**1. Introduction**

More than 5.8 million people die from severe trauma worldwide each year and approximately 40% of which are caused by uncontrolled bleeding or its consequences [1]. Massive blood loss from incompressible injuries has been reported to cause hemorrhagic shock coagulopathy, multiple organ failure, life-threatening sepsis, and acidosis. Moreover, interventional diagnosis and surgical treatment are prone to hemorrhage or intraluminal hemorrhage, especially in sites close to the heart, parenchymal organs, vital blood vessels, etc. [2]. Therefore, research into hemostatic technologies and materials with superior performance is critical to reducing adverse side effects and even saving lives.

Recently, exploring fast and effective methods for controlling bleeding in different application environments has always been an important subject of multidisciplinary research [3]. Sutures and staplers are commonly used to close wounds, however, they have the risk of infection, blood exudation, hyperplasia, and keloid formation [4]. For quick hemostasis in superficial wounds, some conventional hemostatic materials, such as tourniquets [5], hemostatic gauze [6], bandages [7], etc., have been utilized extensively. Nevertheless, common materials struggle to meet the demand for quick and efficient hemostasis in cases of intracavitary hemorrhage or injuries involving essential tissues/organs. Additionally, as gauze and bandages are not biodegradable and can cause secondary injury, delayed healing, and additional discomfort, they need to be removed after hemostasis [8,9]. Therefore, various advanced hemostatic powders, hydrogels, sponges, adhesives, and hemostatic agents [10,11], have been extensively explored (Figure 1).

Adhesives can bind different tissues as well as blood vessels together, whereas hemostatic drugs are known to stop bleeding mechanically or by accelerating the coagulation cascade. Additionally, tissue sealants can stop blood dripping from blood vessels [12]. Nevertheless, some of these products are not universally applicable and have obvious disadvantages. For example, fibrinogen and thrombin-based injection solutions (fibrin sealants) may be washed away by the bloodstream and cannot be used effectively in severe

**Citation:** Han, W.; Wang, S. Advances in Hemostatic Hydrogels That Can Adhere to Wet Surfaces. *Gels* **2023**, *9*, 2. https://doi.org/ 10.3390/gels9010002

Academic Editor: Christian Demitri

Received: 23 November 2022 Revised: 11 December 2022 Accepted: 12 December 2022 Published: 22 December 2022

**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/).

or emergency arterial bleeding [13,14]. As emerging medical adhesives, cyanoacrylates may cause allergic reactions, and their rapid curing process is exothermic [15]. Furthermore, such products have not been used inside the body due to concerns about the potential toxicity of the degradation products. As a consequence, designing an ideal hemostasis technique for effective hemostasis in complicated clinical situations remains challenging. *Gels* **2023**, *8*, x FOR PEER REVIEW 2 of 23

**Figure 1.** The current methods of hemostasis used for external and internal bleeding management. Figure modified from [11] with permission. Copyright 2020. **Figure 1.** The current methods of hemostasis used for external and internal bleeding management. Figure modified from [11] with permission. Copyright 2020.

Adhesives can bind different tissues as well as blood vessels together, whereas hemostatic drugs are known to stop bleeding mechanically or by accelerating the coagulation cascade. Additionally, tissue sealants can stop blood dripping from blood vessels [12]. Nevertheless, some of these products are not universally applicable and have obvious disadvantages. For example, fibrinogen and thrombin-based injection solutions (fibrin sealants) may be washed away by the bloodstream and cannot be used effectively in severe or emergency arterial bleeding [13,14]. As emerging medical adhesives, cyanoacrylates may cause allergic reactions, and their rapid curing process is exothermic [15]. Furthermore, such products have not been used inside the body due to concerns about the potential toxicity of the degradation products. As a consequence, designing an ideal hemostasis technique for effective hemostasis in complicated clinical situations remains challenging. Hydrogel-based biomaterials show many advantages over traditional hemostasis methods [16,17]. A hydrogel is a 3D cross-linked hydrophilic polymer with a structure similar to that of the natural extracellular matrix (ECM) [18]. They are widely used in biomedicine, and due to their injectability and fluidity, hydrogels are crucial for achieving quick and lasting hemostasis for a variety of irregular wounds and intraluminal injuries [19]. In addition, the hydrogel-based biomaterial is safe for use in vivo due to its exceptional biocompatibility and biodegradability [20,21]. An ideal polymer hydrogel for hemostatic applications should have the following properties: (i) the hydrogel should be able to effectively promote wound healing and immediately block the bleeding, [22] (ii) the hemostatic hydrogel should have superior mechanical qualities that enable it to quickly adhere and completely seal the damage, especially in humid and dynamic settings, and [23] (iii) the hydrogels must have quick coagulation to prevent the migration of hemostatic hydrogels from the bleeding site [24].

Hydrogel-based biomaterials show many advantages over traditional hemostasis methods [16,17]. A hydrogel is a 3D cross-linked hydrophilic polymer with a structure similar to that of the natural extracellular matrix (ECM) [18]. They are widely used in biomedicine, and due to their injectability and fluidity, hydrogels are crucial for achieving quick and lasting hemostasis for a variety of irregular wounds and intraluminal injuries High pressures and blood flow rates may remove or destroy general hydrogels due to their limited underwater adhesion and weak adhesion mechanisms [25]. Therefore, it is crucial to enable hemostatic hydrogels to adhere to tissues and maintain their integrity in humid environments. Moreover, an ideal wet-adhesive hydrogel should completely cover the wound area, minimize surgical scope or complications, carry therapeutic cells and drugs, and release them to the wound site [26]. This review introduces the properties of

[19]. In addition, the hydrogel-based biomaterial is safe for use in vivo due to its exceptional biocompatibility and biodegradability [20,21]. An ideal polymer hydrogel for hemostatic applications should have the following properties: (i) the hydrogel should be

the hemostatic hydrogel should have superior mechanical qualities that enable it to quickly adhere and completely seal the damage, especially in humid and dynamic settings, and [23] (iii) the hydrogels must have quick coagulation to prevent the migration of

High pressures and blood flow rates may remove or destroy general hydrogels due to their limited underwater adhesion and weak adhesion mechanisms [25]. Therefore, it is crucial to enable hemostatic hydrogels to adhere to tissues and maintain their integrity in humid environments. Moreover, an ideal wet-adhesive hydrogel should completely

hemostatic hydrogels from the bleeding site [24].

hemostatic hydrogels that can adhere to wet surfaces, briefly discusses the basic principles of hemostasis, and then focuses on the adhesion mechanism of hydrogels on wet surfaces. This review is anticipated to promote further research progress on wet viscous hemostatic hydrogel and create more possibilities for rapid and effective emergency hemostasis.

### **2. Properties of Wet Adhesive Hemostatic Hydrogel**

The complicated dynamic equilibrium environment of the human body should be adapted when hydrogels are employed to stop bleeding. The ideal adhesive hemostatic hydrogel should possess the properties of strong wetting adhesion, hemostasis, antibacterial, and biocompatibility.
