**1. Introduction**

Hydrogels are crosslinked networks of polymers. They have excellent hydrophilicity and can absorb large amounts of water or tissue fluid. At the same time, their volumes can expand to thousands of times that of the anhydrous state [1]. Water absorption and water retention of hydrogels are closely related to the molecular structure of crosslinking network, hydrophilicity, and crosslinking degree of monomers. If the crosslinking network structure is too tight, its water absorption will be reduced. The higher the hydrophilicity of the monomer structure, the better the hydroscopicity. Too high a crosslinking degree will lead to a dense structure of hydrogel, thus reducing water absorption. When the water content is within a certain range, hydrogels have softness and a rubbery consistency similar to that of living tissue, which demonstrates their excellent biocompatibility for cells and tissues [2]. Therefore, hydrogels have great application value in biomedical engineering.

In hydrogels, crosslinking is the key to avoiding dissolution of hydrophilic-polymer chains or segments. Hydrogels can be divided into physical and chemical hydrogels according to differences in crosslinking modes between polymers. In physically crosslinked hydrogels, polymers usually form three-dimensional network structures through hydrogen bonding, ionic bonding, hydrophobic bonding, chain entanglement, microcrystal formations, electrostatic interactions, etc. [3]. Such crosslinking is relatively simple and convenient, but the resulting network structure is not uniform, the mechanical strength is poor, and the crosslinking is usually reversible. Physical gels can subsequently be degraded by changes in temperature, pH, or ionic strength in the environment. This limits their use in complex internal environments. In contrast, chemical crosslinking that usually occurs by covalent bonds is usually irreversible and thus stable under changing conditions. In addition, hydrogels obtained by chemical crosslinking generally have better

**Citation:** Liu, J.; Su, C.; Chen, Y.; Tian, S.; Lu, C.; Huang, W.; Lv, Q. Current Understanding of the Applications of Photocrosslinked Hydrogels in Biomedical Engineering. *Gels* **2022**, *8*, 216. https://doi.org/10.3390/ gels8040216

Academic Editors: Yang Liu and Kiat Hwa Chan

Received: 27 February 2022 Accepted: 30 March 2022 Published: 1 April 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

mechanical stability [4]. Therefore, chemically crosslinked hydrogels are more common in biomedical applications. There are many methods for chemically crosslinking hydrogels, such as crosslinking polymerization of complementary functional groups, enzyme-induced polymeriza-There are many methods for chemically crosslinking hydrogels, such as crosslinking polymerization of complementary functional groups, enzyme-induced polymeriza-There are many methods for chemically crosslinking hydrogels, such as crosslinking polymerization of complementary functional groups, enzyme-induced polymeriza-There are many methods for chemically crosslinking hydrogels, such as crosslinking polymerization of complementary functional groups, enzyme-induced polymeriza-

ment. This limits their use in complex internal environments. In contrast, chemical crosslinking that usually occurs by covalent bonds is usually irreversible and thus stable under changing conditions. In addition, hydrogels obtained by chemical crosslinking generally have better mechanical stability [4]. Therefore, chemically crosslinked hydrogels

ment. This limits their use in complex internal environments. In contrast, chemical crosslinking that usually occurs by covalent bonds is usually irreversible and thus stable under changing conditions. In addition, hydrogels obtained by chemical crosslinking generally have better mechanical stability [4]. Therefore, chemically crosslinked hydrogels

ment. This limits their use in complex internal environments. In contrast, chemical crosslinking that usually occurs by covalent bonds is usually irreversible and thus stable under changing conditions. In addition, hydrogels obtained by chemical crosslinking generally have better mechanical stability [4]. Therefore, chemically crosslinked hydrogels

ment. This limits their use in complex internal environments. In contrast, chemical crosslinking that usually occurs by covalent bonds is usually irreversible and thus stable under changing conditions. In addition, hydrogels obtained by chemical crosslinking generally have better mechanical stability [4]. Therefore, chemically crosslinked hydrogels

*Gels* **2022**, *8*, x FOR PEER REVIEW 2 of 26

*Gels* **2022**, *8*, x FOR PEER REVIEW 2 of 26

*Gels* **2022**, *8*, x FOR PEER REVIEW 2 of 26

*Gels* **2022**, *8*, x FOR PEER REVIEW 2 of 26

are more common in biomedical applications.

are more common in biomedical applications.

are more common in biomedical applications.

are more common in biomedical applications.

There are many methods for chemically crosslinking hydrogels, such as crosslinking polymerization of complementary functional groups, enzyme-induced polymerization, photo- or heat-induced free-radical polymerization, and high-energy irradiationcrosslinking polymerization [5]. Among them, the conditions of crosslinking polymerization with complementary functional groups and enzyme-induced polymerization are mild, and unnecessary functional molecules are not introduced, so they are the two preferred crosslinking methods [6,7]. However, in practical applications, the small molecules and macromolecules suitable for these two crosslinking methods are relatively limited, so there are few hydrogels prepared by using these two polymerization methods [8]. In contrast, light- or heat-induced radical polymerization is a common method in chemical crosslinking. In these methods, initiators must be added to a solution of crosslinked molecules to induce cracking into free radicals with light or heat, attacking the polymer chain withthe crosslinking molecules and initiating a chain reaction to complete polymerization [9]. Therefore, photo- or heat-induced free-radical polymerization is especially widely used because of its simplicity and speed. tion, photo- or heat-induced free-radical polymerization, and high-energy irradiation-crosslinking polymerization [5]. Among them, the conditions of crosslinking polymerization with complementary functional groups and enzyme-induced polymerization are mild, and unnecessary functional molecules are not introduced, so they are the two preferred crosslinking methods [6,7]. However, in practical applications, the small molecules and macromolecules suitable for these two crosslinking methods are relatively limited, so there are few hydrogels prepared by using these two polymerization methods [8]. In contrast, light- or heat-induced radical polymerization is a common method in chemical crosslinking. In these methods, initiators must be added to a solution of crosslinked molecules to induce cracking into free radicals with light or heat, attacking the polymer chain withthe crosslinking molecules and initiating a chain reaction to complete polymerization [9]. Therefore, photo- or heat-induced free-radical polymerization is especially widely used because of its simplicity and speed. With the development of cross-disciplines and deepening of scientific research, an increasing number of photocrosslinked hydrogels have been developed and applied in tion, photo- or heat-induced free-radical polymerization, and high-energy irradiation-crosslinking polymerization [5]. Among them, the conditions of crosslinking polymerization with complementary functional groups and enzyme-induced polymerization are mild, and unnecessary functional molecules are not introduced, so they are the two preferred crosslinking methods [6,7]. However, in practical applications, the small molecules and macromolecules suitable for these two crosslinking methods are relatively limited, so there are few hydrogels prepared by using these two polymerization methods [8]. In contrast, light- or heat-induced radical polymerization is a common method in chemical crosslinking. In these methods, initiators must be added to a solution of crosslinked molecules to induce cracking into free radicals with light or heat, attacking the polymer chain withthe crosslinking molecules and initiating a chain reaction to complete polymerization [9]. Therefore, photo- or heat-induced free-radical polymerization is especially widely used because of its simplicity and speed. With the development of cross-disciplines and deepening of scientific research, an increasing number of photocrosslinked hydrogels have been developed and applied in tion, photo- or heat-induced free-radical polymerization, and high-energy irradiation-crosslinking polymerization [5]. Among them, the conditions of crosslinking polymerization with complementary functional groups and enzyme-induced polymerization are mild, and unnecessary functional molecules are not introduced, so they are the two preferred crosslinking methods [6,7]. However, in practical applications, the small molecules and macromolecules suitable for these two crosslinking methods are relatively limited, so there are few hydrogels prepared by using these two polymerization methods [8]. In contrast, light- or heat-induced radical polymerization is a common method in chemical crosslinking. In these methods, initiators must be added to a solution of crosslinked molecules to induce cracking into free radicals with light or heat, attacking the polymer chain withthe crosslinking molecules and initiating a chain reaction to complete polymerization [9]. Therefore, photo- or heat-induced free-radical polymerization is especially widely used because of its simplicity and speed. With the development of cross-disciplines and deepening of scientific research, an increasing number of photocrosslinked hydrogels have been developed and applied in tion, photo- or heat-induced free-radical polymerization, and high-energy irradiation-crosslinking polymerization [5]. Among them, the conditions of crosslinking polymerization with complementary functional groups and enzyme-induced polymerization are mild, and unnecessary functional molecules are not introduced, so they are the two preferred crosslinking methods [6,7]. However, in practical applications, the small molecules and macromolecules suitable for these two crosslinking methods are relatively limited, so there are few hydrogels prepared by using these two polymerization methods [8]. In contrast, light- or heat-induced radical polymerization is a common method in chemical crosslinking. In these methods, initiators must be added to a solution of crosslinked molecules to induce cracking into free radicals with light or heat, attacking the polymer chain withthe crosslinking molecules and initiating a chain reaction to complete polymerization [9]. Therefore, photo- or heat-induced free-radical polymerization is especially widely used because of its simplicity and speed. With the development of cross-disciplines and deepening of scientific research, an increasing number of photocrosslinked hydrogels have been developed and applied in

With the development of cross-disciplines and deepening of scientific research, an increasing number of photocrosslinked hydrogels have been developed and applied in biomedical engineering. It is therefore necessary to give a summary and a review of the subject, as well as a glimpse into possible future development prospects. First, we introduce the compositions of photocrosslinked hydrogels, including synthetic monomers and modified monomers based on natural materials. Subsequently, we summarize hydrogels with different morphologies, such as films, fibers, microspheres, microneedles, and amorphous (injectable) hydrogels based on these monomers. Then, we summarize recent applications of these hydrogels in biomedical engineering. Finally, based on current development status, we put forward views on the development prospects forphotocrosslinked hydrogels in biomedical engineering. Overall, we hope that this review will give researchers a better understanding of this field and promote further development. biomedical engineering. It is therefore necessary to give a summary and a review of the subject, as well as a glimpse into possible future development prospects. First, we introduce the compositions of photocrosslinked hydrogels, including synthetic monomers and modified monomers based on natural materials. Subsequently, we summarize hydrogels with different morphologies, such as films, fibers, microspheres, microneedles, and amorphous (injectable) hydrogels based on these monomers. Then, we summarize recent applications of these hydrogels in biomedical engineering. Finally, based on current development status, we put forward views on the development prospects forphotocrosslinked hydrogels in biomedical engineering. Overall, we hope that this review will give researchers a better understanding of this field and promote further development. biomedical engineering. It is therefore necessary to give a summary and a review of the subject, as well as a glimpse into possible future development prospects. First, we introduce the compositions of photocrosslinked hydrogels, including synthetic monomers and modified monomers based on natural materials. Subsequently, we summarize hydrogels with different morphologies, such as films, fibers, microspheres, microneedles, and amorphous (injectable) hydrogels based on these monomers. Then, we summarize recent applications of these hydrogels in biomedical engineering. Finally, based on current development status, we put forward views on the development prospects forphotocrosslinked hydrogels in biomedical engineering. Overall, we hope that this review will give researchers a better understanding of this field and promote further development. biomedical engineering. It is therefore necessary to give a summary and a review of the subject, as well as a glimpse into possible future development prospects. First, we introduce the compositions of photocrosslinked hydrogels, including synthetic monomers and modified monomers based on natural materials. Subsequently, we summarize hydrogels with different morphologies, such as films, fibers, microspheres, microneedles, and amorphous (injectable) hydrogels based on these monomers. Then, we summarize recent applications of these hydrogels in biomedical engineering. Finally, based on current development status, we put forward views on the development prospects forphotocrosslinked hydrogels in biomedical engineering. Overall, we hope that this review will give researchers a better understanding of this field and promote further development. biomedical engineering. It is therefore necessary to give a summary and a review of the subject, as well as a glimpse into possible future development prospects. First, we introduce the compositions of photocrosslinked hydrogels, including synthetic monomers and modified monomers based on natural materials. Subsequently, we summarize hydrogels with different morphologies, such as films, fibers, microspheres, microneedles, and amorphous (injectable) hydrogels based on these monomers. Then, we summarize recent applications of these hydrogels in biomedical engineering. Finally, based on current development status, we put forward views on the development prospects forphotocrosslinked hydrogels in biomedical engineering. Overall, we hope that this review will give researchers a better understanding of this field and promote further development.

### **2. Chemically Synthesized Molecules for Preparation of Photocrosslinked Hydrogels 2. Chemically Synthesized Molecules for Preparation of Photocrosslinked Hydrogels**  To prepare photocrosslinked hydrogels exhibitinggood biocompatibility, many **2. Chemically Synthesized Molecules for Preparation of Photocrosslinked Hydrogels**  To prepare photocrosslinked hydrogels exhibitinggood biocompatibility, many **2. Chemically Synthesized Molecules for Preparation of Photocrosslinked Hydrogels 2. Chemically Synthesized Molecules for Preparation of Photocrosslinked Hydrogels**

To prepare photocrosslinked hydrogels exhibitinggood biocompatibility, many polymerizable small molecules have been synthesized. These small molecules usually have carbon–carbon unsaturated bonds, and the polymer network is formed by bond breaking and addition reaction under initiator and light. Depending on the type of polymerizable group, these molecules can be roughly divided into four classes: ethylene, acrylic, acrylamide, and acrylate (Table 1). polymerizable small molecules have been synthesized. These small molecules usually have carbon–carbon unsaturated bonds, and the polymer network is formed by bond breaking and addition reaction under initiator and light. Depending on the type of polymerizable group, these molecules can be roughly divided into four classes: ethylene, acrylic, acrylamide, and acrylate (Table 1). polymerizable small molecules have been synthesized. These small molecules usually have carbon–carbon unsaturated bonds, and the polymer network is formed by bond breaking and addition reaction under initiator and light. Depending on the type of polymerizable group, these molecules can be roughly divided into four classes: ethylene, acrylic, acrylamide, and acrylate (Table 1). To prepare photocrosslinked hydrogels exhibitinggood biocompatibility, many polymerizable small molecules have been synthesized. These small molecules usually have carbon–carbon unsaturated bonds, and the polymer network is formed by bond breaking and addition reaction under initiator and light. Depending on the type of polymerizable group, these molecules can be roughly divided into four classes: ethylene, acrylic, acrylamide, and acrylate (Table 1). To prepare photocrosslinked hydrogels exhibitinggood biocompatibility, many polymerizable small molecules have been synthesized. These small molecules usually have carbon–carbon unsaturated bonds, and the polymer network is formed by bond breaking and addition reaction under initiator and light. Depending on the type of polymerizable group, these molecules can be roughly divided into four classes: ethylene, acrylic, acrylamide, and acrylate (Table 1).


**Table 1.** Four different photocrosslinked molecules and their molecular structures. **Table 1.** Four different photocrosslinked molecules and their molecular structures. **Table 1.** Four different photocrosslinked molecules and their molecular structures. **Table 1.** Four different photocrosslinked molecules and their molecular structures. **Table 1.** Four different photocrosslinked molecules and their molecular structures.

### **Table 1.** *Cont. Gels* **2022**, *8*, x FOR PEER REVIEW 3 of 26 *Gels* **2022**, *8*, x FOR PEER REVIEW 3 of 26 *Gels* **2022**, *8*, x FOR PEER REVIEW 3 of 26 *Gels* **2022**, *8*, x FOR PEER REVIEW 3 of 26


### *2.1. Ethylenes 2.1. Ethylenes 2.1. Ethylenes 2.1. Ethylenes 2.1. Ethylenes*

Structurally, ethylene is the simplest functional group among polymerizable molecules. Photopolymerization of ethylene molecules was also the earliest method discovered and applied. In early studies, styrene and other monomers were mainly used to synthesize resins due to their poor water solubility, and they were usually polymerized by high-energy radiation or heat [10]. At present, thevinyl molecules used in hydrogel preparations are mainly N-vinyl pyrrolidone (NVP). NVP itself has low viscosity, high reactivity, and limitedskin irritation [11], so it is widely used as a typical ethylene molecule [12]. Kao et al. first reported NVP photocrosslinking with four different comonomers to prepare a series of UV-curable bioadhesives with a high water uptake ranging from 25 to 350 wt% [13]. Subsequently, Fechine et al. studied the effects of crosslinking NVP with other polymerizable molecules such as hydrogen peroxide [14,15]. Lee and Devine et al. provideda detailed discussion on the network structure of copolymerized NVP and polyethylene glycol diacrylate (PEGDA) hydrogels and found that the molecular weight of the main chain was mainly related to the NVP content and was not affected by polymerization time [16,17]. In addition to NVP, a variety of other ethylene molecules have been reported for photocrosslinking polymerizations. For example, Sahiner et al. successfully prepared photocrosslinked bulk polyethylene phosphonic acid (PVPA) by mixing and crosslinking PEGDAs with different molecular weights [18,19]. Ren et al. synthesized a hydrogen-bonded calcium-crosslinked PVDT-PAA hydrogel from 2-vinyl-4,6-diamino-1,3,5-triazine (VDT), acrylic acid (AA), and PEGDA through one-step photopolymerization [20]. However, due to the restriction of water solubility and reactivity, vinyl monomers are still rarely used in the preparation of photocross-Structurally, ethylene is the simplest functional group among polymerizable molecules. Photopolymerization of ethylene molecules was also the earliest method discovered and applied. In early studies, styrene and other monomers were mainly used to synthesize resins due to their poor water solubility, and they were usually polymerized by high-energy radiation or heat [10]. At present, thevinyl molecules used in hydrogel preparations are mainly N-vinyl pyrrolidone (NVP). NVP itself has low viscosity, high reactivity, and limitedskin irritation [11], so it is widely used as a typical ethylene molecule [12]. Kao et al. first reported NVP photocrosslinking with four different comonomers to prepare a series of UV-curable bioadhesives with a high water uptake ranging from 25 to 350 wt% [13]. Subsequently, Fechine et al. studied the effects of crosslinking NVP with other polymerizable molecules such as hydrogen peroxide [14,15]. Lee and Devine et al. provideda detailed discussion on the network structure of copolymerized NVP and polyethylene glycol diacrylate (PEGDA) hydrogels and found that the molecular weight of the main chain was mainly related to the NVP content and was not affected by polymerization time [16,17]. In addition to NVP, a variety of other ethylene molecules have been reported for photocrosslinking polymerizations. For example, Sahiner et al. successfully prepared photocrosslinked bulk polyethylene phosphonic acid (PVPA) by mixing and crosslinking PEGDAs with different molecular weights [18,19]. Ren et al. synthesized a hydrogen-bonded calcium-crosslinked PVDT-PAA hydrogel from 2-vinyl-4,6-diamino-1,3,5-triazine (VDT), acrylic acid (AA), and PEGDA through one-step photopolymerization [20]. However, due to the restriction of water solubility and reactivity, vinyl monomers are still rarely used in the preparation of photocross-Structurally, ethylene is the simplest functional group among polymerizable molecules. Photopolymerization of ethylene molecules was also the earliest method discovered and applied. In early studies, styrene and other monomers were mainly used to synthesize resins due to their poor water solubility, and they were usually polymerized by high-energy radiation or heat [10]. At present, thevinyl molecules used in hydrogel preparations are mainly N-vinyl pyrrolidone (NVP). NVP itself has low viscosity, high reactivity, and limitedskin irritation [11], so it is widely used as a typical ethylene molecule [12]. Kao et al. first reported NVP photocrosslinking with four different comonomers to prepare a series of UV-curable bioadhesives with a high water uptake ranging from 25 to 350 wt% [13]. Subsequently, Fechine et al. studied the effects of crosslinking NVP with other polymerizable molecules such as hydrogen peroxide [14,15]. Lee and Devine et al. provideda detailed discussion on the network structure of copolymerized NVP and polyethylene glycol diacrylate (PEGDA) hydrogels and found that the molecular weight of the main chain was mainly related to the NVP content and was not affected by polymerization time [16,17]. In addition to NVP, a variety of other ethylene molecules have been reported for photocrosslinking polymerizations. For example, Sahiner et al. successfully prepared photocrosslinked bulk polyethylene phosphonic acid (PVPA) by mixing and crosslinking PEGDAs with different molecular weights [18,19]. Ren et al. synthesized a hydrogen-bonded calcium-crosslinked PVDT-PAA hydrogel from 2-vinyl-4,6-diamino-1,3,5-triazine (VDT), acrylic acid (AA), and PEGDA through one-step photopolymerization [20]. However, due to the restriction of water solubility and reactivity, vinyl monomers are still rarely used in the preparation of photocross-Structurally, ethylene is the simplest functional group among polymerizable molecules. Photopolymerization of ethylene molecules was also the earliest method discovered and applied. In early studies, styrene and other monomers were mainly used to synthesize resins due to their poor water solubility, and they were usually polymerized by high-energy radiation or heat [10]. At present, thevinyl molecules used in hydrogel preparations are mainly N-vinyl pyrrolidone (NVP). NVP itself has low viscosity, high reactivity, and limitedskin irritation [11], so it is widely used as a typical ethylene molecule [12]. Kao et al. first reported NVP photocrosslinking with four different comonomers to prepare a series of UV-curable bioadhesives with a high water uptake ranging from 25 to 350 wt% [13]. Subsequently, Fechine et al. studied the effects of crosslinking NVP with other polymerizable molecules such as hydrogen peroxide [14,15]. Lee and Devine et al. provideda detailed discussion on the network structure of copolymerized NVP and polyethylene glycol diacrylate (PEGDA) hydrogels and found that the molecular weight of the main chain was mainly related to the NVP content and was not affected by polymerization time [16,17]. In addition to NVP, a variety of other ethylene molecules have been reported for photocrosslinking polymerizations. For example, Sahiner et al. successfully prepared photocrosslinked bulk polyethylene phosphonic acid (PVPA) by mixing and crosslinking PEGDAs with different molecular weights [18,19]. Ren et al. synthesized a hydrogen-bonded calcium-crosslinked PVDT-PAA hydrogel from 2-vinyl-4,6-diamino-1,3,5-triazine (VDT), acrylic acid (AA), and PEGDA through one-step photopolymerization [20]. However, due to the restriction of water solubility and reactivity, vinyl monomers are still rarely used in the preparation of photocross-Structurally, ethylene is the simplest functional group among polymerizable molecules. Photopolymerization of ethylene molecules was also the earliest method discovered and applied. In early studies, styrene and other monomers were mainly used to synthesize resins due to their poor water solubility, and they were usually polymerized by high-energy radiation or heat [10]. At present, thevinyl molecules used in hydrogel preparations are mainly N-vinyl pyrrolidone (NVP). NVP itself has low viscosity, high reactivity, and limitedskin irritation [11], so it is widely used as a typical ethylene molecule [12]. Kao et al. first reported NVP photocrosslinking with four different comonomers to prepare a series of UV-curable bioadhesives with a high water uptake ranging from 25 to 350 wt% [13]. Subsequently, Fechine et al. studied the effects of crosslinking NVP with other polymerizable molecules such as hydrogen peroxide [14,15]. Lee and Devine et al. provideda detailed discussion on the network structure of copolymerized NVP and polyethylene glycol diacrylate (PEGDA) hydrogels and found that the molecular weight of the main chain was mainly related to the NVP content and was not affected by polymerization time [16,17]. In addition to NVP, a variety of other ethylene molecules have been reported for photocrosslinking polymerizations. For example, Sahiner et al. successfully prepared photocrosslinked bulk polyethylene phosphonic acid (PVPA) by mixing and crosslinking PEGDAs with different molecular weights [18,19]. Ren et al. synthesized a hydrogen-bonded calcium-crosslinked PVDT-PAA hydrogel from 2-vinyl-4,6-diamino-1,3,5-triazine (VDT), acrylic acid (AA), and PEGDA through one-step photopolymerization [20]. However, due to the restriction of water solubility and reactivity, vinyl monomers are still rarely used in the preparation of photocrosslinked hydrogels [21,22].

### linked hydrogels [21,22]. linked hydrogels [21,22]. linked hydrogels [21,22]. linked hydrogels [21,22]. *2.2. Acrylic Acid*

*2.2. Acrylic Acid*  Acrylic-acid (AA) molecules have photoactive groups and good water solubility, and due to the free carboxyl structure remaining after polymerization, theycan swell or shrink with environmental pH changes, electric fields, enzyme reactions, and temperature, so that the hydrogel exhibits a tunableresponse. In addition, these free carboxyl groups can interact with other groups under certain conditions, so the hydrogel network can be functionalized by reactions with carboxyl groups or interactions with solutes [23–26]. Therefore, photocrosslinked hydrogels based on AA molecules are very common and are often used for biological adsorption and environmental purification. For example, Liu et al. successfully synthesized a b-cyclodextrin or polyacrylic-acid nanocomposite (b-CD/PAA/GO) grafted with graphene oxide (GO) based on polyacrylic acid (PAA) through an esterification reaction, and prepared a composite PAA hydrogel, with an adsorption capacity of up to 248 mg/g fordye molecules in wastewater [27]. Hu et al. prepared a new PAA hydrogel by improving and optimizing the crosslinking agent usedin the AA polymerization process, and the adsorption capacity fordye molecules reached a record-breaking 2100 mg/g under neutral conditions [28]. Ma and Kong et al. combined PAA hydrogels with organic montmorillonite or GO, and the resultingcom-*2.2. Acrylic Acid*  Acrylic-acid (AA) molecules have photoactive groups and good water solubility, and due to the free carboxyl structure remaining after polymerization, theycan swell or shrink with environmental pH changes, electric fields, enzyme reactions, and temperature, so that the hydrogel exhibits a tunableresponse. In addition, these free carboxyl groups can interact with other groups under certain conditions, so the hydrogel network can be functionalized by reactions with carboxyl groups or interactions with solutes [23–26]. Therefore, photocrosslinked hydrogels based on AA molecules are very common and are often used for biological adsorption and environmental purification. For example, Liu et al. successfully synthesized a b-cyclodextrin or polyacrylic-acid nanocomposite (b-CD/PAA/GO) grafted with graphene oxide (GO) based on polyacrylic acid (PAA) through an esterification reaction, and prepared a composite PAA hydrogel, with an adsorption capacity of up to 248 mg/g fordye molecules in wastewater [27]. Hu et al. prepared a new PAA hydrogel by improving and optimizing the crosslinking agent usedin the AA polymerization process, and the adsorption capacity fordye molecules reached a record-breaking 2100 mg/g under neutral conditions [28]. Ma and Kong et al. combined PAA hydrogels with organic montmorillonite or GO, and the resultingcom-*2.2. Acrylic Acid*  Acrylic-acid (AA) molecules have photoactive groups and good water solubility, and due to the free carboxyl structure remaining after polymerization, theycan swell or shrink with environmental pH changes, electric fields, enzyme reactions, and temperature, so that the hydrogel exhibits a tunableresponse. In addition, these free carboxyl groups can interact with other groups under certain conditions, so the hydrogel network can be functionalized by reactions with carboxyl groups or interactions with solutes [23–26]. Therefore, photocrosslinked hydrogels based on AA molecules are very common and are often used for biological adsorption and environmental purification. For example, Liu et al. successfully synthesized a b-cyclodextrin or polyacrylic-acid nanocomposite (b-CD/PAA/GO) grafted with graphene oxide (GO) based on polyacrylic acid (PAA) through an esterification reaction, and prepared a composite PAA hydrogel, with an adsorption capacity of up to 248 mg/g fordye molecules in wastewater [27]. Hu et al. prepared a new PAA hydrogel by improving and optimizing the crosslinking agent usedin the AA polymerization process, and the adsorption capacity fordye molecules reached a record-breaking 2100 mg/g under neutral conditions [28]. Ma and Kong et al. combined PAA hydrogels with organic montmorillonite or GO, and the resultingcom-*2.2. Acrylic Acid*  Acrylic-acid (AA) molecules have photoactive groups and good water solubility, and due to the free carboxyl structure remaining after polymerization, theycan swell or shrink with environmental pH changes, electric fields, enzyme reactions, and temperature, so that the hydrogel exhibits a tunableresponse. In addition, these free carboxyl groups can interact with other groups under certain conditions, so the hydrogel network can be functionalized by reactions with carboxyl groups or interactions with solutes [23–26]. Therefore, photocrosslinked hydrogels based on AA molecules are very common and are often used for biological adsorption and environmental purification. For example, Liu et al. successfully synthesized a b-cyclodextrin or polyacrylic-acid nanocomposite (b-CD/PAA/GO) grafted with graphene oxide (GO) based on polyacrylic acid (PAA) through an esterification reaction, and prepared a composite PAA hydrogel, with an adsorption capacity of up to 248 mg/g fordye molecules in wastewater [27]. Hu et al. prepared a new PAA hydrogel by improving and optimizing the crosslinking agent usedin the AA polymerization process, and the adsorption capacity fordye molecules reached a record-breaking 2100 mg/g under neutral conditions [28]. Ma and Kong et al. combined PAA hydrogels with organic montmorillonite or GO, and the resultingcom-Acrylic-acid (AA) molecules have photoactive groups and good water solubility, and due to the free carboxyl structure remaining after polymerization, theycan swell or shrink with environmental pH changes, electric fields, enzyme reactions, and temperature, so that the hydrogel exhibits a tunableresponse. In addition, these free carboxyl groups can interact with other groups under certain conditions, so the hydrogel network can be functionalized by reactions with carboxyl groups or interactions with solutes [23–26]. Therefore, photocrosslinked hydrogels based on AA molecules are very common and are often used for biological adsorption and environmental purification. For example, Liu et al. successfully synthesized a b-cyclodextrin or polyacrylic-acid nanocomposite (b-CD/PAA/GO) grafted with graphene oxide (GO) based on polyacrylic acid (PAA) through an esterification reaction, and prepared a composite PAA hydrogel, with an adsorption capacity of up to 248 mg/g fordye molecules in wastewater [27]. Hu et al. prepared a new PAA hydrogel by improving and optimizing the crosslinking agent usedin the AA polymerization process, and the adsorption capacity fordye molecules reached a record-breaking 2100 mg/g under neutral conditions [28]. Ma and Kong et al. combined PAA hydrogels with organic montmorillonite or GO, and the resultingcomposite hydrogel showed good adsorption capacitiesfor lead ions (Pb2+) with an adsorption capacity of 223.84 mg/g [29] and cadmium ions (Cd2+)

posite hydrogel showed good adsorption capacitiesfor lead ions (Pb2+) with an adsorption capacity of 223.84 mg/g [29] and cadmium ions (Cd2+) with maximum adsorption

posite hydrogel showed good adsorption capacitiesfor lead ions (Pb2+) with an adsorption capacity of 223.84 mg/g [29] and cadmium ions (Cd2+) with maximum adsorption

posite hydrogel showed good adsorption capacitiesfor lead ions (Pb2+) with an adsorption capacity of 223.84 mg/g [29] and cadmium ions (Cd2+) with maximum adsorption

posite hydrogel showed good adsorption capacitiesfor lead ions (Pb2+) with an adsorption capacity of 223.84 mg/g [29] and cadmium ions (Cd2+) with maximum adsorption with maximum adsorption capacity up to 316.4 mg/g [30]. In addition, PAA hydrogels can be used in the construction of flexible devices due to their good biocompatibility and flexibility. Based on this, Lu et al. combined PAA with nanocellulose to prepare a flexible hydrogel that can be used for skin sensing [31]. Clearly photocrosslinked hydrogels based on AA derivatives show a wide range of applications.

### *2.3. Acrylamide*

Unlike liquid AA, acrylamide (AAm) molecules are usually solid and exhibit good water solubility. The AAm molecule does not have a free carboxyl group, but instead has a neutral amide bond, so polyacrylamide (PAAm) hydrogels do not exhibit pH responsiveness but show an equilibrium water content in the range of 94.73–96.26 wt%. Thanks to this, PAAm hydrogels maintain stability in environments with variable solutes [32]. However, the amide bond can also be partially hydrolyzed into a carboxyl group under certain conditions, and the PAAm hydrogel can function as a partial PAA hydrogel. For example, Wang et al. used this principle to prepare enzyme-functionalized microspheres for detection and cleaning of objects [33].

If a hydrophobic isopropyl group is introduced to the other end of the acrylamide molecule, isopropyl acrylamide (NIPAm) is obtained. After photocrosslinking, the resulting polyisopropyl acrylamide (PNIPAm) has a critical phase-transition temperature. When the temperature of the PNIPAm hydrogel is increased above the critical phase-transition temperature, the volume of the hydrogel shrinks significantly, and vice versa. It is worth mentioning that the critical phase-transition temperature of PNIPAm hydrogels is 32 ◦C and its low critical-dissolution temperature is close to the physiological temperature, it has important application value in biomedical engineering [34]. Zhang et al. prepared PNIPAmhydrogel microspheres loaded with drugs, which shrank at physiological temperatures and released the loaded drugs for wound repair and disease treatment [35]. When PNIPAm hydrogel is combined with a substance susceptible to photothermal conversions, the new material exhibits photoresponsiveness, which can be used to deter counterfeiting [36,37].

### *2.4. Acrylates*

The reaction of an acrylic derivative (acrylic or methacrylic acid) with the terminal hydroxyl group of another molecule yields an acrylate that can be used for photocrosslinking. For example, polyethylene glycol acrylate (PEGMA), polyethylene glycol diacrylate (PEGDA), polyethylene glycol dimethacrylate (PEGDMA) and other molecules that were obtained after modification at the end of polyethylene glycol (PEG) can be photocrosslinked to form the corresponding polymer network. Compared with acrylic acid and acrylamide hydrogels, acrylate hydrogels are not sensitive to changes in environmental temperature, pH, or other conditions, and are not convenient for functional-group modification; when the surrounding environment changes, this kind of hydrogel maintains good stability. In addition, some acrylate hydrogels, such as PEGDA hydrogels, show good water absorption (about 60 wt%), good biocompatibility, and good adhesion resistance [38]. Therefore, this kind of hydrogel can be used in biomedicine to construct a stable hydrogel skeleton for direct contact with cells or human tissues, biological analyses, and other applications [39]. Hou et al. prepared photocrosslinkedfibers composed of PEGDA with different molecular weights and studied the conversion of acrylate bonds in the hydrogel and the mechanical properties of the fibers in detail. Hou et al. prepared a hydrogel microsphere based on a PEGDA hydrogel and realized the detection of glycoprotein molecules in the solution [40].

### **3. Chemically Modified Natural Materials**

Compared with synthetic materials, natural materials exist widely in nature and have incomparable advantages in sourcing and storage. In addition, natural materials usually have good biocompatibility; they are safer than synthetic materials for use in the biomedical field. At present, hydrogels prepared from natural materials play important roles in cell culture, tissue engineering, and other fields. However, natural materials usually do not have photocrosslinkable groups. In addition to a few complementary functional-group reactions, crosslinking based on natural materials usually relies on physical crosslinking. In practice, the mechanical strength and stability are poor. Therefore, researchers have proposed various strategies for modifying natural materials. The introduction of photocrosslinking groups makes the preparation of natural material hydrogels simpler and more convenient, solves the problems of mechanical strength and poor stability, and further expands their applications. Natural materials used for modification and preparation of crosslinked hydrogels are mainly divided into two categories depending on their composition: polysaccharides and proteins or peptides.

### *3.1. Polysaccharides*

Polysaccharides are carbohydrates with complex and large molecular structures formed by dehydration and condensation of multiple monosaccharide molecules. They are widely distributed in nature and play important roles [41]. For example, peptidoglycan and cellulose are components of the cytoskeletal structure of plants and animals, and starch and glycogen are important energy-storage materials used by animals and plants. The monosaccharides that make up various polysaccharides often have free functional groups; there are many active groups on the polysaccharide chain that can be modified toallow photocrosslinking. Common modified crosslinked hydrogels include alginate, hyaluronic acid, chitosan, heparin, chondroitin sulfate, gellan gum, cyclodextrin, and dextran, among others.

Alginate is a natural polysaccharide that can form a physical hydrogel by chelating its independent hydroxyl group with divalent and trivalent metal and heavy-metal ions. It has wide application value for drug delivery, wound repair, and tissue engineering [42,43]. However, physically crosslinked alginate hydrogels have limitations in practical applications due to their uncontrollable gluing speed and instability after gelation. Therefore, many researchers have modified alginate to graft photocrosslinking groups, and realize chemical crosslinking [44]. For example, Xu et al. chemically grafted aminopropyl vinyl ether after activating the carboxyl groups of sodium alginate and obtainedalginic acid functionalized with vinyl ethers (Figure 1a) [45]. Photoinitiators can affect the crosslinking of hydrogels under UV irradiation. Bukhair et al. obtained cinnamoyl-modified photocrosslinkable alginic acid via multistep modificationand demonstrated that these crosslinked alginate hydrogels have better mechanical properties and stabilities, as well as biocompatibility with physically crosslinked alginate hydrogels due to the formation of cyclobutane bridges connecting the alginate polysaccharide chains through the (2π + 2π) cycloaddition reaction of the inserted cinnamoyl moieties [46]. They have great potential in biomedical applications.

Hyaluronic acid is also a linear macromolecular mucopolysaccharide. It has unique viscoelasticity, excellent water retention, biocompatibility, and nonimmunogenicity. It also has important physiological and biological functions and is widely used in clinical procedures [47,48]. However, natural hyaluronic acid has poor stability, is sensitive to hyaluronidase, and lacks mechanical strength. Therefore, chemical modifications are needed to prevent degradation and improve its mechanical strength, and the modified groups mainly include carboxyl, hydroxyl, and the amino group exposed by deacetylation. Lee et al. used Pluronic F127 to modify hyaluronic acid. The resulting polymers exhibited thermosensitive sol–gel transition behaviors over the temperature range of 20–40 ◦C. After modifying the functional groups of N-(3-dimethylamino propyl)methacrylamide, the HA-F127 polymer was polymerized to form a stable photocrosslinked hydrogel (Figure 1b) [49]. Jenjob et al. prepared microspheres by photocrosslinking bisphosphonates (alendronate) with methyl methacrylate-modified hyaluronic acid. The adsorption efficiency of the microspheres for cationic bone morphogenetic protein 2 (BMP2) reached 91.0% [50].

**Figure 1.** Synthetic route map or structural formula of the photocrosslinked hydrogel. (**a**) Synthetic route for aminopropyl vinyl ether-modified alginic acid [45]. (**b**) Synthetic route to N-(3-aminopropyl) methylacrylamide-modified hyaluronic acid [49]. (**c**) Synthetic roadmap for cinnamoyl chloride chloride-modified [51]. (**d**) Structural formula of heparin modified by methyl acrylate [52]. **Figure 1.** Synthetic route map or structural formula of the photocrosslinked hydrogel. (**a**) Synthetic route for aminopropyl vinyl ether-modified alginic acid [45]. (**b**) Synthetic route to N-(3-aminopropyl) methylacrylamide-modified hyaluronic acid [49]. (**c**) Synthetic roadmap for cinnamoyl chloride chloride-modified [51]. (**d**) Structural formula of heparin modified by methyl acrylate [52].

Chitosan is formed by removing some acetyl groups from the natural polysaccharide chitin. Its chemical structure is similar to that of hyaluronic acid. It is the only cationic polymer in nature [53]. It shows good biodegradability, biocompatibility, bacteriostasis, and other functions. Chitosan is usually insoluble in water and alkali solutions and needs to be dissolved with acid, so chitosan solutions are usually acidic. In addition, the commonly used gelation method for chitosan involves use of aldehyde-containing molecules (such as glutaraldehyde) as crosslinking agents to react with the amino groups of chitosan to form a Schiff base, leading to gelation [34]. In biomedical applications, acidic materials cause irritation to skin or wounds, while residual crosslinking agents have strong biological toxicity. To overcome these shortcomings, Zhou et al. modified chitosan with ethylene groups; the material was dissolved in water and mixed with polyvinyl alcohol modified by methacrylic acid. Photocrosslinked hydrogels were Chitosan is formed by removing some acetyl groups from the natural polysaccharide chitin. Its chemical structure is similar to that of hyaluronic acid. It is the only cationic polymer in nature [53]. It shows good biodegradability, biocompatibility, bacteriostasis, and other functions. Chitosan is usually insoluble in water and alkali solutions and needs to be dissolved with acid, so chitosan solutions are usually acidic. In addition, the commonly used gelation method for chitosan involves use of aldehyde-containing molecules (such as glutaraldehyde) as crosslinking agents to react with the amino groups of chitosan to form a Schiff base, leading to gelation [34]. In biomedical applications, acidic materials cause irritation to skin or wounds, while residual crosslinking agents have strong biological toxicity. To overcome these shortcomings, Zhou et al. modified chitosan with ethylene groups; the material was dissolved in water and mixed with polyvinyl alcohol modified by methacrylic acid. Photocrosslinked hydrogels were formed after a photoinitiatorwas added [54]. Monier et al. modified chitosan molecules with cinnamyl chloride. The crosslinked chitosan hydrogel showed good stability (Figure 1c) [51].

formed after a photoinitiatorwas added [54]. Monier et al. modified chitosan molecules with cinnamyl chloride. The crosslinked chitosan hydrogel showed good stability (Figure 1c) [51]. Heparin is a mucopolysaccharide sulfate composed of glucosamine, L-ieduraldehyde glycoside, N-acetylglucosamine, and D-glucuronic acid. It is strongly acidic. It is a natural

anticoagulant in animals. Heparin specifically binds to growth factors, so it has important value in growth-factor-delivery systems [55,56]. Based on this, Yoon et al. modified heparin with N-methylacrylamide hydrochloride and then crosslinked it with cryloylmodified Pluronic F127 to obtain composite hydrogels for the controlled release of growth factors [57]. Jeong et al. successfully prepared electrospun fiber scaffolds by mixing methyl acrylate-modified alginate and methyl acrylate-modified heparin with polyoxyethylene (PEO) through electrospinning and photocrosslinking, and found that they were effective inregulating cell behavior (Figure 1d) [52].

Chondroitin sulfate is a glycosaminoglycan covalently linked to proteins to form proteoglycans. It is widely distributed in the extracellular matrix and cell surfaces of animal tissues. The sugar chain is polymerized by alternating glucuronic acid and N-acetylgalactosamine disaccharides. It relieves pain and promotes cartilage regeneration [58]. After chemical modification, a chondroitin sulfate hydrogel can be obtained through photocrosslinking. The hydrogel has good biocompatibility and biodegradability, and has broad application prospects in drug delivery and bone repair [59,60]. For example, Kim and others prepared methacrylated PEGDA or chondroitin sulfate hydrogel and used it as a biomineralized three-dimensional scaffold for binding and deposition of charged ions [61]. Ornell et al. used the photocrosslinked methacryl group to covalently modify chondroitin sulfate and form injectable hydrogels, which can be used for sustained release of drugs over a certain period of time (Figure 2a) [62].

Gellan gum is a linear polysaccharide composed of glucose, glucuronic acid, and rhamnose. It is heat-resistant, acid-resistant, and enzyme-resistant and has good chemical stability. Gellan gum is insoluble in nonpolar organic solvents and cold water, but can be dissolved in hot water to form a transparent solution. After cooling, it becomes a transparent and solid gel [63–65]. Because of its good biocompatibility and tunability, researchers have tried to use gellan glue for tissue engineering. However, the gel formed by cations is hard and brittle, which limits its application. For this reason, a variety of photocrosslinking groups were used to modify gellan gum and obtain hydrogels with good biocompatibility and mechanical properties. For example, Oliveriraet al. modified gellan gum with trans-4-aminophenyl pyridine, and the product can be used for catalase immobilization after photocrosslinking (Figure 2b) [66]. Mano et al. modified gellan gum with methacrylic acid to prepare injectable gellan gum, which can be used as a self-generated osteogenic material [67].

Cyclodextrins are a series of cyclic oligosaccharides produced with amylose under the action of cyclodextrin glucosyltransferase. The three common cyclodextrins contain 6, 7, and 8 glucose units and arecalled α-, β-, and γ-cyclodextrins, respectively. These molecules are particularly attractive because they can form inclusion complexes with hydrophobic guests exhibiting appropriate molecular sizes and have high versatility. In addition, they can be chemically modified by hydroxyl substitution [68,69]. For example, Cosola et al. prepared a cyclodextrin modified with polyacrylate, which can prepare photocrosslinked materials with different morphologies via 3D technology [70]. Yamasaki et al. modified cyclodextrin with isophorone diisocyanate and 2-hydroxyethyl acrylate to obtain photocrosslinked cyclodextrin [71]. Microspheres of the prepared photocrosslinked polymer showed good separation efficiency for phenol (Figure 2c) [72].

**Figure 2.** Synthetic routes for some crosslinked hydrogels. (**a**) Route map for the synthesis of chondroitin methacryloyl sulfate [62]. (**b**) Synthetic route for gellan gum modified by trans-4-aminophenyl pyridine[66]. (**c**) Synthetic route to cyclodextrin modified by isophorone diisocyanate and 2-hydroxyethyl acrylate [72]. (**d**) Synthetic route to glycidyl methacrylate modified dextran [73]. **Figure 2.** Synthetic routes for some crosslinked hydrogels. (**a**) Route map for the synthesis of chondroitin methacryloyl sulfate [62]. (**b**) Synthetic route for gellan gum modified by trans-4 aminophenyl pyridine [66]. (**c**) Synthetic route to cyclodextrin modified by isophorone diisocyanate and 2-hydroxyethyl acrylate [72]. (**d**) Synthetic route to glycidyl methacrylate modified dextran [73].

Glucan is a homopolysaccharide formed with glycosidic linkages between glucose. Based on the types of glycosidic bonds, it can be divided into α-glucan and β-glucan. The common glucan is dextran, a common α-glucan. It has good biocompatibility and is widely used in the biomedical field [74]. Dextran is rich in active hydroxyl functional groups, so it can be chemically modified. Casadei et al. modified it with methacrylate to obtain photocrosslinked dextran, which enablesthe controllable release of polymers [75]. Yin et al. used glycidyl methacrylate to modify dextran and crosslinked it with methacrylic acid ethylene glycol-modified concanavalin A and polyethylene glycol dimethacrylateto obtain hydrogels (Figure 2d) [73]. The hydrogelsshowed good biocompatibility and glucose responsiveness and are expected to be used in glucose biosensors and intelligent insulin delivery.
