(5) Metal Coordination Bond and Ionic Bond

The metal coordination bond and ionic bond also affect the wet surface adhesion. A specific type of covalent link known as a metal coordination bond typically has a stronger binding than a hydrogen bond [71]. The coordination bond is reversible, which gives the hydrogel reversible underwater adhesion characteristics in addition to maintaining the stability of the covalent bond [72]. An ionic bond contains two opposite-charged ions, which are also stronger than hydrogen bonds [73]. In order to create strong and durable ampholyte hydrogels, Huang et al. created a synthetic polyamphiphilic electrolyte hydrogel using the complementary interaction of ionic and metallic coordination bonds [74]. Using acrylamide, sodium alginate, and acrylic acid as raw materials, Liang et al. created an ultra-strong and tough hydrogel with excellent mechanical properties, adhesion, high hardness, toughness, fatigue resistance, and salt resistance. This hydrogel formation was based on the establishment of strong ionic and weak hydrogen bonds [75].


**Table 1.** Influencing factors of wet surface adhesion.

### (6) Biomimemtic Strategies

Research interest in the adhesion abilities of mussels, tree frogs, geckos, snails, teleosts, clingfish, and octopuses has led to the development of biomimetic hydrogel adhesives (Figure 5c–j). Biomimetic adhesions mirror the surface interactions caused by the topological structure of naturally adhesive creatures and are less sensitive to environmental cues. The adhesion of geckos and octopuses to wet surfaces primarily originated from the concurrence of physical forces like negative pressure, capillary force, and mechanical interlocking [76]. The sucker patterns, which exhibited a strong capillary force, were mimicked to elevate the wet adhesion content of polyethylene glycol (PEG) hydrogel [65,77]

(Figure 4c). The hydrogel micropillars expanded when placed on a moist surface, which created a capillary force around the suction cups and moved the micropatterns closer to the substrate for adherence. In another study, a PDA hydrogel was tailored to present the micro-channels and mimic the dynamics of the suction cups of geckos and octopuses. Such a PDA hydrogel was able to contract upon heating and expand when cooled, during which a negative pressure was created to suck the surface water into chambers to enable wet surface adherence [78]. Recently, an endoparasites-inspired hydrogel-forming double-layered adhesive microneedle patch, which is composed of a non-swellable silk fibroin-based core and swellable mussel adhesive protein-based shell, was proposed. The double-layered adhesive microneedle patch showed enhanced tissue insertion capability and superior wound-sealing capacity for wet and/or dynamic external and internal tissues [79]. The cohesion (mechanical properties) of the hydrogel is also closely related to the wet surface adhesion strength, as good mechanical properties support the deformation of the hydrogel without breaking. The duration of adhesion is equally important for practical purposes, as biomedical applications require that the hydrogel remains adherent to the implant site until effective hemostasis, tissue regeneration, or therapeutic delivery is complete. For example, the catechol-mediated wet surface adhesion was prone to disrupt by natural oxidation. Accordingly, protecting it from oxidation is the main strategy to enhance wet adhesion [46]. *Gels* **2023**, *8*, x FOR PEER REVIEW 11 of 23

**Figure 5.** (**a**) Exclusion of interfacial water to enhance adhesion strategy. Figure modified from [58] with permission. (**b**) Absorption of interfacial water and rapid light curing strategies. Figure modified from [62] with permission. (**c**) Clingfish photos and SEM images of adherent disc surface morphology. Reprinted (adapted) with permission from [80]. Copyright {2022} American Chemical Society. (**d**) Teleost photographs and (**e**) SEM images of mouth surface morphology. Figure modified from [81] with permission. (**f**) Photographs of octopus tentacles and SEM images of its suckers (scale bar: 1 mm). Figure modified from [82] with permission. (**g**) Ventral diagram of the gecko foot. (**h**) SEM diagram of foot setae morphology. Figure modified from [83] with permission. (**i**) Photographs of the gill cover of the snail and SEM images of the surface morphology. Reprinted (adapted) with permission from [84] . Copyright {2020} American Chemical Society. (**j**) **Figure 5.** (**a**) Exclusion of interfacial water to enhance adhesion strategy. Figure modified from [58] with permission. (**b**) Absorption of interfacial water and rapid light curing strategies. Figure modified from [62] with permission. (**c**) Clingfish photos and SEM images of adherent disc surface morphology. Reprinted (adapted) with permission from [80]. Copyright {2022} American Chemical Society. (**d**) Teleost photographs and (**e**) SEM images of mouth surface morphology. Figure modified from [81] with permission. (**f**) Photographs(a) of octopus tentacles and SEM images(b) of its suckers (scale bar: 1 mm). Figure modified from [82] with permission. (**g**) Ventral diagram of the gecko foot. (**h**) SEM diagram of foot setae morphology. Figure modified from [83] with permission. (**i**) Photographs of the

Photographs of tree frogs and SEM and TEM images of the surface morphology. Figure modified

Dopamine catechol chemical adhesion

Hydrogen bonding and catechol chemical

Strong adhesion of hydrogel due to large

After exposure to UV light, onitrobenzene is converted to onitrobenzaldehyde, which is further cross-linked with amino groups on the

amount of hydrogen bonding

tissue surface.

adhesion

**Influence Factors Hydrogels Adhesion Mechanism** 

Hyaluronic acid and dopamine polymerized

In situ photo-responsive chitosan (CS) hydro-

Konjac glucomannan, dopamine hydrochloride, L-cysteine hydrochloride, and epigallocatechuic acid ester pH-responsive hydrogels [55]

from [85] with permission.

hydrogel [51]

gel [52]

Permanent and dynamic

covalent bonds

Hydrogen bond

gill cover of the snail and SEM images of the surface morphology. Reprinted (adapted) with permission from [84]. Copyright {2020} American Chemical Society. (**j**) Photographs of tree frogs and SEM and TEM images of the surface morphology. Figure modified from [85] with permission.

### **3. Application of Wet Adhesion Hemostatic Hydrogels**

In this section, the applications of wet adhesion hydrogels for the hemostasis of skin, heart, liver, and other kinds of bleeding were summarized.

### *3.1. Skin*

The skin is the largest multi-layered organ in the human body, consisting of the epidermis and dermis [86]. When the entire epidermis is severely injured, the skin loses its basic defense layer, and microbial infection at the wound site can slow the healing process [87]. Unlike other phospholipid-containing biofilms, the skin surface contains amino, carboxyl, and hydroxyl groups that contribute to the wet adhesion of the hydrogel. The Schiff base reaction can be used to cross-link the aldehyde group in the hydrogel with the amino group on the skin tissue to achieve stronger tissue adhesion. For example, Ma et al. prepared a liquid bandage (LBA), which is an in situ imine cross-linked photoactive CS hydrogel (NB-CMC/CMC hydrogel) [52]. NB-CMC was synthesized by modifying o-nitrobenzyl alcohol (NB) with water-soluble carboxymethyl chitosan (CMC). Under UV irradiation, o-nitrobenzene was converted to an o-nitrosobenzaldehyde moiety and cross-linked with amino groups on the tissue surface, resulting in excellent tissue adhesion. The hemostatic and antimicrobial properties of LBA were correlated with the mass ratio of NB-CMC/CMC. LBA exhibited acceptable biocompatibility and biodegradability, can effectively control bleeding, produce strong tissue adhesion, avoid bacterial infection, and accelerate wound healing (Figure 6a). Other molecules, such as sulfhydryl groups, longchain alkyl groups, or DA-like compounds, can also be added to the hydrogel to enhance wet surface adhesion. In a study inspired by mussel mucin, a DA modified ε-poly-lysinepolyethylene glycol-based hydrogel (PPD hydrogel) wound dressing was developed in situ using horseradish peroxidase (H2O2/HRP) cross-linking method. It was shown that the PPD hydrogel had good wet tissue adhesion properties and exhibited excellent hemostatic effects to accelerate skin wound repair [88] (Figure 6b). In other studies, Lu and co-workers prepared several skin adhesive hydrogels based on the adhesion ability of DA [89,90]. These hydrogels can increase shear viscosity by an average of 10–30 kPa.

In addition, metal ions (e.g. zinc ions, silver ions, calcium ions, etc.) can introduce additional functionality to the hydrogel [91]. For example, Wang et al. developed an injectable and in situ photo-crosslinked hybrid hemostatic hydrogel by combining pectin methacrylate (PECMA) and methacrylate-based gelatin (GelMA). It was shown that the PECMA/GelMA hydrogel has good cytocompatibility and synergizes the hemostatic properties of calcium ions on PECMA, amine residues on GelMA, and a highly porous network to achieve rapid blood absorption and coagulation. An in vitro porcine skin bleeding model confirmed that the hydrogel could be injected directly into the wound and rapidly photo-crosslinked, and reduce the coagulation time by 39%. Importantly, the hydrogel can be easily removed to prevent secondary injury to the wound [92,93]. In another study, Yang et al. developed a photo-crosslinked multifunctional antibacterial and antioxidant hemostatic hydrogel dressing. It contained polyethylene glycol monomethyl ether modified glycidyl methacrylate functionalized CS (CSG-PEG), methacrylamide dopamine (DMA), and zinc ions. In a mouse model with intact skin defects infected with methicillin-resistant Staphylococcus aureus, CSG-PEG/DMA/Zn hydrogel not only adhered well to the wound surface but also showed better hemostasis and promoted wound healing of infected skin tissue defects than the commercially available TegadermTM film [94] (Figure 6c). For faster clotting to prevent chronic inflammatory episodes, Chen et al. prepared a novel hemostatic hydrogel by cross-linking inorganic polyphosphate (PolyP) conjugated with polyaspartic hydrazide (PAHP) and PEO<sup>90</sup> dialdehyde (PEO<sup>90</sup> DA) [95]. The dynamic nature of the acyl-hydrazone bond allowed the hydrogel to self-repair when damaged by external forces.

The hydrogel simultaneously exhibited excellent tissue adhesion, biocompatibility, antimicrobial activity, and hemostatic efficacy. In a mouse total skin defect model, this hydrogel was loaded with mouse epidermal growth factor (mEGF) to accelerate wound repair and promote the regeneration of fresh tissue. *Gels* **2023**, *8*, x FOR PEER REVIEW 13 of 23

**Figure 6.** Application of wet-adhesive hemostatic hydrogel in skin wounds. (**a**) Adhesive properties and hemostatic effect of LBA hydrogel. Figure modified from [52] with permission. (**a1**) Photographs of tissue adhesion using LBA in various tissues (pig skin and muscle). (**a2**) Tissue adhesion strength of LBA 1.0 with different precursor solution concentrations. (**a3**) Blood loss during hemostasis with LBA in a rat hepatic hemorrhage model. (**b**) Wet adhesion properties and hemostatic effect of PDD hydrogel. Figure modified from [88] with permission. (**b1**) Total view of livers of bleeding mice treated and untreated with PPD hydrogel, and fibrin glue every 30 seconds for 2 minutes. (**b2**) PPD hydrogels are prepared through an HRP cross-linking reaction. (**b3**) Adhesion strength of PPD hydrogel to porcine tissues. Adhesion of p-nitrophenylchloroformate/PEG/TA hydrogel (PPT) and fibrin glue was used as a control (n = 5, \* *p* < 0.05). (**c**) Adhesion and hemostatic properties of CSG-PEG/DMA/Zn hydrogels. Figure modified from [89] with permission. (**c1**) Adhesion strength of hydrogel. (**c2**) Schematic diagram of the mouse tail amputation model. (**c3**) Photographs of blood stains in a mouse tail amputation model. (**c4**) Quantitative results of blood loss in a mouse tail amputation model (n = 4, \* *p* < 0.05, \*\* *p* < 0.01.). In addition, metal ions (e.g. zinc ions, silver ions, calcium ions, etc.) can introduce **Figure 6.** Application of wet-adhesive hemostatic hydrogel in skin wounds. (**a**) Adhesive propertiesand hemostatic effect of LBA hydrogel. Figure modified from [52] with permission. (**a1**) Photographs of tissue adhesion using LBA in various tissues (pig skin and muscle). (**a2**) Tissue adhesion strength of LBA 1.0 with different precursor solution concentrations. (**a3**) Blood loss during hemostasis with LBA in a rat hepatic hemorrhage model. (**b**) Wet adhesion properties and hemostatic effect of PDD hydrogel. Figure modified from [88] with permission. (**b1**) Total view of livers of bleeding mice treated and untreated with PPD hydrogel, and fibrin glue every 30 seconds for 2 minutes. (**b2**) PPD hydrogels are prepared through an HRP cross-linking reaction. (**b3**) Adhesion strength of PPD hydrogel to porcine tissues. Adhesion of p-nitrophenylchloroformate/PEG/TA hydrogel (PPT) and fibrin glue was used as a control (n = 5, \* *p* < 0.05). (**c**) Adhesion and hemostatic properties of CSG-PEG/DMA/Zn hydrogels. Figure modified from [89] with permission. (**c1**) Adhesion strength of hydrogel. (**c2**) Schematic diagram of the mouse tail amputation model. (**c3**) Photographs of blood stains in a mouse tail amputation model. (**c4**) Quantitative results of blood loss in a mouse tail amputation model (n = 4, \* *p* < 0.05, \*\* *p* < 0.01.).

additional functionality to the hydrogel [91]. For example, Wang et al. developed an injectable and in situ photo-crosslinked hybrid hemostatic hydrogel by combining pectin methacrylate (PECMA) and methacrylate-based gelatin (GelMA). It was shown that the PECMA/GelMA hydrogel has good cytocompatibility and synergizes the hemostatic

network to achieve rapid blood absorption and coagulation. An in vitro porcine skin

### *3.2. Heart*

Cardiac bleeding can occur as a result of trauma, such as injuries from accidents and wounds to the heart. Certain diseases can also lead to the rupture of blood vessels in the heart. Rapid and strong adhesion to wetted tissue walls and surfaces, high mechanical strength, and good biocompatibility to promote tissue regeneration are central and necessary for rapid hemostasis of cardiac arterial dissection. It has been shown that tannin (TA) contains a large number of benzene rings, which can make hydrogels very sticky in humid environments. When TA interacts with gelatin, CS, filamentous fibrin (SF), and Pluronic F127 (PEO99-PPO65-PEO99), low-swelling hydrogels with good mechanical and wet adhesive capacity were formed [96]. The obtained CS/TA/SF hydrogels showed less bleeding and shorter hemostasis time in various arterial and visceral bleeding models compared to previously reported materials (Figure 7a). Later in another study, Liang et al. created a physicochemical double network cross-linked hydrogel (PCT) using acrylic acid, CS, and TA as the main components [97]. The hydrogels have many active sites on their surfaces, allowing fast, strong and repetitive adhesion to artificial solids and biological tissues (Figure 7b). Due to its amide covalent bond, the hydrogel can act for a longer period in tissue regeneration, and the resulting hydrogel-tissue adhesion interface has strong adhesion even after one month of immersion in a physiological environment. Due to its platelet adhesion and high bursting pressure qualities, this hydrogel can be used for good hemostatic properties at sites of heavy bleeding such as the heart.

Bionic strategies are also effective in wet adhesion hemostasis. It has been shown that the cationic polysaccharide intercellular adhesion contained in staphylococcal biofilms plays a key role in surface adhesion to wet and moving surfaces [99]. Inspired by the strong adhesion mechanisms of biofilms and mussels, Han et al. reported a novel dual bionic adhesion hydrogel (DBAH), which is based on CS-grafted methacrylate (CS-MA), DA, and N-hydroxymethylacrylamide (NMA) [46]. When DBAH was contacted with water, hydrophobic residues (-CH3) rapidly generated cohesive forces that self-repel water molecules from the substrate surface. At this time, the catechol group of DA and the cationic free amine group NH<sup>3</sup> <sup>+</sup> of CS-MA are exposed outward to promote sufficient contact with the adherent matrix for rapid and firm wet tissue adhesion, resulting in excellent hemostasis of DBAH even in the wet and active rabbit heart environment. In another study, Hong et al. designed a photo-responsive biological tissue adhesive that mimics the ECM composition. It consisted of GelMA, N-(2-aminoethyl)-4-(4-(hydroxymethyl)- 2-methoxy-5-nitroso)butyramide modified glycosaminoglycan hyaluronic acid (HA-NB), and the polymerization initiator lithium phenyl-2,4,6-trimethylbenzoyl phosphate. Under UV light, this biomolecule-based hydrogel matrix rapidly gelled, adhered, and sealed the bleeding arteries and heart walls. This hydrogel can withstand a blood pressure of up to 290 mm Hg compared to most clinical situations (systolic blood pressure of 60–160 mm Hg). Notably, the hydrogel inhibited high-pressure hemorrhage from a 6-mm diameter cardiac perforation in the porcine heart and a 4- to 5-mm long incisional lesion in the porcine carotid artery [98] (Figure 7c).

**Figure 7.** Wet-adhesive hemostatic hydrogel in heart wounds. (**a**) Adhesion and hemostatic properties of CS/TA/SF hydrogels. Figure modified from [96] with permission. (**a1**) The photos show that the hydrogel has strong adhesion to wet pigskin and glass. (**a2**) Hemostatic images of various untreated wounds covered with gauze or hydrogel. (**b**) Strong adhesion properties of PCT hydrogels. Figure modified from [97] with permission. (**b1**) Optical image of direct adhesion of PCT hydrogel between high-density polyethylene substrate and porcine skin or myocardium in PBS environment. (**b2**) Interfacial toughness of PCT hydrogels with different substrate surfaces before and after 4 days of immersion in PBS. (**c**) GelMA/HA-NB hydrogel adhesion and hemostatic properties. Figure modified from [98] with permission. (**c1**) Optical image of rapid hemostatic closure after a heart puncture wound. Blood exudation completely stopped within 10 seconds. (**c2**) Scanning electron micrographs of the interface between a porcine heart puncture wound and hydrogel. (**c3**) Autopsy images of the heart were performed after two weeks of postoperative recovery. (**c4**) Tissue-stained image of the interface between the heart tissue and the matrix gel of a pig heart 2 weeks after postoperative recovery. **Figure 7.** Wet-adhesive hemostatic hydrogel in heart wounds. (**a**) Adhesion and hemostatic properties of CS/TA/SF hydrogels. Figure modified from [96] with permission. (**a1**) The photos show that the hydrogel has strong adhesion to wet pigskin and glass. (**a2**) Hemostatic images of various untreated wounds covered with gauze or hydrogel. (**b**) Strong adhesion properties of PCT hydrogels. Figure modified from [97] with permission. (**b1**) Optical image of direct adhesion of PCT hydrogel between high-density polyethylene substrate and porcine skin or myocardium in PBS environment. (**b2**) Interfacial toughness of PCT hydrogels with different substrate surfaces before and after 4 days of immersion in PBS. (**c**) GelMA/HA-NB hydrogel adhesion and hemostatic properties. Figure modified from [98] with permission. (**c1**) Optical image of rapid hemostatic closure after a heart puncture wound. Blood exudation completely stopped within 10 seconds. (**c2**) Scanning electron micrographs of the interface between a porcine heart puncture wound and hydrogel. (**c3**) Autopsy images of the heart were performed after two weeks of postoperative recovery. (**c4**) Tissue-stained image of the interface between the heart tissue and the matrix gel of a pig heart 2 weeks after postoperative recovery.

### Bionic strategies are also effective in wet adhesion hemostasis. It has been shown that *3.3. Liver*

the cationic polysaccharide intercellular adhesion contained in staphylococcal biofilms plays a key role in surface adhesion to wet and moving surfaces [99]. Inspired by the To achieve rapid and effective hemostasis of liver bleeding, Shou et al. designed a catechol-hydroxybutyl CS (HBCS-C) hydrogel by attaching catechol and hydroxybutyl

molecules to a CS backbone. This multifunctional HBCS-C hydrogel showed thermal sensitivity, injectability, tissue adhesion, and biocompatibility [100]. The multiple interactions between catechol hydroxyl/amino groups and tissues allow the biocompatible hydrogel to adhere firmly to the tissue surface. The hydrogel effectively blocked the bleeding in a rat liver hemorrhage model by adhering firmly to the bleeding tissue within 30 seconds (Figure 8a). In another work, Chen et al. created an in situ-generated hemostatic hydrogel (GelMA/oxidized dextran/Borax) for incompressible visceral wound hemostasis and antiinflammatory applications [101]. The abundant adjacent hydroxyl groups of dextran can be oxidized to aldehyde groups by sodium periodate, which can be further bound to the amino groups of histones by Schiff base reaction, giving dextran good tissue adhesion ability. In addition, sodium tetraborate produces dynamic borate ester linkages when combined with oxidized dextran. Due to the three-layer network structure, the hydrogel exhibits good hemostatic capacity and can withstand high blood pressure exceeding 165 mm Hg, which is higher than the systolic blood pressure threshold for healthy adults (i.e., 120 mm Hg) (Figure 8c). *Gels* **2023**, *8*, x FOR PEER REVIEW 17 of 23

**Figure 8.** Wet-adhesive hemostatic hydrogel in liver wounds. (**a**) Tissue adhesion and hemostatic effect of HBCS-C hydrogel. Reprinted (adapted) with permission from [100]. Copyright {2020} American Chemical Society. (**a1**) The images show good adhesion of HBCS-C hydrogel on porcine skin (adhesion area of 20 mm × 20 mm and heavy load of 120 g). (**a2**) Total blood loss from liver wounds in hydrogel-treated and untreated rats. (**a3**) Photographs showing the wet bioadhesive behavior and stability of HBCS-C hydrogels in an aqueous environment at 37 °C. (**b**) Antimicrobial, adhesion, and hemostatic properties of GT-DA/CS/CNT hydrogel. Figure modified from [102] with permission. (**b1**) In vitro antibacterial activity of hydrogels induced by NIR illumination, 0, 1, 3, 5, and 10 represent different irradiation times (min). (**b2**) Adhesion strength of the hydrogels after 1 h in the air before testing. (**b3**) Hemostatic ability of GT-DA/CS/CNT hydrogels. (**c**) Adhesion and hemostatic properties of GelMA/oxidized dextran/Borax hydrogels. Figure modified from [101] with permission. (**c1**) Photographs of liver blood loss after different treatments. (**c2**) Blood loss during hemostasis of the liver. (**c3**) Pictures of the modified test method used for the overlapping shear test. (**c4**) Strain–stress curves for the overlapping shear test. Various multifunctional injectable hydrogels for hemostasis have been successfully **Figure 8.** Wet-adhesive hemostatic hydrogel in liver wounds. (**a**) Tissue adhesion and hemostatic effect of HBCS-C hydrogel. Reprinted (adapted) with permission from [100]. Copyright {2020} American Chemical Society. (**a1**) The images show good adhesion of HBCS-C hydrogel on porcine skin (adhesion area of 20 mm × 20 mm and heavy load of 120 g). (**a2**) Total blood loss from liver wounds in hydrogel-treated and untreated rats. (**a3**) Photographs showing the wet bioadhesive behavior and stability of HBCS-C hydrogels in an aqueous environment at 37 ◦C. (**b**) Antimicrobial, adhesion, and hemostatic properties of GT-DA/CS/CNT hydrogel. Figure modified from [102] with permission. (**b1**) In vitro antibacterial activity of hydrogels induced by NIR illumination, 0, 1, 3, 5, and 10 represent different irradiation times (min). (**b2**) Adhesion strength of the hydrogels after 1 h in the air before testing. (**b3**) Hemostatic ability of GT-DA/CS/CNT hydrogels. (**c**) Adhesion and hemostatic properties of GelMA/oxidized dextran/Borax hydrogels. Figure modified from [101]with permission. (**c1**) Photographs of liver blood loss after different treatments. (**c2**) Blood loss during hemostasis of the liver. (**c3**) Pictures of the modified test method used for the overlapping shear test. (**c4**) Strain–stress curves for the overlapping shear test. (\*\* *p* < 0.01, \*\*\*\* *p* < 0.001).

developed, however, these strategies ignore issues such as the ease of removal of these sealants on injured livers and the occurrence of secondary injuries. To address this issue, Bu et al. created a rapidly formed aminolysis tetrapolyethylene glycol (Tetra-PEG) hydro-

erties. The hydrogel showed high hemostatic activity even in the presence of anticoagulation and exhibited remarkable biocompatibility and utility. The drug loading will allow the hydrogel to accelerate wound healing by enhancing the antibacterial and anti-inflammatory effects and hemostatic effects. Liang et al. used gelatin graft-dopamine (GT-DA) and polydopamine-coated carbon nanotubes (CNT-PDA) to design antibacterial, adhesive, antioxidant, and conductive GT-DA/CS/CNT composite hydrogels by oxidative coupling of catechol moieties using an H2O2/HRP catalytic reaction [102]. Then, the antibiotic doxycycline was added to the hydrogel. Together with the photothermal effect of CNT-PDA, the hydrogels gained good antimicrobial action and showed well in vitro and in vivo antimicrobial activity against different microorganisms. In a mouse model of liver hemorrhage, mice in the untreated group drained approximately 700 mg of blood from

Various multifunctional injectable hydrogels for hemostasis have been successfully developed, however, these strategies ignore issues such as the ease of removal of these sealants on injured livers and the occurrence of secondary injuries. To address this issue, Bu et al. created a rapidly formed aminolysis tetrapolyethylene glycol (Tetra-PEG) hydrogel sealant which has good mechanical strength and tissue adhesion [103]. The cyclized succinyl ester moiety gave the sealant adjustable solubility and fast decomposition properties. The hydrogel showed high hemostatic activity even in the presence of anticoagulation and exhibited remarkable biocompatibility and utility. The drug loading will allow the hydrogel to accelerate wound healing by enhancing the antibacterial and anti-inflammatory effects and hemostatic effects. Liang et al. used gelatin graft-dopamine (GT-DA) and polydopamine-coated carbon nanotubes (CNT-PDA) to design antibacterial, adhesive, antioxidant, and conductive GT-DA/CS/CNT composite hydrogels by oxidative coupling of catechol moieties using an H2O2/HRP catalytic reaction [102]. Then, the antibiotic doxycycline was added to the hydrogel. Together with the photothermal effect of CNT-PDA, the hydrogels gained good antimicrobial action and showed well in vitro and in vivo antimicrobial activity against different microorganisms. In a mouse model of liver hemorrhage, mice in the untreated group drained approximately 700 mg of blood from the liver, while mice in the gelatin-DA/CS/CNT hydrogel group shed only 170 mg of blood (Figure 8b). Furthermore, the GT-DA/CS/CNT hydrogels also exhibited good tissue regeneration capacity, as indicated by the collagen deposition, histomorphometric analysis, and immunofluorescence staining for transforming growth factor (TGF) and a cluster of differentiation 31 (CD31). In a study, He et al. developed a conductive self-healing hydrogel for hemostasis using N-carboxyethyl chitosan (CECS), PF127, and CNT as the main ingredients, and further loaded with moxifloxacin hydrochloride [104]. A mouse liver injury model, a mouse liver incision model, and a mouse tail amputation model were used to evaluate the hemostatic ability of the CECS/PF127/CNT hydrogel. It was found that the hydrogel could adhere to the wound site and form the hydrogel within a short period (75 s), which acted as a stable physical barrier and prevented wound bleeding. In addition, the negative charge of CECS triggered an intrinsic coagulation pathway, which ultimately formed a stable platelet plug during hemostasis. Therefore, the blood loss in the CECS/PF127/CNT hydrogel group was significantly less than that in the control group.
