Taking into account the promotion in wound healing possessed by hydrogel itself, photo-crosslinking may provide hydrogel a stable 3D structure with preferable mechanical strength and wet-tissue adhesive capacity without sutures. Moreover, the photoinitiated triggering modulation is spatiotemporally controllable in a simple, precise, and noncontact manner. The specific two-step procedure could effectively avoid the formation of dead space in different kinds of complex nonhealing wounds, followed by the formation of stable solid hydrogel to isolate the defect from the external environment. All the aforementioned factors contribute to the protection of the macromolecular hydrogel bone materials along with the loaded drugs and bioactive substances, thus avoiding any secondary damage to wound tissue while facilitating patients’ daily activities and improving their quality of life (QOF). Here is the specific effect of photo-crosslinking hydrogels to promote wound healing.

When wounds are generated, microorganisms are easy to invade and cause infection, which is a prominent factor affecting wound healing ^[1][10]. Therefore, antibacterial ability is very important for wound healing materials. The photo-crosslinking hydrogel has good in situ curing characteristics and excellent cell loading. The antibacterial effect is achieved through the inherent antibacterial properties of the photo-crosslinking scaffolds and through the loading of therapeutic ions or metal nanomaterials. Chitosan and alginate are the main photo-crosslinking materials with antimicrobial properties. Previous studies have reported that photo-crosslinking hydrogels containing quaternary ammonium chitosan exhibit good antimicrobial properties ^[2][3][52,56]. However, the antibacterial properties of photo-crosslinking materials alone are not excellent enough, so the addition of antimicrobial active ingredients is the most common solution. Pang et al. reported a composite hydrogel prepared by mixing the therapeutic ion Cu²⁺ with borosilicate (BS) and photo-crosslinking methacrylate silk fibroin (MA-SF). When used, the composite system could thoroughly spread to the whole wound through in situ photo-crosslinking, firmly fit the wound, and protect the wound from external pollution. It can also further promote wound regeneration by releasing therapeutic ions ^[4][49]. In addition, Tang et al. encapsulated silver nanoparticles (AgNPs) in hydrogels, which endow the material with long-term broad-spectrum antibacterial activity by continuously transferring silver ions ^[5][48]. Yao et al. produced a ZN-MOF encapsulated methacrylate hyaluronic acid hydrogel, and zinc ions also have the ability to destroy the bacterial envelope ^[6][50]. In addition, the hydrogel combining gallium ion (Ga³⁺) with alginate has the effect of destroying bacterial iron metabolism and exhibits good antibacterial activity ^[7][61].

The first stage of wound healing is the inflammatory phase. After injury, inflammatory pathways and components of the immune system are recruited to remove necrotic tissue ^[8][4]. Excessive and prolonged inflammation can lead to poor wound healing, such as scarring. Limited inflammatory response is conducive to wound healing, so the idea of preparing anti-inflammatory hydrogels is to give them the ability to reduce the number of macrophages and neutrophils, reduce proinflammatory factors, improve inflammatory inhibitory factors, and promote macrophage polarization ^[9][27].

Qi et al. designed a photo-crosslinking sericin hydrogel (SMH), and evaluated inflammatory cells (CD68-stained macrophages and myeloperoxidase (MPO)-stained neutrophils) were approximately twofold lower than conventional treatment. These results suggest that sericin hydrogels can inhibit inflammatory responses during healing, but the specific mechanism has not been clarified ^[10][53].

Reducing proinflammatory chemokine production is a common strategy to reduce inflammation. In one study, a photo-crosslinking hydrogel mixed with thiol–acrylate and alginate/poloxamer activated human keratinocyte proliferation and produced anti-inflammatory effects by inhibiting the extracellular ERK-NF-KB-TNF-α signaling pathway. Its anti-inflammatory test results showed a substantial decrease in the proinflammatory chemokine TNF-α, comparable to the results obtained with the anti-inflammatory drug dexamethasone treatment ^[11][59].

M1 macrophages promote the development of inflammation, and M2 macrophages inhibit M1 macrophages by secreting anti-inflammatory cytokines, such as IL10. Therefore, regulating the polarization of macrophages and realizing the effective transformation from M1 to M2 is also a feasible strategy to reduce the inflammatory response and promote wound healing ^{[4][6][12][13]}[49,50,62,67]. Metformin (Met) is a classic oral hypoglycemic drug. A large number of previous studies have shown that metformin has good immunomodulatory properties in vivo and in vitro, and exogenous metformin can induce macrophage polarization to the anti-inflammatory phenotype M2 ^[14][15][93,94]. An immunomodulatory drug (M@M-Ag-Sil-MA) has been designed in recent studies, which was further loaded with antibacterial silver nanoparticles (AgNPs), and metformin loaded with mesoporous silicon nanoparticles (MET@MSNs) using photo-crosslinking methacrylate silk fibroin hydrogel (Sil-MA) as a scaffold. Both in vitro and in vivo tests confirmed that this material can induce the effective transformation of macrophages M1 to M2, thereby reducing the inflammatory response for wound healing ^[16][58].

Many studies have demonstrated that the presence of excessive reactive oxygen species (ROS) can hinder the process of wound healing ^[17][18][19][95,96,97]. The sustained inflammatory response during wound healing leads to the accumulation of a large number of oxygen free radicals, which exceeds the antioxidant capacity of cells, thus preventing the transition of wounds from the inflammatory phase to the proliferative phase ^[20][98]. Therefore, the use of antioxidant materials in wound healing can effectively promote cells to maintain REDOX balance, thus accelerating wound healing. Huang et al. introduced tofu into GelMA hydrogel by the photo-crosslinking method for the first time, and found that the antioxidant activity of the mixed hydrogel strengthened with the increase in tofu ^[6][50]. In another study, a photo-crosslinking hydrogel mixed with the natural antioxidant glycyrrhizin (GA) showed significant antioxidant activity, with a free radical scavenging capacity of over 90% ^[12][62]. In addition, some stable free radicals can be introduced into photo-crosslinking hydrogels as antioxidants to remove excess oxygen free radicals. For example, grafting phenol groups with good antioxidant properties onto photo-crosslinking carboxymethyl chitosan (CMCS) bones can give hydrogels effective and long-term antioxidant properties ^[2][52].

The inflammatory phase of wound healing requires the coagulation cascade to stop bleeding, which includes vasoconstriction, platelet thrombosis, and blood coagulation ^[8][21][4,5]. Photo-crosslinking hydrogels can be used as tissue adhesives to control wound bleeding due to their in situ curing and sealing properties ^[22][99]. For example, the tissue adhesive methacrylate hyaluronic acid–polyacrylamide (MHA–PAAm) hydrogel was verified to have good hemostatic ability in the model of chronic wound bleeding and acute massive bleeding simulating clinical scenes. SEM electron microscope observation showed that many red blood cells appeared on the surface of the hydrogel. This suggests that the excellent hemostatic performance of MHA–PAAm hydrogel is due to the electrostatic attraction between its positive charge and the negative charge of red blood cells, which promotes the formation of platelet thrombosis ^[5][48]. In addition, because of the hemostatic effect of hydrogel skeleton chitosan and good tissue adhesion ability, CSG-PEG/DMA6/Zn photo-crosslinking hydrogel can be photo-crosslinked in situ and closely fit the wound site, providing a stable gel network as a physical barrier to accelerate blood coagulation. Its hemostatic function was proved to be superior to the traditional chitosan wound dressing previously reported in the mouse liver hemorrhage model and the mouse tail amputation model ^[23][41].

The proliferative phase is particularly important in wound healing, and granulation tissue composed of macrophages, fibroblasts, and endothelial cells is a marker of the proliferative phase. In addition, re-epithelialization is essential for rebuilding tissue integrity ^[21][5]. Loading various growth factors into photo-crosslinking hydrogels is an effective way to improve the efficiency of wound healing ^[24][68], which can improve granulation tissue formation, promote collagen deposition, and accelerate the process of re-epithelialization. For example, Li et al. added endogenous vasoconstrictor peptide endothelin-1 (ET-1) into photo-crosslinking gelatin methylacrylyl (GelMA) hydrogel. ET-1 was encapsulated in the crosslinked hydrogel network through intermolecular hydrogen bond interaction, which improved stability and effectively avoided oxidative degradation. Further in vivo experiments showed that GELMA-ET-1 hydrogel significantly accelerated the formation of new blood vessels, collagen deposition, and epithelial regeneration ^[25][47]. In addition, basic fibroblast growth factor (B-FGF), which promotes tissue regeneration, has also been reported to be combined with photo-crosslinking materials to form gelatin photo-crosslinking hydrogels with rapid wound adhesion, wet tissue surface adhesion, and long-term bFGF release. This material can promote cell migration and improve wound healing and flap formation ^[26][37].

Angiogenesis plays an important role in wound healing by facilitating the transport of nutrients and oxygen to the lesion site ^[27][28][100,101]. Direct loading of angiogenic substances into photo-crosslinking hydrogels is the most common method. Differin (DFO) is an FDA-approved iron chelator for clinical use. Previous studies have shown that DFO can accelerate the formation of new blood vessels under normal and pathological conditions by upregulating the expression of HIF-1α and its downstream gene VEGF ^[29][30][31][102,103,104]. Chen et al. prepared gelatin hydrogels loaded with DFO using physical mixed photo-crosslinking technology. At the early stage of injury, the photo-crosslinking hydrogels released wrapped DFO to promote the formation of a vascular network, deliver a sufficient amount of oxygen and nutrients to the wound area, and promote the proliferation of granulation and epithelial tissues ^[32][66]. In addition, loading the photo-crosslinking hydrogel network with exosomes or extracellular vesicles (EVs) that secrete growth factors has proved to be a feasible strategy. As natural carriers, EVs can directly transfer endogenous bioactive molecules to recipient cells to play therapeutic functions ^[33][34][105,106]. In a study by Wang et al., extracellular vesicles derived from epidermal stem cells (ESCs) were loaded with the HIF-1α stabilizer VH298 and encapsulated in photo-crosslinking GelMA hydrogel. This material effectively promotes wound healing by activating the HIF-1α signaling pathway to locally enhance blood supply and angiogenesis ^[35][64].

The final remodeling stage of wound healing can last for several years. At this stage, extracellular matrix components change to close to normal tissue architecture, the wound margin physically contracts, and granulation tissue stops growing due to apoptosis ^[36][6]. Abnormalities in either process may lead to the formation of keloids and hypertrophic scars. Transforming growth factor-β (TGF-β) plays a pleiotropic role in wound healing by regulating cell proliferation and migration, extracellular matrix production, and immune response ^[37][38][107,108]. Therefore, focal blocking of TGF-β pathway expression has been considered an effective therapeutic target for the treatment of abnormal wound formation and scar hyperplasia. In a study by Zhang et al., pulse-released PLGA (polylactic acid glycolic acid)-NB capsules containing a TGF-β inhibitor (SB-431542) were loaded onto photo-crosslinking HA-NB and HA-CDH hydrogels. They have been proved to inhibit scar formation in a mouse full-thickness skin defect model, rabbit ear hypertrophic scar model, and pig skin defect model ^[39][45]. In addition, Chao et al. developed a photo-crosslinking sericin hydrogel (SMH), which can prevent scar tissue formation by regulating the expression of TGF-β1 and TGF-β3 and recruit mesenchymal stem cells to the injury site to regenerate skin appendages ^[10][53]. In conclusion, these photo-crosslinking hydrogel designs utilizing TGF-β pathway blockade show a potential for scarless wound healing.

Long-term moisturization is also crucial for promoting wound healing. Compared with treatment in a dry environment, a moist environment can protect the formation of new granulation tissue, promote the formation of wound epithelium, and lead to less scar formation ^[40][109]. However, traditional hydrogels tend to evaporate in an open environment, which reduces their tensile properties and water retention ^[41][110]. Therefore, the manufacture of hydrogels with long-term mechanical stability is particularly critical for wound moisture. A recent study introduced tea polyphenol (TP)/glycerol (TG) into a covalent crosslinking network consisting of photo-crosslinking N-allylglycine (NAGA), GelMA, and Laponite so that a multifunctional hydrogel with high water retention, long-term mechanical stability, antibacterial and antioxidant properties was synthesized ^[42][57]. The glycerol/water solvent delayed the diffusion of tea polyphenols in the hydrogel and formed a uniform network, which was conducive to water retention.