Wounds are defined as damage to or destruction of tissue structure and function [1]. Wounds can be caused by a variety of external factors (e.g., freezing, heat, chemicals, radiation, electricity, surgical interventions, and mechanical injuries) and internal factors (e.g., genetic diseases, malignancies, diabetes, and vascular diseases) [2]. The management of wounds is costly and has become a critical global healthcare issue [3]. Wound healing is a complex biological process involving stages of hemostasis, inflammation, proliferation, and remodeling [[4], [5], [6]]. Effective wound healing and tissue repair processes require the coordination of various cells and factors as well as the promotion of different favorable factors [7]. In addition, any adverse effects of the wound microenvironment will hinder normal wound healing [8]. Therefore, there is an urgent need to develop wound dressings that could create a pro-healing microenvironment and act as a physical barrier to prevent secondary injuries to patients.

A wide variety of wound dressings such as gauze, sponge, foam, electrospun fiber membrane, hydrogel, and film have been developed (Table 1) [8]. Among them, hydrogel is receiving increasing attention due to its three-dimensional porous physical structure similar to that of natural extracellular matrix (ECM) [9]. As a new type of biomedical dressing, hydrogel bio-adhesives have multiple unique advantages, such as good biocompatibility, biodegradability, high flexibility, shape adaptability, hydrophilic water retention, self-healing, sufficient flexibility and mechanical strength [10,11]. With the growing clinical needs, the developing of advanced multifunctional hydrogel bio-adhesives has become one of the research trends and hot spots in wound healing. Hydrogels are featured with smooth injectability, stimulus responsiveness, controlled drug release properties, anti-inflammatory activity, antibacterial activity, antioxidant activity, electrical conductivity, and wound monitoring properties [[12], [13], [14]]. As a result, hydrogel bio-adhesives have become ideal choices for wound management.

In recent years, polypeptide-based hydrogel bio-adhesives with numerous attractive pro-healing properties have been widely developed to promote wound healing and tissue repair. Polypeptides are formed by natural amino acid molecules or derivatives linked by amide bonds and have stable secondary structures (e.g. α-helix and β-fold) similar to those of natural proteins [15]. Therefore, polypeptides have good biosafety, low immunogenicity, biodegradability, easy absorption, easy modification, high bioactivity, and functional versatility [[15], [16], [17]]. Gelatin, silk fibroin (SF), fibrin, keratin, poly-γ-glutamic acid (γ-PGA), ɛ-poly-lysine (ɛ-PL), serum albumin (SA), and elastin are some representative members of polypeptides [[18], [19], [20], [21], [22]]. The strengths of hydrogel bio-adhesives are determined by their adhesion and cohesion mechanisms [23]. In general, the mechanical strength and adhesion strength of polypeptide-based hydrogel bio-adhesives are not sufficient to cope with the complex wound environment, thus limiting their further applications. Various modifications have been made on the amino, carboxyl, and sulfhydryl groups of polypeptides to improve the mechanical properties and adhesion properties of the formed hydrogel bio-adhesives [24,25]. In addition, novel adhesion and cohesion mechanism design could endow hydrogel bio-adhesives with multiple intelligent functions [26]. Furthermore, different physical and chemical strategies enable controlled hydrogel degradation in pH/reactive oxygen species (ROS) response, dynamic self-healing, and hydrophobic stabilization in humid environments [[27], [28], [29]]. For example, hydrogel bio-adhesives could control the degradation rate and drug release rate according to changes in ROS concentration at the wound site by using ROS-responsive boronic acid ester bonds as the internal crosslinking dynamic chemical bond and drug coupling point [27]. In the Schiff base reaction, there is a dynamic reversible equilibrium between the aldehyde group and amino group, endowing hydrogels with self-healing cohesion properties [29].

The overall objective of this review is to present the latest progress made in multifunctional polypeptide-based hydrogel bio-adhesives that are used as wound dressings (Scheme 1). Firstly, the physiological mechanisms and evaluation parameters of wound healing will be described in detail. Subsequently, the working principles of hydrogel bio-adhesives will be summarized. The hydrogel bio-adhesives that are based on several typical polypeptides and their functions will also be reviewed. Although there are many reviews on hydrogel bio-adhesives for wound healing, there is still a lack of comprehensive reviews that focus on polypeptide-based hydrogel bio-adhesives. Therefore, the current status, challenges, developments, and future trends of polypeptide-based hydrogel bio-adhesives were finally discussed, in the hope that, further developments would be stimulated to meet the growing needs of their clinical applications.