strength, and high brittleness, which greatly limit the speed of wound repair [31, 32].There are often multiple interactions in the hydrogel network to maintain systematic stability. Nanomaterials in hydrogel have greatly improved the mechanical strength of hydrogels through strong physical crosslinking, such as the formation of hydrogen bonds, electrostatic interactions, covalent bonds, hydrophobic interactions, and other physical crosslinks [33, 34] (Table 1). Although hydrogen bonding groups (-OH, -NH, and -C-O) are ubiquitous in a variety of natural and synthetic polymers, the water molecules in hydrogel usually screen the hydrogen bonding interactions in it [35]. Most polymers can only form hydrogels with weaker mechanical strength through hydrogen bonding, such as gelatin, agarose, and carrageenan [36]. PVA, chitosan, and cellulose can form crystalline domains ranging in size from nanometers to micrometers through hydrogen bonding under certain conditions. This strong physical crosslinking can endow hydrogel with excellent mechanical strength and maintain the stability of the system through a variety of interactions.Table 1
The role of nanotechnology in wound hydrogel.
EffectiveMechanismImproving mechanical propertiesIn situ polymerization [59], electrospinning technology [60], casting and coordination interaction [61–64]Drug releaseThree-tier structure [65] and embedding [66]Cross-linked and direct interaction [26, 49, 58, 67–70]Antibacterial effect [39]Interfering with DNA replication and RNA productionDestroy cell membranesInterference with cellular respirationChange enzyme conformation and inactivate enzyme activityIncreased adhesionCovalent coupling [71] and noncovalent complex [60, 72]Electrostatic interaction usually occurs between the fixed charged polymer and the corresponding ion, such as the physical crosslinking of alginate with divalent cations and the crosslinking of chitosan with multivalent anions [37, 38]. Other biopolymers that can form ionically crosslinked hydrogels include chiral polysaccharides, pectins, cellulose, and sodium polygalacturonate. A series of tough and self-healing hydrogels are produced through the formation of polyionic complexes and the gradual polymerization of oppositely charged monomers. Moreover, electrostatic interactions do not work in isolation. These bonds are caused by other noncovalent interactions, such as van der Waals interactions and hydrogen bonding, to further stabilize the hydrogel network.Covalent bonds are important structures constituting the hydrogel network, and covalent crosslinking is also a common way for nanotechnology to enhance the strength of hydrogels. Chemical crosslinking occurs between the polymer matrix and the crosslinking agent to form a covalent bond, thereby forming a fairly stable, strong, and heat-resistant hydrogel [39]. For example, cobalt oxide magnetic nanoparticles can be used as a covalent crosslinking agent to form acrylamide-based, magnetically responsive hydrogels.


## 2.2. Antibacterial Effect

The danger of antibiotic resistance is the human and economic losses it causes. Owing to the improper use of antibiotics, bacteria with resistance to traditional therapies have developed. Approximately 700,000 people die each year in the world from infections caused by antibiotic-resistant bacteria [40]. For example, in 2017, methicillin-resistant Staphylococcus aureus (MRSA) caused nearly 120,000 blood-borne infections and 20,000 related deaths in the US [41]. Excessive and inappropriate use of antibacterial drugs has led to the emergence of stronger strains, which are less vulnerable to treatment [42]. In addition, traditional antibacterial drugs also have many problems, such as low water solubility, reduced stability, minimal oral bioavailability, complexity of drug targeting, and reduced patient compliance due to frequent medication and different toxicities [43]. Nanomaterial plays an important role in improving the effectiveness of existing treatment methods by improving the physical and chemical properties and stability of antibiotics, increasing the opportunities for internalization of biofilms, extending the release time of antibiotics, and improving the effectiveness of drugs [44]. Nanosystems mainly include inorganic nanosystems, such as metal-based nanoparticles (e.g., silver (Ag NP), copper (Cu NP), metal oxide nanoparticles titanium oxide (TiO2 NP), zinc oxide (ZnO), cerium oxide (CeO2), and yttrium oxide (Y2O3)) and other substances with antibacterial activity, and they are used for wound healing [22, 24, 45]. The mechanism of action is generally as follows: (1) inhibiting bacterial replication by interfering with bacterial DNA replication and RNA production, (2) destroying cell membranes, (3) interfering with cell respiration, and (4) changing enzyme conformation and inactivating enzyme activity [46] (Table 1).There are two types of mechanisms of antimicrobial action of AgNPs: inhibitory action and bactericidal action [47]. The mechanism involves the formation of reactive oxygen species (ROS) resulting from the inhibition of a respiratory enzyme by the Ag + ions, which kills the cell. The bacterial cell contains sulfur and phosphorous, which are the soft bases that interact with the AgNP as soft acid, leading to apoptosis [48].Biocompatibility, high surface reactivity, antibacterial, antioxidation, antiplasmon resonance, and other necessary properties make AuNPs an integral part of the field of therapeutics and diagnosis [49]. AuNPs could inhibit the lipid from peroxidation and prevent the formation of ROS to restore antioxidant discrepancies.ZnO NPs have been used in nanocomposites for wound healing applications as well as for skin infections. The mechanism involved is (a) the inhibitory action and (b) the bactericidal action [48] (Figure 2).Figure 2
The role of nanomaterial in wound hydrogels. Panel is reproduced with permission from ref. [42]. Copyright © 2020MDPI.The protection against oxidative stress damage for wound treatment by CeO2 NPs and Y2O3 NPs can be explained by the three possible mechanisms that follow [50]: (a) these nanoparticles act as direct antioxidants and restrict the generation of ROS, which inhibits the programmed cell death pathway; (b) these nanoparticles directly cause a low level of ROS production, which rapidly induces the ROS defense system before the glutamate-induced cell death program is complete; and (c) the latter is a form of preconditioning that may be caused by the exposure of cells to particulate material known to induce low levels of ROS.


## 2.3. Achieve Sustained Drug Release

A controlled-release drug delivery system minimizes the side effects of drugs by delivering active substances to the site of action, and this type of system has attracted widespread attention [51]. The goal of a controlled-release drug delivery system is to achieve the temporal and spatial distribution of drugs. Nanomaterials are biocompatible, biodegradable, and nontoxic [23]. They combine the characteristics of hydrogels (high water content and flexible mechanical properties) in drug delivery (Figure 3). Fortunately, advances in nanomaterial have promoted the development of smarter nanocarriers, such that various drugs can be packaged, and the wound can be treated in a better way, thereby improving patient compliance. In addition, the nanohydrogel surface can be combined with different types of ligands to improve site-specific delivery, thereby reducing toxicity [52]. Various forms of nanocontrolled release systems are realized by encapsulating or loading drugs (Table 1), including nanospheres, nanogels, solid lipid nanoparticles (NPs), polymer nanoparticles, nanoemulsions, nanofiber mats, graphene-based nanocomposites material, and other forms [53]. In recent years, the incidence of various infectious diseases has increased significantly, which has placed a huge burden on the global economy and public health. Although antibiotics have played a critical role in wound treatment, the abuse of antibiotics has led to the emergence of drug-resistant pathogens, such as Pseudomonas aeruginosa, methicillin-resistant Staphylococcus, and vancomycin-resistant enterococcus [54, 55]. In the process of wound healing, nanomaterials can directly deliver antibacterial drugs to the wound site to make them continue to work [56], reduce the production of multidrug resistant bacteria, and promote wound healing. In addition, they eliminate the main problem of conventional dosage forms—frequent administration—which is beneficial for the treatment of chronic wounds.Figure 3
The role of nanotechnology in wound hydrogels. Panel is reproduced with permission from ref. [47]. Copyright © 2019 Wei Wang et al.


## 2.4. Increased Adhesion

For drug delivery, bioadhesion refers to the attachment of a drug carrier system to a designated biological location. The biological surface can be epithelial tissue or a mucous coating on the surface of the tissue. If it adheres to the mucus coating, this phenomenon is called adhesion [57]. Mucosal adhesions should not be confused with biological adhesions or bioadhesions. In bioadhesion, the polymer attaches to the biofilm. If the substrate is a mucous membrane, the polymer adheres to the mucous membrane. Combining nanotechnology with hydrogels can improve the adhesion of hydrogels and the efficiency of drug delivery by covalent coupling and noncovalent complexes, for example. Furthermore, hydrogels can be used directly on the wound site and can fill the wound area to promote wound healing and the growth of hair follicles and capillaries (Table 1).


## 2.5. Nanoenzyme

A nanoenzyme is a kind of mimetic enzyme that has the characteristics of nanomaterials and the catalytic performance of natural enzymes. Compared with natural enzymes, nanoenzymes have the advantages of high stability, strong catalytic activity, and low cost, so they are widely used in disease diagnosis, treatment, and biosensing. The oxidoreductase activity of nanoenzymes includes peroxidase, catalase, and superoxide dismutase, for example. The catalytic activity of nanoenzymes is determined by the electron transfer process on the surface. At present, the design of nanoenzymes focuses on improving the catalytic activity of nanoenzymes. Although the activity of nanoenzymes has been greatly improved, it is a challenging task to use nanoenzymes to construct multifunctional biological materials so as to meet the needs of different environments [58].


## 3. The Common Materials Used to Design Nanohydrogel for Wound Repair

Wound healing is a complex pathophysiological process involving a variety of cytokines, growth factors, blood, and the ECM [61, 73]. It is a dynamic and complex phenomenon consisting of three main continuous events: inflammation, cell proliferation, and remodeling [67, 78, 79]. Wound healing is divided into four stages [71]: hemostasis, inflammation, new granulation, and tissue remodeling [65]. Treatment at each phase is conducive to wound healing. The natural polymer hydrogel dressings reported in recent years can improve the microenvironment of the wound and promote healing at different stages. It is expected to play a pivotal role in wound healing (Table 2).Table 2
The common materials used to design nanohydrogel for wound repair.
TypeAdvantageApplicationCollagen-based hydrogelForms microenvironment similar to extracellular mechanismsSpontaneous migration of fibroblasts [73], antibacterial [26, 58, 67], and improve mechanical properties [61]Gelatin-based hydrogelGood biocompatibility, solubilityImproved mechanical properties [59], adhesion [71], antibacterial [68], drug release [65], and regeneration [71]Fibrin-based hydrogelGood adhesion, biocompatibilityIncrease mechanical strength [62, 63] and regeneration [62]Chitosan-based hydrogelGood hemostatic propertiesIncrease mechanical strength [72], adhesion [60], antibacterial [74], and drug release [66]Cellulose-based hydrogelMost distributed, contentIncrease the scope of application [75], antibacterial [69, 75], drug release [69], and regeneration [49]Hyaluronic acid-based hydrogelGood hydrophilicity, biocompatibilityIncrease mechanical strength [64] and regeneration [76]Polyethylene glycol-based hydrogelHigh molecular polymerPromote cell proliferation [77], antibacterial [77], and drug release [70]


### 3.1. Collagen

Collagen is a common protein in the human body and an important component of the ECM. In addition to being an indispensable part of the body, collagen also promotes cell migration and protein secretion. As a collagen hydrogel can form a microenvironment similar to that of the ECM on the wound surface, it has obvious advantages in wound healing. However, the mechanical properties of collagen hydrogels are poor, and the degradation rate is relatively fast, which limits further clinical application [59]. Therefore, adding nanoparticles or chemical cross-linking can improve mechanical properties and stability. In addition, this addition can also provide anti-inflammatory, antioxidant, and antibacterial effects [68, 80]. Moreover, the combination of fiber membranes prepared by nanotechnology and collagen hydrogels is also a useful method, which not only enables the spontaneous migration of fibroblasts but also promotes local cell proliferation activity [81]. Sun et al. [62] adopted electrospinning technology to load zinc oxide on collagen/chitosan nanofibers. Curcumin- (CUR-) chitosan nanoparticles (CSNPs) can also be impregnated into collagen scaffolds. Moreover, CSNPs can improve the stability and solubility of CUR, play an anti-inflammatory and antioxidant role, protect the wound surface, and promote healing [32].


### 3.2. Gelatin

Gelatin is a hydrolysate of collagen and is widely used in food processing and biomedicine. Because its structure is similar to collagen, it has good biocompatibility, poor mechanical properties, and faster biodegradation than synthetic polymers in wound treatment. However, the difference is that the solubility of gelatin is significantly better than that of collagen, which greatly promotes its application in 3D printing [63]. Modified by electrospinning technology, the nanohydrogel fiber membrane formed by modified gelatin can be used as a cell presentation system and promote the healing of rabbit full-thickness skin wounds by transplanting human umbilical vein endothelial cells [82]. A recent study showed that the mechanical properties and adhesion of gelatin methacryloyl (GelMA) hydrogels modified with silicate nanosheets (Laponite) were significantly improved, and they exhibited the sustained release of epidermal growth factor (EGF) and the ability to stop bleeding to stimulate complete skin regeneration [66]. Lin produced a multifunctional three-layer wound dressing (sandwich dressing). The inner layer consists of activated carbon fiber and gentamicin, and the outer layer consists of gelatin/chitosan/EGCG nanoparticles and a c-PGA gelatin hydrogel. While preventing bacterial infection and controlling inflammation, this dressing was easy to remove from the wound, promoted the reepithelialization of wound tissue, and accelerated the wound healing process [60]. Xu discovered a composite hydrogel. The hydrogel template is stabilized by a colloidal hybrid of carbon nanotubes (CNTs) and gelatin methenoyl (GelMA) and then undergoes in situ polymerization and antimicrobial peptide incorporation, which can significantly improve the electrical conductivity and mechanical properties of the hydrogel. The GelMA inside of it was found to support cell adhesion and proliferation [72]. The chitosan nanoparticles loaded with curcumin were mixed into the fiber network scaffold of electrospun polycaprolactone and gelatin. The nanoparticles improved its hydrophilicity, wettability, and degradability, enhanced the effect of wound healing, and also played a role as an anti-inflammatory agent, promoting cell adhesion and proliferation [74].


### 3.3. Fibrin

Fibrin is a type of protein that is mostly found in blood and is insoluble in water. It has good biocompatibility and adhesion. Currently, fibrin glue is often used clinically as a hemostatic agent, wound healing agent, and plugging agent. In the treatment of trauma, protein-based polymers also play an important role. In recent years, autologous fibrin glue has been widely used in clinical practice because it is rich in cell growth factors and reduces the risk of viral infection and allergic reactions [83]. However, fibrin glue has relatively poor stability and is easily hydrolyzed [69]. Wang et al. prepared fibrin-silica hydrogel. The nanofiber hydrogel exhibited higher mechanical properties than pure fibrin while retaining its ability to support the proliferation of myoblasts, which had a great effect on the formation and regeneration of tissues [75]. According to a study by Scionti et al. [84], adding nanoparticles to the fibrin-agarose hydrogel significantly increased the density of chemical bonds and improved the mechanical properties of the hydrogel.


### 3.4. Chitosan

Chitosan (CS) is a product of chitin N-deacetylation and a natural polymer with huge reserves. CS is the only alkaline polysaccharide in nature because of its positively charged amino group [64, 76, 85]. This endows CS with many important characteristics of biomedical value, including among others excellent biocompatibility, biodegradation, nontoxicity, adhesion, antimicrobial, antioxidative, and hemostasis [70, 77, 86]. Because of its hemostatic activity, excellent biocompatibility, and antibacterial effect, it is widely used in biomedical fields such as wound dressings, slow drug release, gene transduction, and tissue engineering [87]. At present, we often increase the mechanical strength of chitosan hydrogels by modifying, cross-linking other polymer materials, and electrospinning, thereby increasing its application scenarios. According to Kumbar’s research, chitosan microspheres can be cross-linked by several methods, including the chemical substances glutaraldehyde and sulfuric acid, and heat treatment for drug encapsulation and delivery [88]. Genipin was added to the nanocomposite as a cross-linking agent, which could effectively control the release of the drug from the hydrogel by forming a physical bond. To overcome the disadvantage of poor mechanical properties, Xie et al. synthesized a chitosan hydrogel based on an alkaline urea aqueous solution, using Ag nanoparticles as a filler and secondary reinforcing agent, and using the amino group of chitosan as a chelating agent. Xie et al. improved the mechanical strength of the chitosan hydrogel through coordination interaction [89].


### 3.5. Cellulose

Cellulose is the most widely distributed and polysaccharide in nature that is used in many fields, such as food processing, construction, and biomedicine. Cellulose has good mechanical strength and thermal stability, but it does not have antibacterial activity. In addition, its poor hydrolysis greatly limits its application. Nanocellulose prepared by nanotechnology opens up new application scenarios. Nanocellulose is divided into three main categories: bacterial nanocellulose (also known as microbial cellulose or biocellulose), cellulose nanofibers (also known as nano/microfiber cellulose), and cellulose nanocrystals (also known as nanocrystalline cellulose). Among them, bacterial nanocellulose is applied in antibacterial wound healing and biosensing. By carrying antibacterial and healing factors, a bacterial nanocellulose wound dressing can safely and effectively promote wound healing [90]. Koneru used citric acid (CA) croscarmellose sodium (NaCMC)/hydroxypropyl methylcellulose (HPMC) to prepare a hydrogel film and loaded it with grape seed extract (GFSE). This hydrogel showed excellent antibacterial properties. So it could be used as an antibacterial dressing to meet the needs of wound healing [91]. Loh et al. studied a nonbiodegradable bacterial nanocellulose/acrylic acid (BNC/AA) hydrogel to explore the potential of transferring human dermal fibroblasts (HDF) to the wound surface and the healing effect of HDF in breast-free mice after transfer. The results showed that hydrogel had good properties. Thus, it is beneficial to wound healing and can be used as a wound dressing and cell carrier [92]. To solve the problems of bacterial infection and uncontrollable bleeding during wound healing, Liu et al. designed a green nanocomposite hydrogel, which is a noncovalent (dynamic ionic bridge) cross-linked hydrogel, by introducing aminated silver nanoparticles (Ag-NH2NPs) and gelatin (G) into carboxylated cellulose nanofibers (CNF). The hydrogel had strong mechanical properties, self-healing properties, antibacterial properties, good hemostatic properties, and a suitable liquid balance on the wound surface. More importantly, it showed excellent biocompatibility and wound-healing effect, so it can be used as an improved wound dressing [93].


### 3.6. Hyaluronic Acid

Hyaluronic acid (HA) is a natural acid mucopolysaccharide. HA has excellent hydrophilicity and biocompatibility and is often used as a filler in cosmetology, ophthalmology, and joint surgery. Further, as an ECM, it also plays an important role in wound healing and tissue regeneration. In recent years, with the promotion of the theory of wet wound healing, the potential application value of HA as a dressing matrix has been fully developed. Electrospinning technology, embedded metal nanoparticles, and other methods can strengthen the mechanical strength of HA dressing, allowing it to play a role as an antibacterial agent, promote cell proliferation and adhesion, and effectively promote wound healing [94, 95]. Karimi Dehkordi et al. developed a composite material, that is, nanocrystalline cellulose- (CNC-) reinforced HA chitosan nanoparticles, which improved the mechanical properties of HA-based composite materials. As an effective wound dressing, composite materials have good mechanical properties, release GM-CSF slowly, enhance reepithelialization, and provide an improved healing environment [96]. Moreover, Uppal et al. studied a wound dressing formulation based on HA nanofibers; compared with natural solid HA biomaterials, these HA nanofibers helped cell migration and proliferation, promoted tissue growth, and accelerated wound healing [97].


### 3.7. Polyethylene Glycol

Polyethylene glycol (PEG) is a high-molecular polymer, and different groups can be grafted to the end of PEG according to requirements, which gives it application potential. The adjustable group at the end of PEG can undergo a variety of cross-linking reactions with natural polymer materials, strengthen the internal force of the hydrogel, and improve the mechanical properties of the hydrogel. This can promote the proliferation of wound cells to the greatest extent, and at the same time, improve the sustained release ability of hydrogel drugs. Chu et al. prepared a new type of collagen-nanomaterial-drug hybrid scaffold mediated by PEG that promotes the attachment, proliferation, differentiation of mesenchymal stem cells (MSC), and collagen deposition in diabetic wound repair and angiogenesis [98]. Guo et al. found that polyethylene glycol diacrylate (PEGDA) core/alginate shell-structured hydrogel particles were formed by one-step microfluidic droplets. The granular hydrogel did not contain toxic organic solvents and had good wetting properties, could control the release of corticosteroids, and accelerated wound healing and scar treatment [99]. Li et al. researched and prepared a nanocomposite scaffold composed of PEGDA, forming the main network, and a secondary dynamic network (PABC scaffold) formed between copper-containing bioactive glass nanoparticles (BGNC) and sodium alginate (ALG). It showed strong antibacterial activity and the ability of self-healing and could significantly enhance wound healing and skin tissue formation by promoting early angiogenesis [100].


## 3.1. Collagen

Collagen is a common protein in the human body and an important component of the ECM. In addition to being an indispensable part of the body, collagen also promotes cell migration and protein secretion. As a collagen hydrogel can form a microenvironment similar to that of the ECM on the wound surface, it has obvious advantages in wound healing. However, the mechanical properties of collagen hydrogels are poor, and the degradation rate is relatively fast, which limits further clinical application [59]. Therefore, adding nanoparticles or chemical cross-linking can improve mechanical properties and stability. In addition, this addition can also provide anti-inflammatory, antioxidant, and antibacterial effects [68, 80]. Moreover, the combination of fiber membranes prepared by nanotechnology and collagen hydrogels is also a useful method, which not only enables the spontaneous migration of fibroblasts but also promotes local cell proliferation activity [81]. Sun et al. [62] adopted electrospinning technology to load zinc oxide on collagen/chitosan nanofibers. Curcumin- (CUR-) chitosan nanoparticles (CSNPs) can also be impregnated into collagen scaffolds. Moreover, CSNPs can improve the stability and solubility of CUR, play an anti-inflammatory and antioxidant role, protect the wound surface, and promote healing [32].


## 3.2. Gelatin

Gelatin is a hydrolysate of collagen and is widely used in food processing and biomedicine. Because its structure is similar to collagen, it has good biocompatibility, poor mechanical properties, and faster biodegradation than synthetic polymers in wound treatment. However, the difference is that the solubility of gelatin is significantly better than that of collagen, which greatly promotes its application in 3D printing [63]. Modified by electrospinning technology, the nanohydrogel fiber membrane formed by modified gelatin can be used as a cell presentation system and promote the healing of rabbit full-thickness skin wounds by transplanting human umbilical vein endothelial cells [82]. A recent study showed that the mechanical properties and adhesion of gelatin methacryloyl (GelMA) hydrogels modified with silicate nanosheets (Laponite) were significantly improved, and they exhibited the sustained release of epidermal growth factor (EGF) and the ability to stop bleeding to stimulate complete skin regeneration [66]. Lin produced a multifunctional three-layer wound dressing (sandwich dressing). The inner layer consists of activated carbon fiber and gentamicin, and the outer layer consists of gelatin/chitosan/EGCG nanoparticles and a c-PGA gelatin hydrogel. While preventing bacterial infection and controlling inflammation, this dressing was easy to remove from the wound, promoted the reepithelialization of wound tissue, and accelerated the wound healing process [60]. Xu discovered a composite hydrogel. The hydrogel template is stabilized by a colloidal hybrid of carbon nanotubes (CNTs) and gelatin methenoyl (GelMA) and then undergoes in situ polymerization and antimicrobial peptide incorporation, which can significantly improve the electrical conductivity and mechanical properties of the hydrogel. The GelMA inside of it was found to support cell adhesion and proliferation [72]. The chitosan nanoparticles loaded with curcumin were mixed into the fiber network scaffold of electrospun polycaprolactone and gelatin. The nanoparticles improved its hydrophilicity, wettability, and degradability, enhanced the effect of wound healing, and also played a role as an anti-inflammatory agent, promoting cell adhesion and proliferation [74].


## 3.3. Fibrin

Fibrin is a type of protein that is mostly found in blood and is insoluble in water. It has good biocompatibility and adhesion. Currently, fibrin glue is often used clinically as a hemostatic agent, wound healing agent, and plugging agent. In the treatment of trauma, protein-based polymers also play an important role. In recent years, autologous fibrin glue has been widely used in clinical practice because it is rich in cell growth factors and reduces the risk of viral infection and allergic reactions [83]. However, fibrin glue has relatively poor stability and is easily hydrolyzed [69]. Wang et al. prepared fibrin-silica hydrogel. The nanofiber hydrogel exhibited higher mechanical properties than pure fibrin while retaining its ability to support the proliferation of myoblasts, which had a great effect on the formation and regeneration of tissues [75]. According to a study by Scionti et al. [84], adding nanoparticles to the fibrin-agarose hydrogel significantly increased the density of chemical bonds and improved the mechanical properties of the hydrogel.


## 3.4. Chitosan

Chitosan (CS) is a product of chitin N-deacetylation and a natural polymer with huge reserves. CS is the only alkaline polysaccharide in nature because of its positively charged amino group [64, 76, 85]. This endows CS with many important characteristics of biomedical value, including among others excellent biocompatibility, biodegradation, nontoxicity, adhesion, antimicrobial, antioxidative, and hemostasis [70, 77, 86]. Because of its hemostatic activity, excellent biocompatibility, and antibacterial effect, it is widely used in biomedical fields such as wound dressings, slow drug release, gene transduction, and tissue engineering [87]. At present, we often increase the mechanical strength of chitosan hydrogels by modifying, cross-linking other polymer materials, and electrospinning, thereby increasing its application scenarios. According to Kumbar’s research, chitosan microspheres can be cross-linked by several methods, including the chemical substances glutaraldehyde and sulfuric acid, and heat treatment for drug encapsulation and delivery [88]. Genipin was added to the nanocomposite as a cross-linking agent, which could effectively control the release of the drug from the hydrogel by forming a physical bond. To overcome the disadvantage of poor mechanical properties, Xie et al. synthesized a chitosan hydrogel based on an alkaline urea aqueous solution, using Ag nanoparticles as a filler and secondary reinforcing agent, and using the amino group of chitosan as a chelating agent. Xie et al. improved the mechanical strength of the chitosan hydrogel through coordination interaction [89].


## 3.5. Cellulose

Cellulose is the most widely distributed and polysaccharide in nature that is used in many fields, such as food processing, construction, and biomedicine. Cellulose has good mechanical strength and thermal stability, but it does not have antibacterial activity. In addition, its poor hydrolysis greatly limits its application. Nanocellulose prepared by nanotechnology opens up new application scenarios. Nanocellulose is divided into three main categories: bacterial nanocellulose (also known as microbial cellulose or biocellulose), cellulose nanofibers (also known as nano/microfiber cellulose), and cellulose nanocrystals (also known as nanocrystalline cellulose). Among them, bacterial nanocellulose is applied in antibacterial wound healing and biosensing. By carrying antibacterial and healing factors, a bacterial nanocellulose wound dressing can safely and effectively promote wound healing [90]. Koneru used citric acid (CA) croscarmellose sodium (NaCMC)/hydroxypropyl methylcellulose (HPMC) to prepare a hydrogel film and loaded it with grape seed extract (GFSE). This hydrogel showed excellent antibacterial properties. So it could be used as an antibacterial dressing to meet the needs of wound healing [91]. Loh et al. studied a nonbiodegradable bacterial nanocellulose/acrylic acid (BNC/AA) hydrogel to explore the potential of transferring human dermal fibroblasts (HDF) to the wound surface and the healing effect of HDF in breast-free mice after transfer. The results showed that hydrogel had good properties. Thus, it is beneficial to wound healing and can be used as a wound dressing and cell carrier [92]. To solve the problems of bacterial infection and uncontrollable bleeding during wound healing, Liu et al. designed a green nanocomposite hydrogel, which is a noncovalent (dynamic ionic bridge) cross-linked hydrogel, by introducing aminated silver nanoparticles (Ag-NH2NPs) and gelatin (G) into carboxylated cellulose nanofibers (CNF). The hydrogel had strong mechanical properties, self-healing properties, antibacterial properties, good hemostatic properties, and a suitable liquid balance on the wound surface. More importantly, it showed excellent biocompatibility and wound-healing effect, so it can be used as an improved wound dressing [93].


## 3.6. Hyaluronic Acid

Hyaluronic acid (HA) is a natural acid mucopolysaccharide. HA has excellent hydrophilicity and biocompatibility and is often used as a filler in cosmetology, ophthalmology, and joint surgery. Further, as an ECM, it also plays an important role in wound healing and tissue regeneration. In recent years, with the promotion of the theory of wet wound healing, the potential application value of HA as a dressing matrix has been fully developed. Electrospinning technology, embedded metal nanoparticles, and other methods can strengthen the mechanical strength of HA dressing, allowing it to play a role as an antibacterial agent, promote cell proliferation and adhesion, and effectively promote wound healing [94, 95]. Karimi Dehkordi et al. developed a composite material, that is, nanocrystalline cellulose- (CNC-) reinforced HA chitosan nanoparticles, which improved the mechanical properties of HA-based composite materials. As an effective wound dressing, composite materials have good mechanical properties, release GM-CSF slowly, enhance reepithelialization, and provide an improved healing environment [96]. Moreover, Uppal et al. studied a wound dressing formulation based on HA nanofibers; compared with natural solid HA biomaterials, these HA nanofibers helped cell migration and proliferation, promoted tissue growth, and accelerated wound healing [97].


## 3.7. Polyethylene Glycol

Polyethylene glycol (PEG) is a high-molecular polymer, and different groups can be grafted to the end of PEG according to requirements, which gives it application potential. The adjustable group at the end of PEG can undergo a variety of cross-linking reactions with natural polymer materials, strengthen the internal force of the hydrogel, and improve the mechanical properties of the hydrogel. This can promote the proliferation of wound cells to the greatest extent, and at the same time, improve the sustained release ability of hydrogel drugs. Chu et al. prepared a new type of collagen-nanomaterial-drug hybrid scaffold mediated by PEG that promotes the attachment, proliferation, differentiation of mesenchymal stem cells (MSC), and collagen deposition in diabetic wound repair and angiogenesis [98]. Guo et al. found that polyethylene glycol diacrylate (PEGDA) core/alginate shell-structured hydrogel particles were formed by one-step microfluidic droplets. The granular hydrogel did not contain toxic organic solvents and had good wetting properties, could control the release of corticosteroids, and accelerated wound healing and scar treatment [99]. Li et al. researched and prepared a nanocomposite scaffold composed of PEGDA, forming the main network, and a secondary dynamic network (PABC scaffold) formed between copper-containing bioactive glass nanoparticles (BGNC) and sodium alginate (ALG). It showed strong antibacterial activity and the ability of self-healing and could significantly enhance wound healing and skin tissue formation by promoting early angiogenesis [100].


## 4. Conclusion

Based on current research, we know that hydrogels have shortcomings, such as low mechanical strength, high brittleness, and poor antibacterial ability. Thus, their application to wounds is greatly restricted. Nanomaterial can play a critical role in hydrogels, which improves the application potential of nanohydrogels as wound dressings. Nanotechnology not only improves the mechanical properties, water-solubility, and cell adhesion of the hydrogel but also packages or loads various particles with antibacterial or biological activity in the nanohydrogel to achieve long-term slow drug delivery and play a better curative effect than conventional topical drugs. Moreover, owing to the large surface area of the nanoparticles, a small number of drugs can play a better role, which also reduces the toxicity of the drugs to a certain extent. Therefore, the combination of nanomaterial and hydrogels has unlimited possibilities and will be further explored in future research.



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*Source: 4656037-2022-01-04.xml*