*3.4. Other Applications*

Many gastric diseases can cause gastric bleeding with gastroscopy as well as with surgical treatment [105]. To solve this problem, He et al. prepared injectable pH-responsive self-healing adhesive hydrogels based on acryloyl-6-aminohexanoic acid (AA) and AA-gNhydroxysuccinimide (AA-NHS) with efficient self-healing ability, hemostatic properties, and good biocompatibility. With the introduction of AA-NHS as a micro-crosslinker, the hydrogels exhibited enhanced adhesive strength. An in vivo model of porcine gastric bleeding showed that the hydrogel displayed good hemostatic properties by stopping acute arterial bleeding and preventing the bleeding. Gastric wound models showed that hydrogels exhibited excellent therapeutic effects, with type I collagen deposition, α-SMA expression, and angiogenesis significantly promoting wound healing [106]. In another study, Cheng et al. created an oral keratin hydrogel that adheres specifically to ulcers and accelerates ulcer healing [107]. In ethanol-treated rats, approximately 50% of the ulceradherent keratin hydrogel was able to remain in the stomach for 12 hours, however, only approximately 18% was left in healthy rats during the same period. In addition, keratin hydrogels prevented epithelial cell damage by gastric acid, reduced inflammation, and accelerated epithelial reconstitution of ethanol-induced gastric ulcers.

Intestinal bleeding is a bleeding disorder that may be caused by inflammation, mechanical injury, vascular lesions, or tumors. Recently, Cui et al. designed a high-strength instant self-adhesive organic-inorganic hybrid (OIH) hydrogel. This OIH hydrogel was composed of N-acryloyl 2-glycine (ACG), a biocompatible glycine derivative vinyl monomer, and the naturally occurring mineral hydroxyapatite (HAp) [108]. The hydrogen bonding of the

poly(N-acryloyl 2-glycine) (PACG) side chains, the carboxyl-calcium ion crosslinking, and the PACG chain-HAp physical interactions contribute to the high mechanical properties of the hydrogel. Importantly, this OIH hydrogel exhibited strong adhesion to different substrates, which could be attributed to the synergistic interaction of carboxyl groups and the enhanced contact of PACG chains with the adherent surface.

### **4. Summary and Outlook**

Different substances have been discovered to stop bleeding, however, their effectiveness depends on the type of bleeding and the location of the wound. Although many effective hemostatic bandages, gauze, foams, sprays, adhesives, gels, powders, granules, tourniquets, and tampons have been discovered for externally visible and accessible, and compressible wounds, these uncontrollable and incompressible bleedings remain a challenging problem in treating the internal arterial visceral bleeding and massive surgical blood loss. To stop blood loss, hemostatic hydrogels must firmly adhere to specific tissues under high fluid pressure, moisture, and dynamics while maintaining their good mechanical strength. In recent years, there has been a dramatic increase in the availability of multifunctional polymeric hydrogels to fill the current needs in wound management. In this review, we discussed recent advances in wet-adhesive hydrogel systems as hemostatic agents, sealants, or adhesives, focusing on elucidating the mechanisms of hemostasis, the various factors affecting wet-environment adhesion, and the application of wet-adhesive hemostatic hydrogels in various complex physiological settings such as skin, cardiac and liver wounds, and other mucosal bleeds. Some of the polymer precursors were modified with catechol as well as other groups to provide strong adhesion and good hemostatic properties. These developed hydrogels are not only highly biocompatible but also can effectively exert antiseptic and anti-inflammatory effects when antimicrobial substances are added, thereby promoting wound healing. Moreover, these hydrogels can withstand high blood pressure and have shown advantages over some existing commercial products.

Despite improvements in recent years in research on wet-adhesive hydrogel systems for hemostasis and wound healing, there are still many hurdles that need to be addressed before these hydrogel technologies can be used in the clinic. First, few hydrogels have been able to stop bleeding quickly and effectively in the presence of excess water and heavy bleeding from active tissue. Additional researches are necessary to develop effective injectable hydrogels that can effectively and accurately stop moist, smooth, and dynamic internal tissue and organ bleeding. Second, high-quality raw materials used to prepare wet-adhesive hydrogels should be exploited. Although hemostatic hydrogels prepared by mussel-inspired chemical methods have shown good adhesion and hemostatic properties, substances such as DA are expensive as raw materials for the preparation of these hydrogels, and the potential neurological side effects of DA would limit their mass production and commercialization [109]. There are also low-cost and safe substances considered alternatives to DA, like plant-derived polyphenolic compounds such as TAs containing catechol/pyrogallol molecules. Nevertheless, it should be noted that additional stimuli are required to stimulate the formation of polymer-TA hydrogels [110,111]. Moreover, the incorporation of artificial nanoenzymes with antioxidant properties to fabricate a multifunctional hemostatic hydrogel may also facilitate their translation [112]. Therefore, the development of safe raw materials for viscous hydrogels, as well as the development of new strategies to achieve rapid and effective hemostasis of hydrogels in humid environments, remain to be explored in the future, and it is hoped that this review will inspire future development in this field.

**Author Contributions:** Conceptualization, S.W. and W.H.; validation, W.H.; investigation, S.W.; writing—original draft preparation, W.H.; writing—review and editing, S.W.; supervision, S.W.; project administration, S.W.; funding acquisition, S.W. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research and the APC were funded by Shanghai Rising-Star Program, grant number 20QA1407200.

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

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

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

### **References**


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