*4.3. Thin Film*

Among the many morphologies of photocrosslinked hydrogels, hydrogels with thinfilm morphologies are most widely used because of their excellent size ranges and mechanical strength. Thin films are usually made of homogeneous structures, and by adding functional materials, hydrogel functionality can be enhanced in various ways. For example, incorporation of mesoporous active nanoparticles or a vascular endothelial growth factor can allow the hydrogel membrane to play an obvious promoting role in bone and wound healing [106,107]. Using the opal structure as the template, a hydrogel thin film with the antiopal structure was prepared. The nanoporosityand structure color of the antiopal structure enabled enhanced drug loading, sensing, and driving functions for hydrogels, withgood application prospects [37,108]. For example, Zhang et al. constructed photoresponsive antiopal hydrogel films that can be driven to capture and release objects under the action of light (Figure 5a) [109]. In some cases, two sides of the hydrogel film can be made to have different properties and functions by using different functionalization treatments to obtain a Janus structure thin film. Such films show good results when applied in complex

environments. Zhang et al. prepared a Janus sponge dressing that was hydrophilic on one side and hydrophobic on the other. When the dressing was applied to the wound, the exudate was discharged from the wound to maintain the microenvironment of the wound, thus accelerating wound repair (Figure 5b) [110]. dressing that was hydrophilic on one side and hydrophobic on the other. When the dressing was applied to the wound, the exudate was discharged from the wound to maintain the microenvironment of the wound, thus accelerating wound repair (Figure 5b) [110].

results when applied in complex environments. Zhang et al. prepared a Janus sponge

*Gels* **2022**, *8*, x FOR PEER REVIEW 14 of 26

**Figure 5.** Schematic diagram for application of thin films, microneedles, and injectable morphologies of hydrogels. (**a**) A light-responsive antiopal hydrogel thin film captures and releases objects under light [109]. (**b**) One-way liquid discharge capacity of Janus sponge dressings[110]. (**c**) Schematic representation of the intelligent release of glucagon drugs contained by microneedles in vivo[111]. (**d**) Preparation principle for an injectable hydrogel with a double dynamic covalent bond and schematic diagram of its application in wound healing [112]. **Figure 5.** Schematic diagram for application of thin films, microneedles, and injectable morphologies of hydrogels. (**a**) A light-responsive antiopal hydrogel thin film captures and releases objects under light [109]. (**b**) One-way liquid discharge capacity of Janus sponge dressings [110]. (**c**) Schematic representation of the intelligent release of glucagon drugs contained by microneedles in vivo [111]. (**d**) Preparation principle for an injectable hydrogel with a double dynamic covalent bond and schematic diagram of its application in wound healing [112].

### *4.4. Microacupuncture Needle 4.4. Microacupuncture Needle*

Microneedles are usually arrays of microneedles, typically less than 1mm in length. Due to their size, they only penetrate the surface of the skin without causing bleeding;they cause much less pain than a traditional needle, and the trauma can heal in hours. Therefore, microneedles have obvious advantages in transdermal administration [113–115]. Compared with traditional metal- and silicon-based microneedles, hydrogel microneedles have good biocompatibility, large drug loads, and controllable drug release,and they have great development prospects. For example, Ghavaminejad et al. prepared microgel-loaded glucagon using phenylboric acid as a functional group, and then mixed the microgel with methacrylated hyaluronic acid (MeHA) and added it to the template [111]. After photocrosslinking, a photocrosslinked hydrogel microneedle was obtained. This microneedle can release glucagon to raise blood glucose under hypoglycemic conditions, thus preventing hypoglycemia after insulin injections for patients with diabetes (Figure 5c). The mechanical properties of the microneedles can also be controlled by adjusting the morphology. For example, Yu et al. designedan amifostine-loaded armored microneedle AAMN to havestronger mechanical properties than Microneedles are usually arrays of microneedles, typically less than 1mm in length. Due to their size, they only penetrate the surface of the skin without causing bleeding; they cause much less pain than a traditional needle, and the trauma can heal in hours. Therefore, microneedles have obvious advantages in transdermal administration [113–115]. Compared with traditional metal- and silicon-based microneedles, hydrogel microneedles have good biocompatibility, large drug loads, and controllable drug release, and they have great development prospects. For example, Ghavaminejad et al. prepared microgel-loaded glucagon using phenylboric acid as a functional group, and then mixed the microgel with methacrylated hyaluronic acid (MeHA) and added it to the template [111]. After photocrosslinking, a photocrosslinked hydrogel microneedle was obtained. This microneedle can release glucagon to raise blood glucose under hypoglycemic conditions, thus preventing hypoglycemia after insulin injections for patients with diabetes (Figure 5c). The mechanical properties of the microneedles can also be controlled by adjusting the morphology. For example, Yu et al. designedan amifostine-loaded armored microneedle AAMN to havestronger mechanical properties than traditional conical microneedles, much higher

mechanical strength than conical structuresand high skin permeability, and they can be better used for transdermal administration of amifostine [115].

### *4.5. Amorphous (Injectable) Hydrogels*

Some hydrogels have poor mechanical properties due to limited high-molecular content or minimal crosslinking between large molecules. However, although these hydrogels do not maintain their specific fine structures and appearance, they can be used to cover irregular wounds and can be injected into irregularly shaped defect sites, which provides unique advantages in medical trauma repair. Therefore, such hydrogels have great application value in biomedical engineering. Liang et al. modified chitosan with quaternary ammonium moieties and formed an injectable hydrogel with trivalent iron, a protocatechuic aldehyde containing catechol and aldehyde groups. It can be used for wound healing and healing ofinfectionswith methicillin-resistant Staphylococcus aureus (Figure 5d) [112]. In addition, other functional materials can be added to injectable hydrogels to meet specific needs. For example, Zhao et al. combined drug-loaded hydrogel microspheres with injectable hydrogels to successfully prepare injectable hydrogels that were used for diabetes treatment [116].

### **5. Biomedical Applications**

Photocrosslinked hydrogels are widely used in biomedicine, such as for biosensors, flexible wearable devices, medicine or tissue engineering, cell microcarriers, organ chips, and so on. It should be noted that when constructing hydrogels, appropriate components should be selected according to the application scenarios. For example, when a hydrogel is used for sensing, it should exhibit antiadhesion properties. When applied directly to humans, the hydrogel components should be biocompatible and preferably adaptable.

### *5.1. Biomedical Sensor*

The components of hydrogels usually contain various functional groups, which can combine with molecules or ions in the surrounding environment and cause changes in the physical and chemical properties of hydrogels. By detecting these changes, the corresponding molecules or ions can be analyzed and sensed. For example, Qin et al. prepared hydrogel microspheres with a Janus structure, which changed its volume when the pH of the environment was changed; this led to changes in the intensitiesof surface-enhanced Raman scattering (SERS) signals and fluorescence signal. By collecting and analyzing these two signals, the pH of the solution could be determined (Figure 6a) [117].

When a hydrogel has an ordered micro/nanostructure, it can show structural color, which will change with volume changes of the hydrogel. Therefore, structural color can be used to detect and analyzethe target molecule. The Sun research group has performed a series of studies in this area. They used microspheres or membranes self-assembled with colloidal nanoparticles of silicon wafers as templates, used hydrogels for repeated preparation, and prepared a series of structurally colored hydrogel microspheres and films with different functions. These microspheres showed good sensing ability for detection of tumor markers, glycoproteins, DNA, and heavy-metal ions (Figure 6b) [118].

**Figure 6.** Applications of photocrosslinked hydrogels in biomedical sensors and flexible wearable devices. (**a**)The volume and fluorescence intensity of pH-responsive hydrogel microspheres changed under different pH conditions[117]. (**b**) The color of a mercury-ion-responsive hydrogels with structural color in mercury-ion solutions with different concentrations and reflection spectra of responses [118]. (**c**,**d**) Schematic diagram of hydrogel interferometer response to the target and demonstration of information encryption [119]. (**e**) Commercial contact lenses (top) and biosensing contact lenses (bottom) [120]. (**f**) Origami hydrogel for motion-signal sensing [121]. (**g**) Self-powered triboelectric nanogenerator that collects motion energy [122]. **Figure 6.** Applications of photocrosslinked hydrogels in biomedical sensors and flexible wearable devices. (**a**) The volume and fluorescence intensity of pH-responsive hydrogel microspheres changed under different pH conditions [117]. (**b**) The color of a mercury-ion-responsive hydrogels with structural color in mercury-ion solutions with different concentrations and reflection spectra of responses [118]. (**c**,**d**) Schematic diagram of hydrogel interferometer response to the target and demonstration of information encryption [119]. (**e**) Commercial contact lenses (top) and biosensing contact lenses (bottom) [120]. (**f**) Origami hydrogel for motion-signal sensing [121]. (**g**) Self-powered triboelectric nanogenerator that collects motion energy [122].

When a hydrogel has an ordered micro/nanostructure, it can show structural color, which will change with volume changes of the hydrogel. Therefore, structural color can be used to detect and analyzethe target molecule. The Sun research group has performed a series of studies in this area. They used microspheres or membranes self-assembled with colloidal nanoparticles of silicon wafers as templates, used hydrogels for repeated preparation, and prepared a series of structurally colored hydrogel microspheres and films with different functions. These microspheres showed good sensing ability for detection of tumor markers, glycoproteins, DNA, and heavy-metal ions (Figure 6b) [118]. In addition to construction with micro/nanostructures, optical hydrogels can be directly prepared by using the principle of thin-film interference and the swelling characteristics of hydrogels. For example, Qin's team proposed a hydrogel interferometercol-In addition to construction with micro/nanostructures, optical hydrogels can be directly prepared by using the principle of thin-film interference and the swelling characteristics of hydrogels. For example, Qin's team proposed a hydrogel interferometercolor-change system that was simple to prepare, quick to respond, and easily patterned, and demonstrated various applications in detection and information encryption [119]. This kind of hydrogel does not need a fine micro/nanoconstruction unit, but is used to fabricate a film by rotating the coating on a highly reflective substrate with grafted functional groups. According to the principle of film interference, the hydrogel-film thickness is controlled to cause instant discoloration (Figure 6c). To achieve a portable detection device, researchers have also developed the necessary mobile phone software [119]. When an unknown sample must be analyzed, one takes a picture with the mobile phone, and the software

or-change system that was simple to prepare, quick to respond, and easily patterned, and demonstrated various applications in detection and information encryption [119]. This kind of hydrogel does not need a fine micro/nanoconstruction unit, but is used to automatically analyzes the subject and provides the test results. Reversible encryption and decryption can be realized according to whether the film is damp or not (Figure 6d) [119].

### *5.2. Flexible Wearable Devices*

The concept of hydrogels was first proposed by Wichterle et al. in 1960. They constructed a three-dimensional hydrogel network comprising hydroxyethyl methacrylate (HEMA) containing a small amount of the crosslinking agent EGDMA to overcome the poor biocompatibility and stability of plastic products at that time. This hydrogel has a soft texture, good light permeability, adjustable mechanical properties and water content, and a certain degree of biological inertia. Based on these excellent properties, Wichterle used it forthe preparation of contact lenses [123]. Subsequently, many researchers made improvements on this material and developed cosmetic pupils with their own structural colors, which can be used for detection of substances in tear drops (Figure 6e) [120,124–126].

In addition to contact lenses, many flexible hydrogels are used in combination with sensing elements to produce flexible electronic devices that convert and conduct signals [127,128]. For example, Yu et al. developed a photocrosslinked acrylic hydrogel film with controllable thickness and excellent mechanical properties. During polymerization of the hydrogels, Zr4+ added to the solution coordinated with some of the carboxyl groups in polyacrylic acid, and the resulting hydrogels exhibited high stability. Akirigami structure for the hydrogel was obtained by photolithographic polymerization, so the hydrogel exhibited elevated ductility and flexibility to wrap the curved surface. After combining this origami hydrogel with a liquid metal, the resulting hydrogel sensor was used to sense arm or finger-bending motions (Figure 6f) [121]. To solve the need for a power supply for flexible electronic devices, Wang's research group developed a stretchable triboelectricnanogenerator (TENG) based on elastomer hydrogels. The tensioning, transparent, ultrathin single-electrode TENG with a double-layer structure fit firmly to human skin and deformed as the human body moved. TENGs can also capture energy during deformation processes (pressing, stretching, bending, and twisting) to drive electronic devices (Figure 6g) [122].

### *5.3. Drug Delivery and Tissue Engineering*

The traditional methods of drug administration such as injection and oral administration need to be given frequently, and will cause the problem of high drug concentration in a short time, resulting in side effects. Therefore, sustainable and low-dose drug delivery has important application prospects. The hydrogel material has a three-dimensional network structure that "locks" the drug in a grid, allowing it to be released slowly. As a result, hydrogels could be used for drug delivery, which in turn could play a role in tissue engineering. For example, Lei et al. prepared a photocrosslinked methacrylated hyaluronic acid (HAMA) microsphere loaded with vascular endothelial growth factor (VEGF) by a microfluidic electrospray technique and used in the treatment of thin endometrium. The combination of VEGF and HAMA can promote endometrial regeneration and embryo implantation, while hyaluronic-acid hydrogel scaffolds can work with VEGF to promote endometrial hyperplasia after degradation. Therefore, this drug-loaded hydrogel has a good application prospect (Figure 7a) [129–131].

**Figure 7.** Application of photocrosslinked hydrogels in drug delivery, tissue engineering, and cell microcarriers. (**a**) Schematic diagram for the preparation of hydrogel microspheres for thin endometrium therapy [129]. (**b**) Application and principles of structural colored microspheres for treatment of osteoarthritis [132]. (**c**) Effects of different hydrogels on regulation of cell metabolism [133]. **Figure 7.** Application of photocrosslinked hydrogels in drug delivery, tissue engineering, and cell microcarriers. (**a**) Schematic diagram for the preparation of hydrogel microspheres for thin endometrium therapy [129]. (**b**) Application and principles of structural colored microspheres for treatment of osteoarthritis [132]. (**c**) Effects of different hydrogels on regulation of cell metabolism [133].

By selecting suitable responsive hydrogels or changing the structure of nanopores, hydrogels can be designed to have tunable drug-delivery effects. The stimuli used to trigger the hydrogel's response are usually light, heat, molecules, or ions. For example, Zhao et al. developed a glucose-responsive injectable hydrogel. Injected into the body, this hydrogel can maintain quasi-homeostasis in the normal range of blood glucose levels for approximately two weeks [116]. Salahuddin et al. prepared a light-controlled hydrogel. When exposed to light, the mesh of the hydrogel changes, altering the diffusion rate of the molecules being convenient for the controlled release of the drug [134]. Yang et al. prepared an antiopal microsphere and used its nanoporous structure to load drugs injected into the joint cavity. Elevated local temperatures during exercise or arthritis can promote the release of drugs, and vice versa. Therefore, this ingenious drug-delivery system could play an important role in the treatment of osteoarthritis (Figure 7b) [132]. By selecting suitable responsive hydrogels or changing the structure of nanopores, hydrogels can be designed to have tunable drug-delivery effects. The stimuli used to trigger the hydrogel's response are usually light, heat, molecules, or ions. For example, Zhao et al. developed a glucose-responsive injectable hydrogel. Injected into the body, this hydrogel can maintain quasi-homeostasis in the normal range of blood glucose levels for approximately two weeks [116]. Salahuddin et al. prepared a light-controlled hydrogel. When exposed to light, the mesh of the hydrogel changes, altering the diffusion rate of the molecules being convenient for the controlled release of the drug [134]. Yang et al. prepared an antiopal microsphere and used its nanoporous structure to load drugs injected into the joint cavity. Elevated local temperatures during exercise or arthritis can promote the release of drugs, and vice versa. Therefore, this ingenious drug-delivery system could play an important role in the treatment of osteoarthritis (Figure 7b) [132].

### *5.4. Cellular Microcarrier*

Photocrosslinked hydrogels can be used to load cells as microcarriers for cell culture, and biocompatibility and bioadhesion of hydrogels can be evaluated according to the growth status of the cells. For example, Liu et al. used microcarriers constructed from different hydrogels for cell culture, and found that the growth status of the cells with different microcarriers was inconsistent. This indicated that hydrogel-cell microcarriers can be used to study biological adhesion of different hydrogels [135].

When photocrosslinked hydrogels are used in cell culture, they can also be used as a platform to study cell growth, proliferation, and interaction between cells, which is also the preliminary basis for the application of hydrogels in tissue engineering in vivo. In earlier studies, Burdick's research group prepared hydrogels with gradient-crosslinking density using microfluidic technology, which were used to study the migration and other behaviors of cells in vitro [136]. Dadsetan et al. obtained hydrogels with different crosslinking degrees and mechanical properties by changing the ratio of crosslinking agent and polymerizer in photocrosslinking hydrogels. When these hydrogels were used for chondrocyte culture, cells showed different adhesion effects and morphologies on hydrogels with different crosslinking densities [137]. Huang et al. found that by adding different ionic residues to the hydrogel, it can improve its mechanical properties and regulate the metabolic activity and collagen secretion of the loaded chondrocytes without changing the polymer content and swelling behavior (Figure 7c) [133]. These results indicated that hydrogels, when used as cell microcarriers, can simulate tissues in vitro and preliminarily monitor and regulate cell behavior [138].

### *5.5. Bionic Organ*

As mentioned earlier, photocrosslinked hydrogels can be used in cell culture. If microfluidic and other technologies are integrated into the cell-culture process, multiple cell cocultures can be realized, and the structures and functions of some organs can be simulated and realized through interactions between cells. The system is called an organ chip or organoid. These biomimetic organs can have important application value in the biomedical field. One of the most important applications is for drug evaluation. Today's drug development process often requires multiple rounds of animal or human trials to verify the drug's efficacy. Due to the differences between species, animal experiments often do not truly reflect the effects of drugs on humans, and both animal experiments and human experiments are faced with ethical problems. In addition, animal trials and human trials often take a long time, which greatly increases the cost of new drug development. Comparatively speaking, organ chips or organoids can prevent ethical problems and reduce time cycles, which is a good way to solve these problems. For example, Zhang et al. used a 3D microfluidic cell-culture system to construct microchips for liver, lung, kidney, and other organs for drug screening for related organ diseases [139]. Huh's team constructed a biomimetic lung-chip microdevice, that simulated lung respiration by applying mechanical force, and this can be used to evaluate the biotoxicities of nanoparticles [140]. Furthermore, they conducted an evaluation study on the toxicities of drugs with lung microchips [141]. Toh et al. cocultured a variety of cells to construct a three-dimensional liver-organ chip. Studies have shown that this chip can simulate the function of the liver and be used for toxicity testing [142]. Zhao et al. combined structurally colored hydrogels with cardiomyocytes to construct a novel heart chip [143] and used optical signals to monitor cardiomyocyte activity and drug evaluation (Figure 8a) [144].

**Figure 8.** Application of photocrosslinked hydrogels in bionic organoids.(**a**) Bionic heart chip for cardiac drug evaluation [144].(**b**) Bionic liver chip for the study of alcohol metabolism [145]. **Figure 8.** Application of photocrosslinked hydrogels in bionic organoids. (**a**) Bionic heart chip for cardiac drug evaluation [144]. (**b**) Bionic liver chip for the study of alcohol metabolism [145].

In addition to using bionic organs for drug evaluation, researchers have built organ chips for direct treatment of diseases. For example, Fu's team used 3D printing technology to construct a bionic liver with microchannels and nanoparticles for metabolism and adsorption of toxic substances [85]. Wang et al. constructed a bionic enzyme-cascade microcapsule by using microfluidic electrojet technology and a structurally e-colored microsphere enzyme carrier. In such microcapsules, the cascade metabolism of alcohol in the liver can be simulated with an enzyme-cascade reaction (Figure 8b) [145]. In addition to using bionic organs for drug evaluation, researchers have built organ chips for direct treatment of diseases. For example, Fu's team used 3D printing technology to construct a bionic liver with microchannels and nanoparticles for metabolism and adsorption of toxic substances [85]. Wang et al. constructed a bionic enzyme-cascade microcapsule by using microfluidic electrojet technology and a structurally e-colored microsphere enzyme carrier. In such microcapsules, the cascade metabolism of alcohol in the liver can be simulated with an enzyme-cascade reaction (Figure 8b) [145].

### **6. Conclusions and Prospects 6. Conclusions and Prospects**

In general, synthetic photocrosslinked hydrogels are usually constructed by introducing molecules containing double bonds that can be polymerized by light at the end of the molecule, such as ethylene, acrylic acid, acrylamide, acrylic ester, etc. Natural-polymer photocrosslinked hydrogels are usually modified by acrylates or acrylamide derivatives, which are prepared by acylation of natural polymers containing reactive groups. In the presence of photoinitiator, photocrosslinked hydrogels can be carried out under mild conditions. Compared with other chemical crosslinking, photocrosslinked In general, synthetic photocrosslinked hydrogels are usually constructed by introducing molecules containing double bonds that can be polymerized by light at the end of the molecule, such as ethylene, acrylic acid, acrylamide, acrylic ester, etc. Natural-polymer photocrosslinked hydrogels are usually modified by acrylates or acrylamide derivatives, which are prepared by acylation of natural polymers containing reactive groups. In the presence of photoinitiator, photocrosslinked hydrogels can be carried out under mild conditions. Compared with other chemical crosslinking, photocrosslinked hydrogels can achieve

in situ polymerization crosslinking and have the characteristics of fast reaction rate, mild reaction conditions, easy control of geometric shape, and low reaction heat release.

Photocrosslinked hydrogels are biomedical materials, and they have good development prospects. However, they still have some limitations. The synthetic monomers used to prepare photocrosslinked hydrogels are usually toxic. Removing these harmful substances and free-radical residues from photocrosslinked hydrogels is a challenging problem. Although chemically modified natural materials can vent monomer toxicity, their types are still limited, and the resulting mechanical properties are not as easy to control as those of hydrogels prepared from synthetic monomers. In addition, their high biocompatibility allows easy contamination with many bacteria, which limits their application in other fields. Therefore, in future research, more natural materials with chemical modifications designed to meet actual demand should be developed. In terms of preparation and application, although a variety of techniques have been used to prepare photocrosslinked hydrogels with different morphologies, it is still a great challenge to prepare photocrosslinked hydrogels that effectively simulate tissues or organs in vivo. In future research, the intersection of advanced processing technology, new materials and human-tissue mechanics will be important in solving this problem. We hope that with further combinations of biology, chemistry, engineering, and other disciplines, applications of photocrosslinked hydrogels in biomedical fields will be expanded and more remarkable achievements will be realized.

**Author Contributions:** Conceptualization, Q.L.; methodology, Q.L. and W.H.; investigation, J.L.; C.S.; Y.C.; S.T. and C.L.; resources, W.H.; data curation, S.T. and C.L.; writing—original draft preparation, J.L. and Q.L.; writing—review and editing, C.L. and W.H.; visualization, Y.C., S.T. and C.L.; supervision, Q.L.; funding acquisition, W.H. and Q.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** National natural science foundation of China (No. 31860708), Improvement project of the basic scientific research capacity of young and middle-aged teachers in Guangxi universities (No. 2022KY0565) and scientific research start-up fund for high-level talents of Yulin Normal University (No. G2021ZK12, G2022ZK02).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data are contained within the article.

**Acknowledgments:** The authors thank Tao Wang (College of Veterinary Medicine, Northwest A&F University) for helping to polish the English language.

**Conflicts of Interest:** The authors declare no conflict of interest.
